Download 10th conference on retroviruses and opportunistic infections

Highlights from the
10 TH CONFERENCE ON
RETROVIRUSES AND
OPPORTUNISTIC INFECTIONS
FEBRUARY 10-14, 2003, BOSTON, MA, USA
Contributors
RONALD BAKER, PhD, BRIAN A. BOYLE, MD,
ANDREW CARR, MD, MARK DYBUL, MD,
ROSS HEWITT, MD, CHARLES HICKS, MD,
GRAEME MOYLE, MD, MICHAEL YOULE, MD
Edited by
BRIAN A. BOYLE, MD, & RONALD BAKER, PhD
Produced by
HIV AND HEPATITIS.COMTM
Supported by
an Educational Grant from
BOEHRINGER INGELHEIM
www.HIVandHepatitis.com
Figure 1. Baseline Characteristics of Patients Enrolled in 2NN
Figure 3. Adverse Events Leading to Change or
Discontinuation of Therapy in 2NN
Figure 4a. Increase in CD4 cells
Figure 2. Virologic Success by Baseline Viral Load in 2NN
Figure 4. Changes in Lipid Parameters in 2NN
Figure 4b.
Highlights from the
10 TH CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS
FEBRUARY 10-14, 2003, BOSTON, MA, USA
TA B L E O F C O N T E N T S
Abbreviations and Symbols .................................................................................................................................................................................................................1
Introduction.........................................................................................................................................................................................................................................................2
Summary of Antiretroviral Therapy Clinical Trials
The 2NN Study: Nevirapine- versus Efavirenz-based HAART Regimens ....................................................................................................3
Clinical Trials in Treatment Naïve and Experienced Patients......................................................................................................................................5
Treatment Interruption Strategies and Immunology .........................................................................................................................................................9
Resistance Testing .......................................................................................................................................................................................................................................12
Adverse Events Related to Antiretroviral Therapy ............................................................................................................................................................15
Metabolic Disturbances and Lipodystrophy ...........................................................................................................................................................................17
Notable Drug-Drug Interactions ...................................................................................................................................................................................................21
New Antiretrovirals in Development ..........................................................................................................................................................................................23
Hepatitis Co-infection and Liver Disease ................................................................................................................................................................................25
Other Studies of Interest....................................................................................................................................................................................................................27
Glossary of Terms .......................................................................................................................................................................................................................................28
A B B R E V I AT I O N S A N D SY M B O L S
> .....................greater than
< .....................less than
AA .................African American(s)
AE .................adverse event(s)
AIDS ............Acquired Immune Deficiency Syndrome,
also Acquired Immunodeficiency Syndrome
bid .................twice daily dosing
BMI ..............body mass index
BW ................body weight
CD4+ ...........helper T cell; expressed as cells per millimeter cubed (cells/mm3)
CNS ..............central nervous system
CPK ..............Creatine PhosphoKinase (muscle enzyme)
d .....................day(s)
DNA.............deoxyribonucleic acid
HAART......Highly Active AntiRetroviral Therapy. HAART implies a
multiple drug combination in which, generally, two agents
are nucleoside reverse transcriptase inhibitor (NRTI) drugs
and one agent is either a protease inhibitor (PI) or a nonnucleoside reverse transcriptase inhibitor (NNRTI) drug.
GI...................gastrointestinal
HBV .............hepatitis B virus
HCV .............hepatitis C virus
HIV...............human immunodeficiency virus
IFN ...............interferon
mcg...............microgram
mg .................milligram
mL ....................................milliliter
mo ....................................month(s)
NIH .................................National Institutes of Health
NRTI, NRTIs .............Nucleoside Reverse Transcriptase Inhibitor
(anti-HIV agent)
NNRTI, NNRTIs .....Non-Nucleoside Reverse Transcriptase
Inhibitor (anti-HIV agent)
NtRTI, NtRTIs .........Nucleotide Reverse Transcriptase Inhibitor(s)
OI .....................................opportunistic infection(s)
PCR .................................polymerase chain reaction
PEG-IFN ......................pegylated interferon(s)
PI, PIs .............................Protease Inhibitor(s); anti-HIV agent(s)
RBV ................................ribavirin
RNA ................................ribonucleic acid
QD ...................................once daily dosing
qwk ..................................once weekly
STI, STIs ......................Structured (scheduled) treatment (therapy)
Interruption(s)
tid .....................................three times daily dosing
TIW .................................three times weekly dosing
ULN.................................upper limit of normal
wk .....................................week(s)
TM
Copyright 2003 by HIV and Hepatitis.comTM. All rights reserved.
HIV and Hepatitis.comTM
Highlights from the
10 th Conference on Retroviruses and Opportunistic Infections
February 10-14, 2003, Boston, MA, USA
Contributors Ronald Baker, PhD, Brian A. Boyle, MD, Andrew Carr, MD, Mark Dybul, MD,
Ross Hewitt, MD, Charles Hicks, MD, Graeme Moyle, MD, Michael Youle, MD
INTRODUCTION
By Brian A. Boyle, MD
Medical Editor, HIV and Hepatitis.com;Attending physician, New York-Presbyterian Hospital;Assistant Professor of Medicine, Department of International
Medicine and Infectious Diseases at Weill Medical College of Cornell University; Medical Director, International Center for Equal Healthcare Access
Editor’s Note: Unless otherwise indicated, all references are to the Abstracts of the 10th Conference on Retroviruses and Opportunistic
Infections. February 10-14, 2003, Boston, MA, USA.
In February, 2003, the 10th Conference on Retroviruses and Opportunistic Infections (10th CROI) took place in Boston, Massachusetts.This
major conference was attended by nationally and internationally known scientists, researchers, and clinicians who presented and
discussed the latest developments regarding HIV research, management and treatment. It is clear from the studies and information
presented at these conferences that progress continues to be made in the understanding and treatment of HIV, the usage of antiretroviral
medications, the complications and toxicities which afflict HIV-infected patients, and the treatment of co-infections including hepatitis
C virus and hepatitis B virus.
While the focus of the 10th CROI is largely scientific, the opening ceremony was especially notable for two impassioned speeches, one from
a member of Sinikithemba, a singing group from South Africa, and the other from former President Bill Clinton.These speeches eloquently
thanked the gathered clinicians and scientists for the work they have done, but also reminded them of the difficult tasks that lie ahead.
The woman who spoke on behalf of the members of Sinikithemba, many of whom are HIV-infected, is from Durban, South Africa. She
described her struggle with HIV/AIDS, a story all too familiar to those who provide care to patients in developing countries. She has
been infected for sometime, has lost her job due to being infected and has had many opportunistic infections, wasting and other AIDSrelated complications. Now, however, she is on HAART (Zerit [stavudine], Epivir [lamivudine], Sustiva [efavirenz]), has never missed a
dose and has had a remarkable improvement in her CD4 count and overall health. She had two messages: First, to thank the gathered
researchers and clinicians for their efforts. Second, to tell them that treatment was possible in developing countries and is desperately
needed. She received a much deserved standing ovation at the conclusion of her remarks.
President Bill Clinton was the keynote speaker and used this forum to remind us of the devastation caused by HIV in developing
countries and that we live in an interdependent world and “cannot escape each other”. Mr. Clinton stated a clear truth:We cannot
tackle many of the issues currently causing instability in the world without tackling and controlling HIV. Mr. Clinton continued by
stating that while some questions have to be answered by science others need to be answered by politics and citizen action. Mr. Clinton
praised the gathered researchers and clinicians “thanks to you we have hope”, but he went on to say that “We know that we can do
more to help infected patients”. Mr. Clinton emphasized repeatedly the importance of organizing systems to treat HIV in developing
countries to achieve adequate therapy and to appropriately monitor the cost and delivery of the needed treatment. Barriers persist
including drug costs, but “we need to get things in order where the people need the therapy.” Mr. Clinton emphasized that treatment is
a needed part of any program and that prevention efforts by themselves are not enough. Mr. Clinton urged all of those assembled to
explain to those who are in power why treatment and care are necessary, not just prevention. Mr. Clinton also urged those assembled to
advocate to Congress for the funding promised and needed to treat HIV in developing countries. Mr. Clinton urged increase funding
for research into HIV vaccines and therapies.
This opening session helped to put the conference in context and to heighten the awareness of those in attendance regarding what is at
stake on a personal, national and international level. As reflected in the reports that follow, the efforts continue unabated to find the
answers to eliminating, or at least controlling, this horrible disease. Based on the audience response to Mr. Clinton’s remarks, I think it
can be fairly stated that most believe that these efforts should result in benefits being provided to everyone with HIV, regardless of
where they are located or how much they can afford to pay.
This Internet Conference ReportTM focuses on selected highlights regarding advances in the diagnosis, pathophysiology, and
treatment of HIV, HBV and HCV infections and co-infection with HIV and HBV or HCV that were presented at the 10th
Conference on Retroviruses and Opportunistic Infections that was held from February 10-14 in Boston, Massachusetts. An expanded
version of the report appears on the HIV and Hepatitis.comTM web site at www.HIVandHepatitis.com, where visitors will find
Internet Conference ReportsTM on all major HIV/AIDS and viral hepatitis conferences in 2002.
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Corrections or clarifications to this report will be posted on the web site.To receive a copy of this booklet or to comment on the
report, please send an email to [email protected] or write to HIV and Hepatitis.comTM, P.O. Box 14288,
San Francisco, CA 94114. Duplication of any part of this report is prohibited without the written permission of the publisher. Brief
sections may be quoted for review purposes or photocopied for personal use.
Production and distribution of this document is made possible by an unrestricted educational grant from Boehringer Ingelheim.The
content of the report reflects the views and opinions of the individual authors and the editors of HIV and Hepatitis.comTM, who
have exercised full control over its planning and implementation.
Disclaimer: Many of the treatment approaches and dosing information discussed in this report are experimental and not approved by
the US Food and Drug Administration (FDA), the European Union or by other drug regulatory agencies. Please consult the product
package inserts concerning standard dosing and other important information about the FDA-approved medications discussed in this
report. Although every effort has been made to ensure the scientific accuracy of the information contained in this report, HIV and
Hepatitis.comTM assumes no responsibility for any errors contained herein or from clinical outcomes.
S u m m a r y of A n t i re t rov i ra l T h e ra py C l i n i c a l Tr i a l s
T H E 2 N N S T U DY: N E V I R A P I N E - V E R S U S E FAV I R E N Z - BA S E D H A A R T R E G I M E N S
By Julio S.G. Montaner, MD, FRCPC, FCCP
St. Paul’s Hospital and the University of British Columbia,Vancouver, Canada
The role of the non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the treatment of HIV infection was originally established by
the results of the INCAS Trial, first presented at the Vancouver International AIDS Conference in 1996 (1). Equally promising results
were presented at the same time regarding the role of protease inhibitor based triple drug therapy, particularly indinavir [Crixivan] (2).
A fair bit of controversy regarding the relative merits of PI versus NNRTI-based triple drug therapy was generated as a result of these
and later studies. The body of data in support of the effectiveness of PI-based therapy continued to grow rapidly since then as other
protease inhibitors became available, including saquinavir Invirase), ritonavir (Norvir) and nelfinavir (Viracept).
In contrast, the database in support of the effectiveness of NNRTI-based strategy was off to a slow start. It was not until the late 90’s
that new evidence was presented emerging from the Atlantic trial, which clearly demonstrated comparable efficacy for nevirapine versus
indinavir-based therapy (3).
Despite these encouraging results the controversy persisted, particularly in North America where PI-based HAART was still regarded
as the preferred initial treatment option.
By this time it had become abundantly clear that highly active antiretroviral therapy (HAART) could not eradicate HIV infection. The
consequent need for long-term therapy coupled with the complexity of available PI-based regimens forced to a re-evaluation of the
relative merits of PI versus NNRTI based therapy.
At about the same time, data from Study-006 (also known as DMP-006), a pivotal open label study of efavirenz (Sustiva) versus indinavir
in combination with zidovudine (Retrovir) and lamivudine (Epivir) became available (4). The results of this study showed that efavirenz
was statistically significantly more effective than indinavir.
Of note, this difference was largely attributable to a high frequency of early discontinuations in the indinavir arm of the study, even in
the absence of documented adverse effects. Despite this important limitation of the study, efavirenz emerged as a new and attractive
NNRTI option.
Even in the absence of head to head comparative trials between the available NNRTIs some were ready to assume that the newer
compound, efavirenz, was more effective than nevirapine.
Most notably,the US Department of Health and Human Services (DHHS) Panel on Clinical Practices for Treatment of HIV Infection as recently
as a year ago continued to place efavirenz as a “strongly recommended” first-line antiretroviral agent and nevirapine as an “alternative” (5).
Of note this position was not shared by 2001 British HIV Association (BHIVA) Guidelines (6) or the IAS-USA Guidelines (7), which
listed efavirenz and nevirapine as comparable options for initial combination antiretroviral therapy. The controversy grew further as a
result of cohort studies (9, 10), which despite significant limitations, concluded that efavirenz was superior to nevirapine-based HAART.
The 2NN Trial presented at the 10th Conference of Retroviruses and Opportunistic Infections on February 14, 2003 finally set the record straight.
The 2NN Study
The 2NN Trial was an open-label, randomized, comparative trial of nevirapine versus efavirenz-based HAART regimens. Randomized
patients received either efavirenz, nevirapine once daily or nevirapine twice daily, or both NNRTIs together in addition to stavudine
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(d4T) [Zerit] plus lamivudine (3TC), as shown below:
u
u
u
u
Nevirapine, 400 mg once daily (n = 220)
Nevirapine, 200 mg twice daily (n = 387)
Efavirenz, 600 mg once daily (n = 400)
Nevirapine 400 mg once daily plus efavirenz, 800 mg once daily (n = 209)
Total daily doses of efavirenz and nevirapine in the single NNRTI arms of the study were as currently recommended. The nevirapine
arms of the study incorporated a dose escalation from 200 mg daily to 400 mg daily on day 14, as per current standard of practice.
The dose of efavirenz in the double NNRTI arm was increased to 800 mg once daily to maintain full exposure to this agent, based
on a previous pharmacokinetic study, which demonstrated that nevirapine co-administration decreases the bioavailability of efavirenz.
The 2NN study randomized over 1200 individuals, and a full 84% of the patients completed the anticipated 48 weeks of follow-up.
The patient groups were well matched at baseline with regard to key prognostic variables, such as CD4 cell count and plasma viral
load. The overall CD4 cell count at baseline was just below 200 cells/mm3 and the overall median plasma viral load was slightly in
excess of 4.5 log10 copies/mL. Also, of note, over one third of study participants were women. (Figure 1, inside front cover.)
The overall efficacy analysis of the study was based on the percent of patients with treatment failure at week 48 based on a composite
pre-defined end point, which included virological failure, as well as disease progression events or change in randomized treatment.
Based on this analysis, the dual NNRTI arm was statistically significantly less effective than the other study arms (i.e., the two
nevirapine containing arms (once daily and twice daily) and the efavirenz arm). Of note, this was largely attributable to a greater rate
of adverse effects related discontinuations in the dual NNRTI arm of the study.
With regard to antiviral potency, as measured by the fraction of patients achieving a plasma viral load <50 copies/mL at 48 weeks, the
2NN Study showed that the two nevirapine arms and the efavirenz arm of the study were equivalent, both in an intent-to-treat and
on-treatment analysis. (Figure 2, inside front cover.)
Specifically, a full 70% of patients in the nevirapine once daily and the efavirenz once daily arms of the study achieved <50
copies/mL at 48 weeks in an intent-to-treat analysis. Similarly, a full 87% and 89% of patients treated with efavirenz once daily and
nevirapine once daily, respectively achieved <50 copies/mL at 48 weeks in the on-treatment analysis.
CD4 responses between treatment arms were also equivalent.
Safety analyses demonstrated, a trend towards more hepatobiliary and rash events in the nevirapine treated patients and more CNS
and psychiatric events in the efavirenz treated patients. A total of 25 patients died during the study. Two deaths were attributed to
nevirapine use. There were no statistically significant differences with regard to mortality endpoints between study arms.
(Figure 3, inside front cover.)
In a lipid sub-study (11) conducted in a sub-set of patients within the 2NN Study, differing trends were observed between treatment
arms. In particular, HDL increases were more pronounced for patients receiving nevirapine as part of the treatment. Similarly, the total
cholesterol to HDL ratio was more favorably affected among patients receiving nevirapine as part of their treatment. (Figure 4,
inside front cover.)
Dr. Joep Lange, the principal investigator of the 2NN Study, concluded that nevirapine and efavirenz have comparable efficacy.
Furthermore, nevirapine whether given once daily or twice daily has equivalent antiviral potency to efavirenz. Finally, co-administration
of nevirapine and efavirenz should not be recommended as it resulted in higher treatment failure due to increased toxicity.
Commentary
The 2NN Study represented a tremendous effort organized by a group of independent investigators through the International AIDS
Treatment Evaluation Centre in the Netherlands under the leadership of Dr. Joep Lange. A total of 65 centers from 17 countries
participated in this trial. Boehringer Ingelheim, the manufacturer of nevirapine (Viramune®) provided funding for the study.
The results of the 2NN Study should have a significant impact on current antiretroviral therapy practices. This study demonstrates that
nevirapine has comparable potency to efavirenz in the context of NNRTI-based highly active antiretroviral therapy. In addition,
nevirapine is associated with substantial improvements in lipid profiles that one would expect would translate in decreased long-term
cardiovascular morbidity. The latter is an important emerging concern, particularly as data continues to accumulate regarding increasing
rates of cardiovascular morbidity in cohorts of HIV-infected individuals on long term antiretroviral therapy.
Finally, given the substantial price differential in favor of nevirapine, it is anticipated that third party payers and HIV treatment programs
around the world would welcome these results as an opportunity to help to deal with the sustainability of antiretroviral therapy, a
problem that currently affects not only the developing but also the developed world.
In summary, the results of the 2NN Study finally set the record straight regarding the relative efficacy and safety of nevirapine and efavirenz.
In brief, both agents have comparable clinical efficacy. Also, both agents have equivalent antiviral potency and identical effects on CD4
cell counts. Furthermore, both agents lend themselves well to the development of simplified, compact, and once daily regimens.
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Some differences between these compounds are readily apparent. Among them, there are subtle differences regarding their safety profile,
with more hepatobiliary and rash events among nevirapine treated patients and more CNS events among efavirenz treated patients.
Also, nevirapine has a rather intriguing effect on lipids.
Finally, nevirapine has a definitive advantage in terms of price. Based on the results of the 2NN Study, the choice between nevirapine
and efavirenz in the clinic will most likely be driven by a combination of factors, primarily including the individual patients
characteristics (i.e., co-morbidities, and cardiovascular risk), as well as cost.
References
Montaner JSG, Reiss P, Cooper D,Vella S, Harris M, Conway B,Wainberg MA, Robinson P, Hall D, Myers M, Lange JMA. A randomized,
double-blinded trial comparing combinations of nevirapine, didanosine and zidovudine for HIV infected patients. The INCAS
Trial. JAMA 1998; 279(12):930-937.
Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD,Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA.
Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior
antiretroviral therapy. NEJM 1997;337(11):734-9.
Gatell J, Murphy R, Katlama C, et al. The Atlantic study. 7th European Conference on Clinical Aspects and Treatment of HIV Infection. October 23,
1999. Lisbon. Abstract #1243.
Staszewski S, Morales-Ramirez J,Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus
zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 1999;341:1865-1873.
US DHHS Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-infected
adults and adolescents. February 4, 2002. http://www.aidsinfo.nih.gov/guidelines/adult/html_adult_02-04-02.html.
BHIVA Writing Committee. British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral
therapy. July 27, 2001. http://www.aidsmap.com/about/bhiva/bhivagd.asp.
Yeni PG, Hammer SM, Carpenter CCJ, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katsenstein DA, Montaner
JSGM, Richman DD, Saag MS, Schechter M, Schooley RT,Thompson MA,Vella S,Volberding PA. Antiretroviral treatment for adult HIV
infection in 2002. Updated recommendations of the International AIDS Society-USA panel. JAMA 2002; 288(2):222-235
Cozzi-Lepri A, Phillips AN, d’Arminio Monforte A, et al. Virologic and immunologic response to regimens containing nevirapine or
efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) Study. J Infect Dis
2002;185:1062-1069.
Matthews GV, Sabin CA, Mandalia S, et al. Virological suppression at 6 months is related to choice of initial regimen in antiretroviralnaive patients: a cohort study. AIDS 2002;16:53-61.
van Leth F, Hassink E, Phanuphak P, et al. Results of the 2NN study: a randomized comparative trial of first-line antiretroviral therapy
with regimens containing either nevirapine alone, efavirenz alone or both drugs combined, together with stavudine and
lamivudine. 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston. Abstract 176.
van Leth F, Phanuphak P, Gazzard B, et al. Lipid changes in a randomized comparative trial of first-line antiretroviral therapy with
regimens containing either nevirapine alone, efavirenz alone or both drugs combined, together with stavudine and lamivudine
(2NN study). 10th Conference on Retroviruses and Opportunistic Infections. February 10-14, 2003. Boston. Abstract 752.
C L I N I C A L T R I A L S I N T R E AT M E N T N A Ï V E A N D E X P E R I E N C E D PAT I E N T S
By Charles Hicks, MD
Duke University Medical Center, Durham, NC
CLINICAL TRIALS IN TREATMENT-NAÏVE PATIENTS
The 2NN Study
As described in the report by Dr. Julio Montaner above, the 2NN study was designed as a head-to-head comparison of nevirapine
and efavirenz, but also included additional objectives. In summary, the study demonstrated that nevirapine administered once or twice
daily was not inferior to efavirenz in the defined measures of treatment success, and resulted in comparable rates of virologic
suppression after 48 weeks of treatment.
In contrast, the dual NNRTI arm was less efficacious primarily due to increased toxicity. Since it was not demonstrably superior,
there seems little point in pursuing this strategy further as it is obviously more expensive and requires a higher pill burden.
As regards adverse events, hepatic toxicity was greatest in the qd nevirapine arm, significantly greater than in the efavirenz arm.
Moreover there were 3 treatment-associated deaths, one from lactic acidosis attributed to d4T, and two related to nevirapine. One
nevirapine-associated death was from hepatitis, the other from Staphycoccal sepsis during hospitalization for Stevens Johnson
syndrome. Overall, when adverse events leading to change/discontinuation of study therapy were evaluated, there were statistically
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significant differences (p<0.001) between the treatment arms in the percentage of patients with at least one change to their therapy
or discontinuation of the study medication; this occurred in fewer individuals in the efavirenz arm (15.5%) than in the other
treatment arms (21.2%, 24.1%, and 29.7%).
So what lessons are we to take from this large, well-done study? First, although the best treatment success rate was seen in the
efavirenz arm, it was not statistically better than either of the two nevirapine arms (although the efavirenz arm was better than the
dual NNRTI arm). When considering only virologic success rates, the response rates were virtually identical. Secondly, from an
adverse event perspective, nevirapine was associated with more liver toxicity and there were two deaths attributed to nevirapine
toxicity. Finally, there were modest differences in lipid changes between the two arms that appear to favor nevirapine.
Taken together, these data appear to establish nevirapine as a reasonable alternative to efavirenz in treatment-naïve patients, albeit with
a somewhat increased risk of serious drug-associated toxicity. These findings add to the considerations involved in deciding which
regimen best matches which patient.
F Van Leth and others. Results of the 2NN Study: A Randomized Comparative Trial of First-line Antiretroviral Therapy with
Regimens Containing Either Nevirapine Alone, Efavirenz Alone or Both Drugs Combined, Together with Stavudine and
Lamivudine. Abstract 176 (oral session).
F Van Leth and others. Lipid Changes in a Randomized Comparative Trial of First-line Antiretroviral Therapy with Regimens
Containing Either Nevirapine Alone, Efavirenz Alone or Both Drugs Combined, Together with Stavudine and Lamivudine (2NN
Study). Abstract 752 (poster).
The NEAT Study
The second major study of treatment-naïve patients was the GlaxoSmithKline-sponsored trial dubbed the NEAT Study.This trial was
a comparison of the investigational protease inhibitor fosamprenavir, or GW 433908 (commonly referred to as just 908) to nelfinavir
when given with abacavir (ABC) and lamivudine (3TC) in treatment-naïve patients. In this study 251 patients were randomized on a
2:1 basis to 908 dosed as 1400mg bid or nelfinavir, 1250mg bid given with standard doses of ABC and 3TC. A diverse population
was enrolled (44% Latino and 32% African-American; 31% female) with entry characteristics balanced across the study arms – median
baseline VL 4.82 log10 copies, median CD4 count 212 cells/mm3. The study was designed to last only 48 weeks and these final data
were presented. The premature discontinuation rate for both arms was relatively high – 30% in the 908 arm and 46% in the NFV
arm. Virologic and CD4 responses as well as lipid changes are shown below.
The NEAT Study (GW433908 vs. NFV): 48-week Data
Outcome measure
908
NFV
VL<400 copies, ITT, M=F
66%
51%
VL<50 copies, ITT, M=F
55%
41%
Virologic failure
14%
28%
CD4 change
+201 cells
+216 cells
LDL Cholesterol
+33mg/dL
+33mg/dL
Triglycerides
+1mg/dL
+46mg/dL
Overall adverse events were similar in frequency in the two treatment arms, but diarrhea rates were significantly higher in patients
receiving nelfinavir (17%) compared to 908 (5%). Rash was more common in the 908 arm (8%) versus the nelfinavir arm (2%).
This study is the first to show a non-boosted protease inhibitor with superior efficacy to nelfinavir. The trial was not blinded and the
very high drop-out rate limits the certainty of the conclusions. It would also have been nice if the study had been continued for
more than 48 weeks since it is important to establish durability beyond 48 weeks. Nonetheless, it is probably fair to say that these
data indicate that fosamprenavir can be considered a reasonable first protease inhibitor option whose favorable characteristics include a
relatively low pill burden, acceptable tolerability, modest lipid effects, and good potency in treatment-naïve patients.
J Nadler and others. The NEAT Study: GW433908 Efficacy and Safety in ART-naïve Subjects, Final 48-week Analysis Abstract 177 (oral session).
Gilead 903 Study: 96- week Follow-up Data
An update of the Gilead 903 study with follow-up now extended to 96 weeks was reported. To review the baseline data as presented
in Barcelona, this blinded study of 600 treatment-naïve patients randomized participants to receive 3TC + efavirenz and either d4T
or tenofovir (TDF). The mean viral load was 4.9 log10 copies/mL and the mean CD4 count was 279 cells/mm3. At 96 weeks of
follow-up, 78% of patients receiving TDF and 74% of those receiving d4T had VL <50 copies/mL (Figure 5, inside front cover).
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CD4 increases were +266 cells in the d4T arm and +261 cells in the TDF arm. For a report on lipid and fat changes see Adverse
events related to antiretroviral therapy below.
CLINICAL TRIALS IN TREATMENT-EXPERIENCED PATIENTS
Context Study
This study was intended to assess the efficacy and safety of fosamprenavir (GW433908, or 908) boosted with ritonavir in the
treatment of patients experiencing virologic failure on a protease inhibitor-containing antiretroviral regimen. The data reported
represented 24-week outcomes data. The comparator arm was lopinavir/ritonavir (LPV/r) co-formulated capsules. The study design
was interesting and needs to be described in some detail in order to interpret the results of this trial.
Patients were randomized on a 1:1:1 basis in the study to receive either 908/ritonavir at a dose of 1400mg/200mg qd, 908/ritonavir
at a dose of 700mg/100mg bid, or the standard dose of LPV/r (3 capsules bid). Importantly, patients were only permitted to enter
the study if resistance testing verified that there were at least two nucleoside reverse transcriptase inhibitors that retained sufficient
activity (per the protocol this was worded as, “Subjects must have been able to construct an active background regimen of 2 RTIs”).
The interpretation of the genotype was done via “Guideline Rules” from Visible Genetics.
These rules were updated 3 times during the course of the study as new information became available. In the actual conduct of the
trial, some 543 patients were screened and 320 were randomized. Thus 223 patients who screened were not randomized, most
presumably due to lack of active NRTIs. Thus the study population is a pretty selective one since it represents only the proportion
of PI-experienced patients who are more likely to achieve treatment success with a new regimen, given that they are presumably
receiving several active agents with the new regimen. Use of NNRTIs was not allowed, a somewhat controversial issue.
Patients had to be on their first or second PI regimen and had to have a viral load >1000 copies at screening. Prior tenofovir or
adefovir use was an exclusion criterion. A somewhat unfamiliar primary endpoint was used – a time-averaged viral load
measurement called the “average area under the curve minus baseline”, or AAUCMB. The study was powered as an non-inferiority
study and was of sufficient size to determine if the upper limit of the 97.5% confidence interval was less than 0.5 log10 copies/mL for
the AAUCMB. Of the 320 randomized patients, 315 received study drug. Baseline characteristics are shown below:
908/ritonavir qd
908/ritonavir bid
LPV/r
Number
105
107
103
BL viral load
4.19 log10
4.13 log10
4.13 log10
BL CD4 count
250 cells
292 cells
234 cells
1 prior PI
49%
60%
67%
2 prior PI
40%
34%
28%
908/ritonavir qd
908/ritonavir bid
LPV/r
AAUCMB
-1.48 log10
-1.50 log10
-1.66 log10
VL <400 copies
58%
60%
69%
VL <50 copies
40%
42%
48%
Virologic failure
34%
27%
21%
Results at week 24 are shown below:
Changes in CD4 lymphocytes did not differ among the treatment arms, nor were there appreciable differences in toxicity or lipid
changes over 24 weeks.
While this data was interpreted as indicating the non-inferiority of the two 908 regimens to LPV/r, some questions were raised.
First, the LPV/r arm appeared to have superior efficacy, albeit not statistically significantly so. Secondly, Joe Eron inquired from the
audience regarding the appropriateness of AAUCMB as an indicator of efficacy. His point was that using an average area under the
curve minus baseline probably underestimates the efficacy of therapy in patients who achieve suppression <50 copies, especially if
they start from a relatively low viral load at treatment initiation. From a clinician’s perspective, we really are more interested in who
achieves suppression below the level of detection and how long does this suppression last. I think it is fair to say that 24-week data is
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a good first step but longer-term follow-up is crucial to assess the real value of these regimens. While they all did relatively well in
this study, the patient screening criteria was a likely important issue in the success rates observed. This study allows us to say that 908
is a potentially useful agent for second or third line PI therapy, but more data is needed.
E DeJesus and others. The Context Study: Efficacy and Safety of GW433908/RTV in PI-experienced Subjects with Virological
Failure (24 Week Results). Abstract 178 (oral session).
BI 1182.52 – Tipranavir/ritonavir in Multiple PI-experienced Patients
This study reported data from a double-blind, randomized, dose-optimization study of TPV/ritonavir in patients with three class ART
failure and prior experience with more than one protease inhibitor. The design called for patients to discontinue their current failing
PI on day 0 and substitute one of three bid doses of TPV/r: 500mg/100mg, 500mg/200mg, or 750mg/200mg. Initial efficacy was
measured at week 2 after which the background NRTI regimen was optimized based on resistance testing and prior treatment
history. Additional follow-up for up 24 weeks+ to assess both safety and efficacy was then completed. Patients had to have at least
one primary PI mutation, but were excluded if they had more than one of three key mutations:V82L/T, I84V, or L90M. Entry
characteristics included:
TPV/r 500/100
TPV/r 500/200
TPV/r 750/200
73
72
71
Baseline VL
4.49 log10
4.57 log10
4.53 log10
Baseline CD4
140 cells
162 cells
133 cells
Number
Patients enrolled were predominantly male (84.3%), white (76.4%), and had a median age of 42 years. The study groups were evenly
balanced for baseline characteristics.
The viruses isolated from the patients in this study had high rates of resistance to currently available protease inhibitors. By genotypic
analysis, rates of resistance varied from a low of 27% (lopinavir) to a high of 94% (nelfinavir). Rates of genotypic resistance exceeded
60% for all PIs except LPV. By phenotypic testing, the fold-change susceptibility of these viruses ranged from 7.0-fold for saquinavir
to 94.2-fold for ritonavir.
The phenotypic susceptibility for TPV was essentially unchanged from wild type (1.1-fold). Trough drug concentrations interestingly
demonstrated that the 500mg/200mg dose was the one with the least variability and the greatest proportion of trough concentrations
>20uM. Virologic response rates at 2 weeks were –0.87, –0.98, and –1.18 log10 copies/mL for the 500/100, 500/200, and 750/200
arms, respectively.
Based on additional analysis of phenotypic results with genotypic data, the authors proposed that 4 protease mutations be considered
as “universal protease associated mutations”, or UPAMs. These include the aforementioned mutations at positions 82, 84, and 90 as
well as L33I/V/F.
Combinations of these four mutations conferred significant reductions in phenotypic susceptibility to all the currently available PIs,
but for TPV, there was only modest effect unless 3 or more of these mutations were present. Adverse events were more common in
the patients in the 750/200 arm and were most often gastrointestinal (diarrhea or nausea), or ALT elevations. Adverse events leading
to study drug discontinuation were most common in the 750/200 arm (15.5% at 24 weeks). Based on these data, the 500mg/200mg
dose is being studied in a larger phase III trial in treatment-experienced patients. Additional patient experience is obviously required
to determine how efficacious tipranavir will be for patients with extensive prior PI treatment, but this study provides an important
foundation for additional trials.
J Gathe and others. Tipranavir/Ritonavir Demonstrates Potent Efficacy in Multiple Protease Inhibitor Experienced Patients: BI
1182.52. Abstract 179 (oral session).
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T R E AT M E N T I N T E R R U P T I O N S T R AT E G I E S A N D I M M U N O L O G Y
By Mark Dybul, MD
National Institutes of Health, Bethesda, MD
TREATMENT INTERRUPTION BASED ON CD4 COUNT
Two studies evaluated treatment interruptions based on CD4 T cell count. Ruiz and colleagues presented follow-up data on their
study of a single interruption in patients with viral load < 80 copies/ml and CD4 > 500 for 1 year and nadir CD4 > 100. Patients
were randomized to continue therapy or to stop. At 48 weeks of interruption, 35/61 (57%) had resumed therapy due to increased
viral load > 100,000 c/ml (96%), decreased CD4 to <350 (4%) or both (23%). However, 43% remained off therapy for nearly 1 year.
These results are similar to those that have been presented by Joel Gallant. The major predictors for resuming therapy were pre-ART
therapy nadir CD4 and viral load. Of note, 41% of patients with interruption experienced minor events and 10% experienced acute
retroviral syndrome.
Jean Ananworanich and associates presented data from their innovative randomized, controlled trial of continuous ARV therapy versus
CD4-driven intermittent therapy (patients resume therapy when CD4 drops <350 or by >30%), versus 7 days on/7 days off therapy.
At week 48, none of the 23 patients in the CD4-driven arm had failed by criteria and the mean percentage of time off therapy was
67%, the mean decrease in CD4 T cell count was 178 cells/mm3 and one patient had an acute retroviral syndrome. Of note, there was
no significant reduction in serum triglyceride or total cholesterol levels between the arms. As reflected by Figure 6 (inside back
cover), in the week on/week off arm, more than half of the 26 patients had virologic failure and the DSMB had closed the arm.
Anaworanich noted that these patients were significantly different in several ways than the NIAD cohort in which failure has not
been seen in pilot studies of 7 days on/7 days off: 1) patients in this cohort were heavily pre-treated and may have entered with
resistance, and 2) perhaps of greatest importance, the regimen used was SQV/RTV which may be less potent that IDV/RTV or EFV
used in the NIAID studies. If one is off therapy for 50% of the time, potency matters. In this regard, Gunthard and colleagues
reported that 8/14 patients, 7/14 of whom were treated with nelfinavir-based regimens, had > 100 copies/ml of plasma HIV RNA at
Day 8 of treatment interruption. In contrast, Dybul reported that of 76 patients in NIAID studies, 8 (11%) had > 50 copies/ml (range
62-955) at day 7 of treatment interruption: few patients received nelfinavir and none received SQV.
L Ruiz and others. A Multi-center, Randomized Controlled Clinical Trial of Continuous vs Intermittent HAART Guided by CD4+
T-cell Counts and Plasma HIV-1 RNA Levels. Abstract 65 (oral session).
J Ananworanich and others. HIV-NAT 001.4: A Prospective Randomized Trial of Structured Treatment Interruption in Patients with
Chronic HIV Infection. Abstract 64 (oral session).
H Gunthard and others. HIV-plasma RNA Rebounds within Days during Structured Treatment Interruptions. Abstract 639 (poster).
M Dybul and others. A Randomized, Controlled Trial of Long Cycle Structured Intermittent Versus Continuous ARV Therapy for
Chronic HIV Infection. Abstract 68lb (oral session).
LONG-CYCLE TREATMENT INTERRUPTION
Two randomized, controlled trials of long cycle intermittent ARV therapy with pre-determined time periods on and off ART (as
opposed to CD-driven where the off intervals are determined with each cycle based on the CD4 count) were presented. Stephano
Vella presented the largest trial: 273 patients have been randomized to receive continuous ARV therapy or intermittent therapy of 2
cycles of 1 month off and 1 cycle of 2 months off ARV therapy; the period on ARVs is 3 months regardless of the off-drug duration.
An interim analysis at 6 months showed that of 136 patients randomized to intermittent therapy, 13% had dropped out versus 4% in
the continuous arm. Resistance was seen in 21% of patients in the interruption arm; however, after analysis of resistance prior to
interruption, 8/72 (11%) of patients had new resistance. Resistance was seen in both patients treated with PI or NNRTI-based
therapy. The most frequent mutations were to NRTIs; of note, nevirapine was stopped 3 days prior to NRTIs and efavirenz was
stopped 6 days prior to NRTIs given the longer half-life of NNRTIs. AT the end of the 3rd STI, 92% of patients had plasma HIV
RNA < 400 (versus 100% in the continuous arm), but only 40 patients had achieved this endpoint. There may a trend to decreased
grade 3 or 4 toxicity in the interruption arm (19 events in continuous arm versus 8 in intermittent arm), but Vella noted that it was
too early to evaluate the effects on toxicity.
Dybul presented data from their randomized, controlled trial of continuous ARV therapy versus 4 weeks off/8 weeks on ARVs. The
study, designed for 90 patients, was stopped to new enrollment after 52 patients had enrolled (26 per arm) due to new resistance to
NNRTI (efavirenz; nevirapine was excluded) and/or 3TC in 3 of 8 patients in the intermittent arm after 4 to 6 cycles. In addition, 2 of
18 patients receiving a PI developed NRTI mutations during the second cycle off ART. Of the 52 patients who enrolled, 41 (19
intermittent and 22 continuous) had 48 week data. At week 48, there was no significant difference in serum triglyceride, total
cholesterol or LDL cholesterol levels. At week 40 there was a significant difference in triglyceride and total cholesterol (P=0.4 for each),
but by week 48 that was abrogated. Although the transient decreases may be important, there was no difference at any time in hs-CRP,
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the most sensitive marker for risk of cardiovascular disease. In addition, there was no difference ALT or AST at any time evaluated.
S Vella and others. ISS-PART: A Prospective, Randomized, Multi-center Clinical Trial of Intermittent Therapy in HIV+ Subjects with
Persistent Suppression of Viral Replication. Abstract 66 (oral session).
M Dybul and others. A Randomized, Controlled Trial of Long Cycle Structured Intermittent Versus Continuous ARV Therapy for
Chronic HIV Infection. Abstract 68lb (oral session).
AUTO-IMMUNIZATION AND IMMUNE CONTROL OF HIV INFECTION
Bruce Walker set the tone for the potential role of STI for auto-immunization when he stated that “the further one goes out the
more depressing it gets.” Longer follow-up in the cohort of patients treated during acute HIV infection has revealed that a
significant number of the 14 patients have now failed to maintain control of plasma HIV RNA following multiple STIs. In a
Kaplan-Meier evaluation of time to reaching greater than 30,000 copies/ml of plasma HIV RNA, 40% of patients who underwent
STI had less than 30,000 copies/ml at 900 days compared to a control cohort of approximately 25%. Although these data may
indicate an advantage to STI in acute HIV infection, the loss of control in a reasonable number of patients treated during acute
infection when the potential for STI to have the greatest auto-immunization impact may not bode well for auto-immunization in
chronic HIV infection.
In fact, there was not a single oral or poster presentation devoted to auto-immunization in chronic HIV infection. Two presentations
on studies of long cycle treatment interruptions to reduce drug exposure did provide data on auto-immunization in chronic HIV
infection. Stefano Vella presented data on 3 interruptions (1 month off/3 months on, then 2 months off/3months on) in 136
patients. The mean log HIV rebound was 2.3, 2.1 and 2.2 for the 1st, 2nd and 3rd cycle. In a study of 1 month off/2 months on,
Dybul, there was no significant difference in mean plasma HIV RNA levels from the 1st to the 2nd (-0.33 log), 1st to the 4th (-0.46
log) cycles off ARVs (P>0.5).
Walker, Draenert, Connors and Price all addressed the issue of how there could be relatively high level quantities of HIV-specific
immune responses in the face of poor control of HIV plasma viremia.Walker showed that substitutions of only 15 to 22 base pairs
were seen in individuals who lost control of plasma viremia – a relatively small number indicating that escape may not be the major
cause of loss of immune control of HIV infection. Draenert presented data on advanced patients with mean CD4 T cell counts of
141 and mean plasma HIV RNA of 186,271 copies/ml. All 30 patients evaluated had detectable CD8 T cell responses with a
breadth and magnitude comparable to 25 patients with good control of plasma HIV RNA. Interestingly, sequence analysis failed to
identify escape mutations in 9 of 13 patients who were evaluated. While the majority of patients had a low percentage of cells in the
mature effector category (CD45RA+CCR7-), some patients had up to 38% of cells in this category. These data indicated a
possibility that was echoed in other talks: quality may be more important than quantity.
Price presented intensive immunologic data from the Swiss-Spanish Intermittent Therapy Trial that has previously reported a lack of
auto-immunization in approximately 100 patients treated during chronic HIV infection. In that study, there was no correlation
between the quantity of HIV-specific immune responses and control of plasma HIV RNA. Using novel techniques, Price
demonstrated that patients with high quantity HIV-specific CD8 T cells exhibited an impaired functional phenotype in relationship
to an increased viral load.This dysfunction was not associated with direct HIV infection of the CD8 T cells. Connors demonstrated
that both progressors and long-term non-progressors (LTNPs) had similar quantities of HIV-specific CD8 T cells, but that by CFSE,
only LTNPs maintained a functional ability to proliferate that was coupled with an increased capacity to express perforin. In
addition, 15 patients with high CD4 T cell proliferation to HIV, equal to LTNPs, while receiving suppressive ARV therapy had nearly
complete abrogation of the functional correlate of immune responses with viremia. Taken together, these data indicate that HIV
viremia results in a quantitative response to HIV, but that viremia may lead to dysfunction in both CD4 and CD8 HIV-specific
responses. These results may help explain the disappointing results in studies of auto-immunization.
BD Walker and others. Immune Control and Immune Failure in HIV Infection. Abstract 164 (oral session).
S Vella and others. ISS-PART: A Prospective, Randomized, Multi-center Clinical Trial of Intermittent Therapy in HIV+ Subjects with
Persistent Suppression of Viral Replication. Abstract 66 (oral session).
M Dybul and others. A Randomized, Controlled Trial of Long Cycle Structured Intermittent Versus Continuous ARV Therapy for
Chronic HIV Infection. Abstract 68lb (oral session).
R Draenert and others. Vigorous HIV-specific CD8 T-cell Responses in Late Stage HIV Infection. Abstract 35 (oral session).
M Connors and others. Shifting the Paradigm of Immunologic Control of HIV. Abstract 165 (oral session).
DA Price and others. Functional Discrepancies in HIV-specific CD8+ T-lymphocyte Populations Reflect the Kinetics of Virus
Exposure Abstract 32 (oral session).
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THERAPEUTIC IMMUNIZATION AND STI
Harrer presented a safety and immunogenicity of an MVA vector expressing HIV-1 Nef in 14 patients with plasma HIV RNA < 50
copies/ml and CD4 > 400. Patients were given 3 doses of the immunogen at weeks 0, 4 and 16; 2 weeks following the final
immunization, patients interrupted their ARV therapy. Other than local inflammation and systemic effects, the immunizations were
well tolerated. Following 3 immunizations, 7/14 patients recognized new CTL epitopes and 3/14 had Nef-specific CD4 T cells.
The mean historic pre-ARV plasma HIV RNA level was approximately 20,000 copies/ml; following immunization and STI the
mean viral load was 46,000 copies/ml.
In a trial of ALVAC,Tubiana administered 4 immunizations over 12 weeks in 48 patients receiving ARV therapy with a viral load <
200 copies/ml and CD4 > 400; at week 16 ARV therapy was interrupted. No significant clinical events were recorded. 36 patients
with low CD4 proliferation SI (mean 3.3) to p24 antigen prior to immunization had a mean SI of 6.8 at the time of interruption.
There was a 3-fold increase in CD8 responses to gag in 7 patients. 38/48 patients had significant increases in plasma viremia
following interruption and were required to resume therapy.
In an interesting twist, Levy presented data from 70 pts who received ARV therapy alone (37 pts) or 4 ALVAC immunizations every
4 weeks followed by 3 cycles of subcutaneous IL-2 every 8 weeks. At week 40 (weeks after final IL-2 dose), all patients stopped
ARVs. 15/32 immunized versus 8/33 controls had sustained CD4 proliferation to p24 Antigen at week 36. Time to virologic failure
was statistically different between the groups, but only by 13 days (42 versus 29). 2/37 (5%) controls versus 8/33 (24%) remained off
ARVs at week 52.
Although therapeutic immunization remains the greatest hope for the future, and it was encouraging that the immunogens used were
safe and well tolerated, the virologic results were less than impressive. In fact, there did not seem to be a difference in therapeutic
immunization compared to what has been reported for several cycles of STI alone for auto-immunization.
E Harrer and others. Phase-I Study with a Therapeutic MVA-BN-Nef Vaccine in HIV-1 Infected Patients on HAART. Abstract 60 (oral
session).
R Tubiana and others. Therapeutic Vaccination with ALVAC-HIV vCP1433: A Recombinant Canarypox Vaccine in Chronically HIV-1
Infected Patients Treated with HAART:VACCITER (ANRS 094). Abstract 61 (oral session).
Y Levy and others. Immunological and Virological Efficacy of ALVAC-VIH 1433 and HIV Lipopeptides (Lipo-6T) Combined with
SC IL-2 in Chronically HIV-infected Patients-Results of the ANRS 093 Randomized Study. Abstract 62 (oral session).
SALVAGE THERAPY
Interruptions of Antiretroviral Therapy
Deeks and colleagues continued their pioneering strategies in this field. 20 patients with a mean viral load of 3.9 log and CD4 of
336 receiving PI-based salvage therapy stopped either the NRTI (5) or the PI (15) component of their therapy. The point here was
to see if patients could maintain good clinical outcomes while potentially reducing toxicity. The patients who stopped the PI had a
mean log change in plasma HIV RNA of 0.005 log copies/week, a mean decrease in serum triglycerides of 90 mg/dl (P=0.02) and
non-HDL cholesterol of 30 mg/dl (P=0.03) at week 12, and stable genotypic and phenotypic mutations. In contrast, the patients
who stopped the NRTIs had a sustained increase in viremia of 0.03 log copies/week; 3 of 5 exhibited a delayed loss of M184V that
was temporally associated with an increase in viremia.
The controversy regarding STI in salvage therapy rages on. Lawrence presented data from the large CPCRA study that was
terminated to new enrollment by the DSMB because the study could not demonstrate a virologic or clinical benefit to patients who
underwent an interruption. 270 patients with mean viral load 5.0 log10 and CD4 180 were randomized to undergo a 16 weeks
interruption and then resume therapy or to continue therapy. Genotypic resistance results were available for all patients; mean
number of new drugs was 3.6 (2.7 active) in the STI arm and 3.8 (2.8 active) in the no STI arm. There were 22 progression of
disease or death endpoints in the STI arm versus 12 in the no STI arm; there were 8 deaths in each group. Interestingly, the events
occurred after the ARVs had been resumed in the STI arm. However, a significant difference in CD4 T cells remained between the
STI and no STI arm to 8 months (47 cells, P<0.001) but not at 12-20 months (31 cells, P=0.11). There was no difference in quality
of life between the groups.
Katlama presented follow-up data to week 48 of the GIGHAART. 63 patients who were randomized to an 8 weeks interruption
followed by mega-ARV therapy (median 11 drugs!) or to begin mega-ARV immediately. Despite the fact that the majority of
patients did not have a return of drug-susceptible HIV during the relatively short off-ARV period, there remained a statistically
significant difference at week 48 in change in viral load at week 48; however the P value changed from 0.013 at week 24 to 0.4 at
week 48. In addition, at week 48 the p value for the percent of patients with <400 copies/ml was >0.05.
The difference in results may be due to the duration of the STI period or the large number of drugs used in the GIGHAART study.
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But it may be important to note the trend in the P values in the GIGHAART study in trying to resolves the clinical benefit of STI
in salvage therapy.
SG Deeks and others. Continued Reverse Transcriptase Inhibitor Therapy is Sufficient to Maintain Short-Term Partial Suppression of
Multi-drug Resistant Viremia. Abstract 640 (poster).
J Lawrence and others. CPCRA 064: A Randomized Trial Examining Structured Treatment Interruption for Patients Failing Therapy
with Multi-drug Resistant HIV. Abstract 67 (oral session).
C Katlama and others. Long-term Benefit of Treatment Interruption in Salvage Therapy (GIGHAART ANRS 097). (oral session).
R E S I S TA N C E T E S T I N G
By Michael Youle, MD
Royal Free Hospital, London, UK
REPLICATION CAPACITY
The new tests of Replicative Capacity and resistance assays for fusion and entry inhibitors are now being evaluated and refined to
play a similar role for these exciting new drug classes.
In an oral presentation Susan Little and coworkers presented data to establish whether drug susceptibility and viral replication capacity
(RC, i.e. fitness) are associated with baseline plasma viral load levels in treatment naïve subjects with primary HIV infection.
They measured plasma viral load (VL), drug susceptibility, RC, and pol sequence analysis a median of 119 days after the estimated
date of HIV infection for 202 treatment naïve subjects. Drug susceptibility and RC were measured using PhenoSense™ HIV. ABI
sequence analysis of pol was used to identify drug resistant mutations. The subjects were mainly gay white males. At baseline Median
VL at baseline was not significantly different among subjects infected with drug resistant virus, defined by phenotype as a >10 fold
reduction in susceptibility to at least one drug and by genotype as the detection of at least one major drug resistance mutation,
compared to subjects infected with drug sensitive virus.
Hypersusceptibility (HS), defined as an IC50 fold-change ≤ 0.4, to one or more protease inhibitors (PI) was noted in 27% of subjects.
The median RC in subjects with either PI HS virus (29%) or phenotypically resistant virus (32%) at baseline was significantly lower
than for subjects with drug susceptible virus that did not exhibit PI HS (48%, p<0.01).
Baseline VL was significantly higher (5.06 vs. 4.69 log, p=0.005) for subjects with baseline RC values above the median RC of 42%
for the entire group. Thus higher baseline viral RC, but not drug resistance, was a significant predictor of higher baseline viral load in
subjects presenting with primary HIV infection. PI HS and phenotypic resistance were associated with a lower baseline RC.
Although the clinical significance of RC requires further study, it may be an important determinant of the rate of disease progression
among untreated patients with recent HIV infection.
SJ Little and others. High Replication Capacity Is Associated with High Baseline Viral Load in Untreated Subjects with Primary HIV
Infection. Abstract 152 (oral session).
DISCORDANT CD4 COUNT AND VIRAL LOAD
A group from Duke University found that discordant responses to ART occurs when CD4 counts are stable or increased over time despite
persistently detectable viral load (VL). For PI-based ART, this outcome is associated with CCR-5 co-receptor tropism and diminished viral
replication capacity. However the discordant responses in patients on NNRTI-based ART are not yet well characterized.
Twenty HIV+ individuals on NNRTI-based ART were studied in 2 groups: Discordant (D-NN):VL >400 copies/mL sustained >1
year, CD4 >200 cells/mm3 with stable or increasing trend >1 year; Success (S-NN):VL <400 copies/mL, CD4 >200 cells/mm3 with
increasing trend sustained >1 year. Data from this cohort were compared to previously reported data from PI patients including those
with discordant responses (D-PI), virologic success (S-PI), and treatment failures [increasing viral load with declining CD4 count (F-PI)].
Phenotypic and genotypic drug susceptibility testing (PhenoSense HIV, GeneSeq HIV), and replication capacity (RC) testing
(modified PhenoSense) were performed. Both D-NN and D-PI patients had high-grade phenotypic and genotypic resistance to their
ART regimens, as did F-PI patients.Viral isolates were available for 6 D-PI patients, 9 D-NN patients, and 9 F-PI patients.
All 15 viruses from discordant patients (D-NN and D-PI) were R5 tropic (NSI); in contrast, 7/9 failure patients had X4 tropic (SI)
viruses (p=0.0007).While viruses from D-PI patients had diminished replication capacity compared to F-PI patients, the RC of
viruses from D-NN patients was significantly higher and similar to those failing ART (median RC values: D-NN=27% D-PI=12%
F-PI=22%; D-NN vs. D-PI: p=0.002, D-NN vs. F-PI: p=0.6).
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So it appears that HIV from patients with discordant CD4/VL responses is consistently R5-tropic while HIV from patients failing
PI-based ART is most often X4-tropic.
PI-based ART appears to impact replication capacity to a greater extent than NNRTI-based ART, perhaps reflecting differing barriers
to resistance generation.
D Linden and others. Viral and Immune Correlates of Discordant CD4/VL Responses to NNRTI-based HAART and Comparison to
a Discordant Cohort Receiving Protease Inhibitor-Based HAART. Abstract 146 (oral session).
NEW ENTRY INHIBITOR ASSAY FROM VIROLOGIC
In an oral session Michael Greenberg from Trimeris gave his usual eloquent rendition of results from the pivotal studies of T-20, the
novel fusion inhibitor jointly being developed with Roche. He showed for the first time resistance data determined with a newly
developed single cycle entry inhibitor assay from ViroLogic, based in South San Francisco.
TORO 1 and TORO 2 are randomized, open-label, controlled, multicenter, Phase III studies of patients receiving 90 mg BID of
enfuvirtide (ENF, formerly T-20) by subcutaneous injection in combination with an optimized background (OB) regimen.
The intent to treat population included 661 patients randomized to ENF+OB. Resistance data were generated using the novel
GeneSeq and PhenoSense Entry Assays on viral envelope (Env) amplified from patient plasma samples to assess susceptibility to ENF
(pEC50). Combined study data for TORO 1 and TORO 2 were analyzed using summary statistics. ENF pEC50 were available from
612 (92.6%) patients at baseline (BL).
By Week 24, 301 patients had virological failure and 204 of these had genotype and phenotype available for BL/failure time points.
BL pEC50s were approximately log-normally distributed with a geometric mean (GM) of 0.259 µg/mL (range 0.007 to 7.526
µg/mL). Sixteen patients had BL pEC50s greater than 1.956 µg/mL (GM + 2 SD), but did not have a diminished virological
response nor were they predisposed to virological failure (p=0.7186 and p=0.4579, respectively).
Neither BL viral tropism nor clade was associated with virological response.The GM pEC50 for patients at failure was 5.645 µg/mL
and ∆pEC50 was 21-fold (range <1 to 422-fold).There was a correlation with decreased ENF susceptibility at virological failure and
changes in gp41 amino acids 36-45 (p<0.0001).Varying ∆pEC50 was observed for distinct substitutions in gp41 36-45.
So in conclusion it appeared that patients achieved similar virological suppression across the range of BL ENF susceptibility observed
but that those failing had on average a 21-fold loss of ENF susceptibility with mutations in gp41.
ML Greenberg and others. Baseline and On-treatment Susceptibility to Enfuvirtide Seen in TORO 1 and TORO 2 to 24 Weeks.
Abstract 141 (oral session).
T-20 SUSCEPTIBILITY AND CO-RECEPTOR TROPISM
A presentation evaluated the baseline (BL) ENF susceptibility, co-receptor tropism and genetic variation of entry-inhibitor naïve
HIV-1 in patients from TORO 1 & 2 [4]. Designation of viruses as R5, X4 or dual tropic was based on the ability to generate
reportable phenotypic susceptibility results on CD4/CXCR4 and/or CD4/CCR5 cells.
To adjust for differences in susceptibility of the X4 and R5 reference viruses, fold change in IC50 (FC) values were normalized (nFC)
such that the geometric mean of the results determined on either X4 or R5 cells was set to1.The env gene was sequenced, amino
acid sequences of gp41 were compiled and substitutions relative to HXB2 were reported.
The percentages of R5, X4, and dual tropic viruses at BL were 62% (n=378), 4% (n=23) and 34% (n=211), respectively, 2% (n=12)
were non-B clade.The distribution of nFC values was broader for viruses that replicated on CXCR4 cells (IQR_X4=0.4-2.7)
compared to CCR5 cells (IQR_R5=0.5-1.8).
Pure X4 tropic viruses exhibited slightly higher nFC (GM=2.7, IQR=1.7–4.6) compared to pure R5 (GM=1.2, IQR=0.6-2.1) and
dual tropic viruses (GM_X4=0.9, IQR_X4=0.3-2.3, GM_R5=0.8, IQR_R5=0.4-1.5). BL gp41 substitutions in amino acids 36-45
relative to HXB2 were uncommon (≤2%) except at amino acids 42 (N42S=15%), which was more prevalent in viruses that were
most susceptible to ENF (p<0.001).
In these two studies, pure R5 tropic viruses were more prevalent than dual tropic viruses, and pure X4 tropic viruses were rare. BL
ENF susceptibility distributions were generally similar for all virus populations; however pure X4 tropic viruses had slightly higher
nFC compared to R5 and dual viruses.The natural polymorphism in the ENF binding site at codon 42 was associated with lower
nFC to ENF and so may predict some degree of resistance.
JM Whitcomb and others. Analysis of Baseline Enfuvirtide (T-20) Susceptibility and Co-receptor Tropism in Two-phase III Study
Populations. Abstract 557 (poster).
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INTERPRETATION OF PHENOTYPIC TEST RESULTS AND WILD-TYPE VIRUSES
The phenotypic assay PhenoSense™ is an accurate and reproducible assay for measurement of HIV drug susceptibility. For some
drugs, especially stavudine, didanosine, and tenofovir, reductions in susceptibility that are below 2-fold are clinically relevant.
Thus, appropriate interpretation of phenotypic test results should take into consideration the natural variability in susceptibility of
wild-type (WT) viruses and inherent assay variability.The ViroLogic phenotype-genotype database (n > 12,000) was queried for
clinical samples lacking any drug-selected mutation in RT (certain amino acids at positions 41, 65, 67, 69, 70, 74, 75, 100, 101, 103,
106, 151, 181, 184, 188, 190, 210, 215, 219, 225, 227, 236) or PR (positions 23, 24, 30, 32, 33, 46, 47, 48, 50, 54, 82, 84, 88, 90) [5].
The upper end of each wild-type virus fold change (FC) distribution was defined by the mean plus 2 SD and the 99th percentiles of
the distribution.To assess assay variability for each drug, 10 reference viruses with varying drug susceptibilities were tested 8 to 30
times each; and the average coefficient of variation (CV) across samples was calculated for each drug.
The average CV for the reference viruses ranged from 12% to 23% for all drugs except ZDV (36%).The log10-transformed FC data
from clinical isolates were normally distributed. Results are summarized below:
RTI
ZDV
3TC
ddI
ddC
d4T
ABC
TDF
NVP
DLV
EFV
Median
0.89
1.01
0.99
0.97
0.95
0.90
0.86
0.89
1.25
0.86
Mean+2SD
1.80
1.59
1.35
1.40
1.34
1.36
1.19
3.18
4.69
2.25
99th percentile
2.08
1.74
1.50
1.56
1.48
1.53
1.26
4.58
7.03
2.73
Number
2262
2262
2256
1991
2262
2166
1420
2261
2227
2254
PI
APV
IDV
NFV
RTV
SQV
LPV
ATV*
Median
0.70
0.78
1.04
0.82
0.70
0.69
0.70
Mean+2SD
1.92
1.88
3.09
2.29
1.54
1.58
1.90
99th percentile
2.08
2.25
3.78
2.69
1.77
1.67
2.33
Number
2175
2262
2261
2258
2260
1242
284
*ATV=atazanavir
It would seem that the mean+2SD FC value for all drugs in wild-type viruses is lower than previously described for “biological” cutoffs using other phenotypic assays.The larger variability in WT drug susceptibility for some drugs (e.g. NFV and the NNRTIs) is not
due to differences in assay variation, since the CVs are low and not significantly different between drugs.
These observations indicate that this assay can be used to reliably determine clinically relevant breakpoints at low fold-change values
(< 2-fold). Greater precision in phenotypic data will facilitate the development of more accurate genotype interpretation algorithms.
NT Parkin and others. Distribution of Phenotypic Drug Susceptibility Among More than 2,000 Wild-type Viruses. Abstract 585 (poster).
EFFECT ON RESISTANCE OF STRUCTURED INTERRUPTION OF PI OR NRTI COMPONENT OF COMBINATION REGIMEN
Steven Deeks presented a prospective non-randomized pilot study of patients interrupting either the protease inhibitor (PI) or reverse
transcriptase inhibitor (NRTI) component of a combination regimen to evaluate the effect of this interruption on various factors
including changes in drug resistance genotype and phenotype.
Twenty subjects were studied who had persistent viremia (>400 copies/mL) and > 90% adherence to a regimen containing both
NRTIs and PIs.The decision to interrupt either PI or NRTI therapy was based on subject-specific toxicity. Median baseline viral
load was 3.9 log copies/ml (IQR 3.6 - 4.5) with a median CD4 cell count of 336 cells/mm3.
The mean change in viremia of the 15 PI patients after cessation of therapy was 0.005 log copies/week (95% CI -0.01 to +0.02;
p=0.49). Significant decreases in fasting triglyceride (-90 mg/dL; p=0.02) and non-HDL cholesterol (-30 mg/dL, p=0.03) were
observed at week 12. Genotypic and phenotypic resistance remained stable in all patients interrupting PI therapy (through week 1624); however, PI mutations waned and replicative capacity and viremia increased in two patients after week 24.
In contrast, all 5 subjects that interrupted NRTI therapy (and continued PI therapy) exhibited immediate and sustained increases in
HIV RNA (+0.03 log copies/week, P < 0.001).Three of 5 subjects interrupting NRTI therapy exhibited a delayed loss of M184V,
which was temporally associated with a rise in viral load.
SG Deeks and others. Continued Reverse Transcriptase Inhibitor Therapy is Sufficient to Maintain Short-Term Partial Suppression of
Multi-drug Resistant Viremia. Abstract 640 (poster).
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BENEFIT OF TREATMENT INTERRUPTION FOLLOWED BY SALVAGE THERAPY
This study seems to help to explain some of the changes seen by Christine Katlama in the GigHAART study which examined the
effect of an 8 week treatment interruption in 63 very heavily pre-treated individuals failing therapy and with a median CD4 cell
count of 27 cells/mm3.
There was no significant rise in viral load in the interruption group, but at weeks 12 and 24 there was significant difference in viral
load response by intent to treat analysis.The percentage of subjects with a >1 log drop in HIV RNA was 26% and 24% at these
time-points in the immediate switch group versus 62% and 50% in the interruption arm (p= 0.007 and 0.043 respectively).
The CD4 cell rise was +7 cells/mm3 in the immediate versus +51 and +69 at weeks 24 and 48 in the deferred group. Major factors
associated with success to this strategy consisted of treatment interruption with reversion of resistance (RH = 12.4), adequate drug
concentrations (RH = 5.6) and the use of lopinavir (RH = 6.0).
C Katlama and others. Long-term Benefit of Treatment Interruption in Salvage Therapy (GIGHAART ANRS 097). Abstract 68 (oral session).
DIMINISHED HIV REPLICATION CAPACITY MODERATES CLINICAL CONSEQUENCES OF CERTAIN RESISTANCE MUTATIONS
In an effort to more clearly define a role for reduction in replicative capacity in the presence of thymidine analog mutations (TAMs)
Michael Miller and his group characterized the RC of a large panel of clinical isolates with defined mutations in RT and/or protease.
Patient isolates with defined genotypes were selected from samples submitted to ViroLogic for routine genotypic, phenotypic and RC
analysis. Of 1829 samples, 37.6% had no NAMs or TAMs (n=688), 48.8% had TAMs (mutations at codons 41, 67, 70, 210, 215 or
219; n=893), 11.5% had M184V without other NAMs (n=211), 1.3% had Q151M complex or T69S insertions (n=23), and 0.7% had
K65R (n=14). RC is reported as the percent of wild-type using a defined cohort without resistance mutations.
Without adjusting for PI-associated resistance mutations (PI-R), all RT genotypic groups showed significant reductions in RC
compared to the no NAM control group (p<0.05). However, among patient samples without PI-R (n=1040) significant reductions in
RC were observed only for isolates containing M184V alone or K65R alone (median RC 57% and 56%, respectively, p<0.03).The
few samples with K65R+M184V and no other NAMs had lower median RC (29%).
Similarly, median RC for patient isolates with Q151M+M184V or T69S Ins+M184V was 28-29%. In the absence of K65R, M184V
and PI-R, patient isolates with 1-2, 3-4 or >4 TAMs showed a slight reduction in RC that was not significantly different than
control.TAMs+M184V showed significantly reduced RC (47-66%) that was comparable to samples with M184V but no TAMs.
So it would appear in this large sample set that TAMs were common (49%) but that K65R was infrequent (<1%). Patient isolates
with K65R or M184V exhibited decreased RC and these effects appear additive. However, isolates with TAMs alone do not have
significantly reduced RC.The results with K65R are consistent with the sustained reductions in HIV RNA observed among patients
in clinical trials of tenofovir DF who had developed K65R.
MD Miller and others. Decreased Replication Capacity of HIV-1 Clinical Isolates Containing K65R or M184V RT Mutations. Abstract
616 (poster).
A DV E R S E E V E N T S R E L AT E D TO A N T I R E T R OV I R A L T H E R A P Y
By Graeme Moyle, MD, MB BS
Chelsea and Westminster Hospital, London, UK
NUCLEOSIDE AND NUCLEOTIDE ANALOGUE-RELATED ADVERSE EVENTS
In the on-going, randomized, double-blind, placebo-controlled Gilead Sciences 903 study comparing Viread and Zerit (stavudine,
d4T) in combination with the standard of care Epivir (lamivudine, 3TC) + Sustiva/Stocrin (efavirenz) backbone, no differences in
drug-related discontinuations were observed. However, reported adverse events differed.Total and LDL cholesterol and triglycerides
rose significantly more in individuals randomized to Zerit as compared with those receiving Viread. On the other hand, individuals
in the Viread arm had a greater increase in HDL cholesterol. Individuals in the Zerit group were more likely to initiate lipidlowering therapy and initiated lipid-lowering therapy earlier than individuals randomized to Viread. Clinical adverse events also
differed between groups. The proportion of individuals diagnosed with peripheral neuropathy was three percent of Viread recipients
but 10 percent of Zerit recipients over the course of 96 weeks of treatment. Investigator defined lipodystrophy was diagnosed in 1
percent of Viread recipients and 12 percent of Zerit recipients over 96 weeks. Bodyweight rose by approximately one kilogram in the
Zerit group and approximately 6 kilograms in the Viread group (Figure 7, inside back cover). A cross-sectional DEXA scan study
indicated that individuals in the Viread group had greater amounts of subcutaneous limb fat than Zerit recipients after 96 weeks of
treatment. No differences in the rate of creatinine elevation or phosphate elevation were seen.
S Staszewski and others. Efficacy and Safety of Tenofovir DF (TDF) versus Stavudine (d4T) When Used in Combination with
Lamivudine and Efavirenz in Antiretroviral Naïve Patients: 96-week Preliminary Interim Results Abstract 564b (poster).
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POTENTIAL TENOFOVIR RENAL TOXICITY
Two case series reported individuals receiving Viread where hypophosphatemia and renal dysfunction were observed. One series
of three individuals who developed hypophosphatemia which resolved following the discontinuation of Viread and recurred on
rechallenge with Viread indicated that all individuals where this problem developed had previously experienced renal tubular acidosis
while receiving adefovir therapy. In the other case series, three individuals at a single center in France developed hypophosphatemia
and proximal renal tubular acidosis with proteinuria and decreased creatinine clearance between 8 and 11 months after initiating
Viread therapy. All the patients weighed less than 60 kilograms and 2 of the 3 individuals were either female or had some degree of
renal insufficiency at baseline. However no other predisposing factors were identified. All patients experienced resolution of renal
tubular dysfunction upon withdrawal of Viread. Given that this problem has not been observed in two large clinical trials, one with
48 week’s follow-up and one with 96 weeks follow-up reported and involving approximately 600 individuals exposed to Viread, the
available control data would suggest that renal tubular dysfunction during Viread therapy is an infrequent phenomenon for which
specific risk factors may be required.
G Blick and others. Tenofovir May Cause Severe Hypophosphatemia in HIV/AIDS Patients With Prior Adefovir-induced Renal
Tubular Acidosis. Abstract 718 (poster).
J Reynes and others. Renal Tubular Injury and Severe Hypophosphoremia (Fanconi Syndrome) Associated with Tenofovir Therapy.
Abstract 717 (poster).
NEVIRAPINE AND EFAVIRENZ IN THE 2NN STUDY: DIFFERENT ADVERSE EVENT PROFILES
In the 2NN study, the efficacy of efavirenz and nevirapine were fairly similar, efavirenz have a numerical but not statistical
advantage over the two nevirapine groups (BD and QD).Thus, differences in the adverse events seen with each drug, and physician
and patient anxiety about those adverse events, will be important in choosing between these two NNRTIs. Physicians and patients
when considering their NNRTI choice need to ‘rank’ their concern about the different toxicities. Adverse events can be examined
by looking at all adverse events (not reported so far from 2NN), the number of severe or potentially life threatening events (so called
grade 3 and 4 events) or the number of events which lead to discontinuation of the drug (Figure 3, inside front cover). Events
may be clinical, ones that are apparent to the patient or physician, or laboratory events which are only picked up on blood tests.The
proportion of patients who changed off their randomized NNRTI during the course of the study were 20% in efavirenz group, 22%
with nevirapine BD, 29.1% with nevirapine QD, and 34.5% in the group receiving both NNRTIs (called the 2NN arm for the rest
of this report). Differences in the types of adverse event were seen between groups. For nevirapine recipients liver and skin problems
were more common whereas efavirenz recipients more commonly reported central nervous system effects. Clinical hepatotoxicity
events (i.e. becoming jaundiced or other physically evident liver problems) were more common in nevirapine recipients with 1.4% of
nevirapine QD and 2.1% of nevirapine BD recipients experiencing at least one grade 3-4 event compared with just 0.3% of efavirenz
recipients. At a laboratory level, grade 3-4 liver function tests abnormalities (values of at least >5-times the upper limits of the normal
range) were significantly more common in the nevirapine QD group as compared with the efavirenz group. Whereas only 4.5% of
efavirenz recipients experienced grade 3-4 transaminitis (AST or ALT liver enzyme elevations), these changes were seen in 13.2% of
nevirapine QD, 7.8% of nevirapine BD and 8.6% of 2NN recipients. Risk factors for the events, such as the presence of hepatitis B or
C co-infection and time to discontinuation were not reported. Skin problems were also more common in the nevirapine group.
Grade 3 rashes are those which include skin blisters and grade 4 rashes involved the mucosa such as mouth, genitals or eyes. Grade 34 rash was reported in 4.1% of nevirapine QD and 3.1% of nevirapine BD recipients and 1.8% of efavirenz treated patients as well as
3.8% of those on the 2NN arm. CNS effects such as sleep disturbance, abnormal dreams and anxiety were reported in 1.8% of
nevirapine QD, 4.9% of nevirapine BD, 6.5% of efavirenz and 8.1% of 2NN recipients. The difference between nevirapine QD and
the 2NN arm was statistically significant.
Perhaps most important to patients and physicians is how many people stopped their NNRTI therapy due to toxicity.The percentage
of patients in each group who discontinued therapy due to adverse events was statistically significant (p < 0.001) with 15.5% of
efavirenz patients compared to 24.1% of nevirapine QD, 21.2% of nevirapine BD, and 29.7% of 2NN patients discontinuing due to
adverse events. Of note, 2 deaths during the study were attributed to nevirapine; one secondary to fulminant hepatic failure (a woman
with no hepatitis co-infection) and one to MRSA sepsis (blood infection with an antibiotic resistant bacteria) following Steven’s
Johnson Syndrome (a severe blistering rash).
These differences in adverse event profile are likely to influence drug choice. However, further analysis of the study is needed to
appreciate whether specific baseline characteristics influence risks of specific toxicities.
F van Leth and others. Results of the 2NN Study: A Randomized Comparative Trial of First-line Antiretroviral Therapy with
Regimens Containing Either Nevirapine Alone, Efavirenz Alone or Both Drugs Combined, Together with Stavudine and
Lamivudine. Abstract 176 (oral sesson).
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EFAVIRENZ EFFECTS UPON SLEEP
Two studies reported investigation of sleep patterns in individuals receiving efavirenz-based regimens. In one study, 33 individuals
underwent a questionnaire of sleep quality and baseline and subsequent time points after starting efavirenz with a subset of 8
individuals undergoing overnight polysonography, a standardized EEG based technique for investigating sleep quality. Overall 12
individuals dropped out of from the study. Sixteen patients reported poor baseline sleep quality and after the initiation of efavirenz
14 of these individuals remained poor sleepers. Six individuals who reported good sleep at baseline remained good sleepers. Of five
individuals where a complete overnight polysonograph was available before efavirenz and four weeks after the initiation of efavirenz,
the proportion of time spent in the slow wave of sleep increased by approximately 10 percent at four weeks. Slow wave sleep is
generally considered the deepest form of sleep and the latter are consistent with a modest perceptive effect [8].
In the second sleep study, 18 individuals receiving efavirenz for at least one month were compared with a control group of 13 healthy
volunteers with sleep quality assessed through questionnaires and ambulatory EEG monitoring. Patients who were receiving efavirenz
and self-reported poor sleep were noted to spend shorter periods of time in REM and stage 2 sleep and longer total times awake.
Those individuals on efavirenz who did not describe sleep disturbances were noted to have shorter periods of stage three and four
sleep. The authors could not find a relationship between efavirenz trough levels and the presence of sleep abnormalities.
Taken together these studies suggest that efavirenz may have some impact on sleep quality, although the results of this impact are
conflicting one study suggesting more time spent in deep sleep and the other study suggesting some modest changes in other aspects
of sleep architecture. However, the prospective study indicated the majority of individuals who report sleep disturbances whilst
receiving efavirenz are individuals who are experiencing sleep disturbances prior to the initiation of efavirenz. This underlines that
before physicians consider changing therapy away from efavirenz due to self reported of sleep disturbance it is worth considering that
the sleep disturbances may not be caused by the efavirenz. Managing patients’ anxiety and evaluating issues that the may disturb sleep
prior to the initiation of any antiretroviral therapy may reduce the overall prevalence of reported sleep disturbance in studies.
Comparator groups of individuals receiving other antiretroviral regimens may be more useful comparators for future studies.
R Landovitz and others. Efavirenz Increases Slow-wave Sleep.Abstract 715 (poster).
L Gallego and others. Abnormalities in Sleep Architecture in Patients Receiving Efavirenz. Abstract 716 (poster).
ENFUVIRTIDE INJECTION SITE REACTIONS
Histological examinations of 7 injection site reactions (ISR’s) were made in individuals where the biopsies were taken between 3 and
40 hours after the injection of enfuvirtide. Regardless of whether the individuals reported a nodule, erythema, induration or no
clinical reaction pathological changes were seen in all samples. Observed changes varied with regards the intensity of inflammatory
response and whether it was localized in the dermis or subcutaneous tissue. This may reflect the precise area into which the
enfuvirtide was injected. The inflammatory infiltrate was characteristic of a local hypersensitivity reaction with some disruption of
local connective tissue. The inflammatory cells include histiocytes aggregated in areas of collagen change, reminiscent of some
granulomatous conditions. In some cases, much of the change was likely to be consistent with trauma such as local areas of fat
necrosis or hemorrhage. Specific staining for enfuvirtide indicated that it was present in the areas of greatest inflammatory response.
Most of the lymphocytes present in the samples were T cells.This may be consistent with some clinical observations where physicians
who are experienced in the use of enfuvirtide have noted that individuals who experience the greatest CD4 cell rise are often also
those individuals who experience the greatest problem with ISRs.The data suggest that individuals should be careful to minimize
trauma when injecting enfuvirtide, and indicated that local anti-inflammatories may be useful in managing ISRs.
RA Ball and others. Pathology of Injection Site Reactions with Enfuvirtide. Abstract 714 (poster).
M E TA B O L I C D I S T U R BA N C E S A N D L I P O DY S T R O P H Y
Andrew Carr, MD
St.Vincent’s Hospital, Sydney, Australia
LIPODYSTROPHY
Buffalo Humps
Following on from the somewhat controversial presentation of the FRAM study at Barcelona, the study had 3 adjacent posters, one
of which presented new data. At Barcelona, we were told that buffalo hump was as common in men with and without HIV
infection. Further analysis of these data found that buffalo hump was significantly associated with greater total, arm, head and intraabdominal fat than in those without buffalo hump. Furthermore, buffalo humps in men with HIV infection were larger (8 x 8 cm)
than in men without HIV infection (5 x 4.5 cm). No analysis was presented as to the impact of antiretroviral therapy, HIV disease
parameters or patient characteristics on the prevalence or size of buffalo hump.Whether the fat accumulation observed in the 2
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populations are the same or pathogenetically different or similar can not be determined, of course, without pathological investigations.
B Gripshover and others. Lipoatrophy is the Dominant Feature of the Lipodystrophy Syndrome in HIV-infected Men.Abstract 732 (poster).
M Saag and others. Body Composition in HIV+ Men with and without Peripheral Lipoatrophy is Different than Controls. Abstract 733 (poster).
A Zolopa and others. Buffalo Hump in Men with HIV Infection: Larger, but Not More Common. Abstract 734 (poster).
Fat Changes in HIV-Infected Women
An interesting presentation reported on the prevalence of lipoatrophy and fat accumulation in the Women’s Interagency HIV Study.
As was shown cross-sectionally in FRAM, HIV-infected women had more frequent onset of peripheral lipoatrophy than did HIVuninfected women (30% and 12%, respectively).The same applied for central lipoatrophy (25% and 15%). It is not clear that this
atrophy is ART-induced, HIV wasting, both or neither. Nevertheless, the incidence of fat accumulation was similar both centrally and
peripherally in both groups, suggesting that at least some of the fat accumulation reported as HIV lipodystrophy-related is age-related
(or at the very least not all is HIV/ART-related).The question remains how much.
PC Tien and others. Incidence of Lipoatrophy and Lipohypertrophy in the Women’s Interagency HIV Study. Abstract 736 (poster).
HIV Lipodystrophy Case Definition
Ongoing analysis of the HIV lipodystrophy case definition study data found that subjective clinical lipodystrophy severity (both
physician and patient assessed) correlated significantly with 6 objective measures of lipodystrophy severity.These 6 measures included
trunk:limb fat ratio on DEXA,VAT:SAT ratio on abdominal CT scan, and waist:hip ratio using a tape measure. However, the best
correlate was the lipodystrophy case definition score, being the score used to diagnose lipodystrophy that is derived from the 10
objective parameters in the lipodystrophy case definition (age, gender, HIV duration, CDC stage, waist:hip ratio, anion gap, HDL
cholesterol, trunk:limb fat ratio,VAT:SAT and leg fat percent). Furthermore, the case definition score correlated well with multiple
lipid, glycemic and acid-base parameters that we know correlate with lipodystrophy severity; this correlation was better than that
using subjective lipodystrophy severity scores.These data suggest that this case definition can be used to objectively both diagnose and
rate the severity of lipodystrophy.This score has the added advantage, unlike DEXA and CT, of generating gender-independent
values, meaning that a single scoring system could be used to develop a grading scale for use in clinical trials. Of course, this
possibility needs prospective validation.
A Carr and others. An Objective Comparison of Physician- and Patient-rated Severity of HIV Lipodystrophy. Abstract 731 (poster).
Effect of Nucleoside Analogue Sparing Regimens
A non-randomized switch study from dual NRTI therapy to efavirenz plus boosted indinavir found that peripheral fat increased, but
that visceral fat increased also. It was inferred that nucleosides play a greater role in lipoatrophy than does boosted indinavir (but what
about other protease inhibitors?).The authors also suggested that the mechanisms leading to visceral fat gain might be separate, at least
in part, to those responsible for peripheral fat loss, and that maybe protease inhibitors really do specifically lead to increases in central
fat independently of changes in peripheral fat.
M Boyd and others. Lipodystrophy in Patients Switched to Indinavir/Ritonavir 800/100 mg BID and Efavirenz 600 mg QD after
Failing Nucleoside Combination Therapy: A Prospective, 48-week Observational Sub-study of HIV-NAT 009. Abstract 738 (poster).
DYSLIPIDAEMIA
Niacin for Lipid Control
A pilot study evaluated the value of niacin in 14 HIV-infected adults with LDL cholesterol at least 130 mg/dl and triglycerides at
least 200 mg/dl. Patients initiated the NCEP step 1 diet for 4 weeks, then added niacin (500 mg daily, increasing by 500 mg every 2
weeks if tolerated to a maximum of 2000 mg daily) for 14 weeks. 6 patients experienced flushing, and 2 ceased niacin for this reason.
In terms of efficacy, total cholesterol and triglycerides both declined significantly (14% and 34%, respectively). However, LDL
cholesterol did not alter, and there was evidence that insulin resistance worsened. So this intervention cannot be recommended
without further evaluation.
M Gerber and others. Niacin in HIV-infected Individuals with Hyperlipidemia Receiving Potent Antiretroviral Therapy.Abstract 726 (poster).
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Insulin Resistance
Two groups found that the adipocyte cytokine, adiponectin, was a better marker of insulin sensitivity than the other major adipokine,
leptin. Adiponectin levels also correlated with lipodystrophy severity on imaging.Whether measurement of adiponectin is useful for
diagnosing either abnormal glucose tolerance or lipodystrophy cannot be determined from these cross-sectional data, although they
do suggest a role for adiponectin in the pathogenesis of both.
C Vigouroux and others. Serum Adipocytokines are Related to Lipodystrophy and Metabolic Alterations in HIV-infected Men Under
PI-Based HAART. Abstract 754 (poster).
K Yarasheski and others. Impaired Insulin Sensitivity in HIV-infected Individuals is Associated with Higher Hepatic Lipid Content and
Visceral Adiposity. Abstract 757 (poster).
MITOCHONDRIAL TOXICITY
Measuring Mitochondria Levels
Several groups reported on the utility of measuring mitochondrial DNA (mtDNA) in either peripheral blood mononuclear cells or
subcutaneous fat as a marker of nucleoside analog-related lipoatrophy. Overall, significant differences in mtDNA levels were much
more likely to be observed when subcutaneous fat was used, with lower levels in those with peripheral neuropathy and/or subjective
lipoatrophy.The variability of change was not well reported, however, nor was a comparison of the technique with DEXA, which
directly measures peripheral, subcutaneous fat mass. Also, the variability cross-sectionally was quite substantial when ART-naïve and
ART-exposed subjects were compared, suggesting the test may not be that useful diagnostically. Of course, not all lipoatrophy involves
nucleoside analog mitochondrial toxicity, and so it is not surprising that an assay that only assesses the lipotoxicity of one drug class
would have limited value.
C Cherry and others. Longitudinal Associations between Antiretroviral Treatments and Quantification of Tissue Mitochondrial DNA
from Ambulatory Subjects with HIV Infection. Abstract 133 (oral session).
K Thompson and others. Improvements in Body Fat and Mitochondrial DNA Levels are Accompanied by Decreased Adipose Tissue
Cell Apoptosis after Replacement of Stavudine Therapy with either Abacavir or Zidovudine. Abstract (poster).
JF Hoy and others. Changes in Mitochondrial DNA in PBMCs from Patients with Lipoatrophy Randomized to Switch to Abacavir
or Continue Thymidine Analogue-containing ARV Regimens. Abstract 729 (poster).
M van der Valk and others. Relation between Use of Nucleoside Reverse Transcriptase Inhibitors, Mitochondrial DNA Depletion, and
Severity of Lipoatrophy: Results from a Randomized Trial Comparing Stavudine and Zidovudine-based Antiretroviral Therapy.
Abstract 739 (poster).
CARDIOVASCULAR DISEASE
Risk of Myocardial Infarction
It remains controversial whether exposure to combination antiretroviral treatment (ART) leads to an accelerated risk of myocardial
infarction (MI), possibly via dyslipidemia and insulin resistance, perhaps by altering the inflammatory milieu, or perhaps by promoting
thrombosis. Several studies reported data with conflicting results.
Probably the most important single presentation of new toxicity data at the conference was the D:A:D study. D:A:D is an ongoing
prospective observational study of 23,468 patients from 11 cohorts in Europe, USA and Australia, enrolled from July 1999 to April
2001 with follow-up analyzed through February 2002.The studies objectives were:
1. to assess the association of exposure to combination ART with incidence of MI; and
2. to identify factors associated with increased risk of MI
The study was powered to detect a 2-fold increase in the rate of MI in patients receiving 3-drug antiretroviral therapy (in 99% of
patients 1-2 nucleosides plus either a protease inhibitor and/or a non-nucleoside reverse transcriptase inhibitor) relative to those who
were ART-naive. 23,468 patients were followed for a total of 36,199 patient years after enrolment.Their median age was 39 years,
24% were female, 45% had acquired HIV through homosexual sex, and 20% by injecting drug use, 26% had a prior clinical AIDS
diagnosis, the median CD4 count was 418 cells/mm3, and 55% of subjects had an undetectable plasma HIV RNA. In terms of
antiretroviral exposure, 67% had received a PI (median 2.6 years), 34% a non-nucleoside reverse transcriptase inhibitor (median 0.9
years) and 81% a nucleoside analog RTI (median 3.3 years), leaving 19% antiretroviral-naïve (the patients has been enrolled in their
local cohorts well before enrollment into D:A:D so their total ART exposure was greater).
Using WHO definitions of definite, probable and unclassifiable acute myocardial infarctions (based upon presence of cardiac pain,
cardiac enzymes, troponin, EKG changes, and autopsy findings) 126 patients developed a 1st MI.The overall incidence of acute MI
was 3.5 per 1000 person years (PY). Of these, 28% were fatal (survival less than 28 days).These deaths represented 7% of all deaths on
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study, with by far the greater being HIV-related, even in the presence of so much ART. Using WHO criteria, 55% were definitive,
29% possible, and 16% unclassifiable.
The incidence of MI increased with longer exposure to CART (RR per year of exposure was 1.26 [95% confidence interval 1.121.41, p<0.0001]) after adjustment for demographic risk factors, including increasing age with increased time on CART. Quite
amazingly, the increase in risk became apparent after only 1 year’s therapy with combination ART, and appeared linear out to 4 years
of therapy (too few patients have been followed for longer than 4 years to produce reliable estimates).
Other factors associated with MI were: age (per 5 years increase: RR 1.38), current or ex-smoking status (RR 2.17), history of
cardiovascular disease (RR 5.84) and male gender (RR 1.99), but not family history of cardiovascular disease.Total serum cholesterol
level and diabetes mellitus were also associated with an increased rate, but (possibly) not independently of each other.The relationship
between increased exposure to CART and the rate of MI tended to be reduced after adjustment for total cholesterol, but was
unaffected by adjustment for nadir and current CD4+ lymphocyte count, level of HIV-RNA, duration of HIV infection, and
presence of diabetes or lipodystrophy. Interestingly, the presence of clinically detected lipodystrophy (lipoatrophy or abnormal fat gain)
tended to be associated with a reduced risk of MI on simple univariate analysis and after adjustment for body mass index and
cholesterol. No one could explain this finding.
The authors also noted that the absolute risk of MI appeared low and should be balanced with the marked benefit of antiretroviral
treatment.They presented no data as to whether any particular subgroup was at higher baseline risk of MI, by virtue of ART
exposure, than at risk of AIDS without ART exposure.
One of the first questions that arose was the relative contributions of each antiretroviral drug class, and of individual drugs, to the
increased risk observed.The authors stated that these analyses had not occurred yet as too few patients had developed an MI to allow
for such sub-analyses. However, follow-up of D:A:D will continue until at least 2005, and so another 100-200 definite or probable
MIs should occur and so increase the power of the study to allow such analyses. It was also noted that HDL cholesterol did not figure
in the presentation; this was because HDL cholesterol data was missing for about the study participants (it was not collected routinely
in some cohorts).
So why has D:A:D yielded significantly different results to other observational cohort studies, in particular the VA study presented by
Sam Bozzette last year at this meeting? There are numerous significant differences between these studies that appear to have passed
unnoticed by many at the meeting:
1. D:A:D is a prospective study;
2. all MI endpoints are prospectively validated and generally within 2 months of occurrence;
3.The duration of follow-up is longer in D:A:D;
4.The mean duration of ART is longer in D:A:D, as is the proportion of patients who had received combination ART;
5. D:A:D is a closed cohort, whereas the VA database continually enrolls patients; and
6. D:A:D has been able to record complete risk factor data (except for HDL cholesterol).
Whether these differences explain the differences between the studies is unknown of course. Reassuringly, both studies will have
ongoing data collection for at least another 2 years.
N Friis-Møller and others. Exposure to HAART Is Associated with an Increased Risk of Myocardial Infarction:The D:A:D Study.
Abstract 130 (oral session).
Retrospective analysis of the John Hopkins cohort provided similar conclusions.The authors reported a case-control analysis of the 2672 patients
enrolled (mean follow-up about 3 years, although the cohort is 12 years old, suggesting substantial ongoing enrolment and/or loss to follow-up).The
MI event rate was 10.5/1000 person years of follow-up, compared with population event rates of 2 to 2.5/1000 (and 3 to 3.5/1000 for stroke).
Factors independently associated with having had a MI were increasing age, hypertension, hypercholesterolemia and, most surprisingly, use of d4T
(use of PI therapy was associated on univariate analysis, but not multivariate analysis).
RD Moore. Increasing Incidence of Cardiovascular Disease in HIV-infected Persons in Care. Abstract 132 (oral session).
A prospective study found that carotid artery intima media thickness (a known corollary of atherosclerosis) was greater at baseline in patients who
were older, had higher LDL-cholesterol, hypertension and nadir CD4 less than 200. After 1 year, thickness was accelerated by PI therapy and in
those with greater age.This begs the question of whether such a tool could be used to screen those at greatest cardiovascular risk, although
variability of the technique as well as predictive value of the test needs evaluation in larger samples at multiple sites.
P Hsue and others. Increased Atherosclerotic Progression in Patients with HIV: The Role of Traditional and Immunologic Risk
Factors. Abstract 139lb (oral session).
BONE DISEASE
Tebas and colleagues presented results of a phase 2 study exploring the activity of vitamin D (400 IU daily), calcium carbonate (1000
mg daily) and aledronate 70 mg weekly or placebo. Subjects (n=31) were included who had received at least 6 months ART, and who
had osteopenia (t-score of less than -1; ie bone mineral density at least 1 standard deviation below mean bone mineral density in
adults of the same age and sex).The study was powered to detect a 3% change in spine bone mineral density at 48 weeks. Of the 31
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subjects, 87% were male, 29% smokers and 16% moderate drinkers.Their mean t scores in the spine and hip were -1.5 and -1.0,
respectively. After 48 weeks, the placebo had no significant improvement in BMD overall or in the hip or femur, although markers of
bone turnover (e.g., bone alkaline phosphatase) improved. In contrast, in the aledronate group spine BMD improved by 3.8%, a 5.2%
difference between the 2 groups. Aledronate had no significant effects on BMD elsewhere.This is perhaps not surprising, as spine
bone normally turns over more rapidly than does femoral bone.The question remains whether the osteoporosis being treated was
HIV or ART-related, and whether aledronate would also be beneficial in adults with osteoporosis (t-score less than -2.5), the group
for which aledronate generally offers greatest benefit. A larger ACTG study will commence shortly.
P Tebas and others. Alendronate,Vitamin D, and Calcium for theTreatment of Osteopenia/Osteoporosis Associated with HIV
Infection. Abstract 134 (oral session).
N OTA B L E D R U G - D R U G I N T E R AC T I O N S
Brian Boyle, MD
Cornell University Medical College, New York, NY
VIREAD INTERACTIONS
Previous studies have shown that Videx (didanosine) and Viread (tenofovir) interact to increase Videx levels.This study evaluated that
interaction in healthy volunteers using Videx EC, the enteric coated formulation of Videx.The study compared the Videx levels
achieved with Videx EC (400 mg) alone or with Videx EC (250 mg) in combination with Viread (300 mg). As shown in the table 1
below, the Viread and Videx EC combination was given in 3 ways: (1) Videx EC in a fasted state 2 hrs prior to Viread TDF, (2) Videx
EC and Viread together with a light meal (373 kcal, 20% fat), or (3) Videx EC and Viread together in a fasted state.The results are
shown in the Figure 8:
Figure 8
Thus it appears that Videx EC can be co-administered with Viread so long as the dose is adjusted appropriately, i.e., to 250mg/day.
This combination can be taken with a light meal, thus eliminating the relatively strict meal requirement associated with Videx.
In 2 other studies, other interactions with Viread were evaluated. In one study [Abstract 534], the extended release form of Zerit,
Zerit XR (stavudine XR), was found not to have a significant interaction with Viread when the 2 drugs were given concomitantly
with a light (373 Kcal) meal [Abstract 537].
In the second study,Viread was found to have a significant drug interaction with the new protease inhibitor atazanavir, which is
currently in expanded access. In this study, which involved 10 male patients who received Viread and Norvir (ritonavir) enhanced
atazanavir in a salvage therapy regimen.These patients received Norvir and atazanavir without Viread for the first 2 weeks and then
had Viread added to the regimen.The levels of atazanavir and Norvir before (2 weeks) and 4 weeks after (6 weeks) the addition of
Viread are shown in table 2:
Table 2
ATV
RTV
wk 2
wk 6
wk 6/wk 2
wk 2
wk 6
wk 6/wk 2
4,422
3190
0.72 (0.50–1.05)
886
642
0.72 (0.43–1.21)
Tmax (h)
3 (2–5)
5 (1–5)
-
3 (2–8)
3 (0-5)
-
AUC24 (ng.h/ml)
46,073
34,459
0.75 (0.58–0.97)
7,011
5217
0.75 (0.44–1.24)
Cmin (ng/ml)
636
491
0.77 (0.54–1.10)
43
39
0.91 (0.73–1.13)
C24 (ng/ml)
696
513
0.74 (0.53–1.02)
50
44
0.88 (0.69–1.13)
Cmax (ng/ml)
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These data show a decline of roughly 25% in atazanavir levels and 10-25% in Norvir levels 4 weeks after the addition of Viread.The
clinical significance of these decreases are unclear, as is the mechanism.
B. P. Kearney and others. Didanosine and Tenofovir DF Drug-drug Interaction: Assessment of Didanosine Dose Reduction. Abstract 533
(poster).
S Kaul and others. Lack of Interaction between Stavudine Extended-release Formulation and Tenofovir Disoproxil Fumarate. Abstract
534 (poster).
AM Taburet and others. Pharmacokinetic Parameters of Atazanavir/Ritonavir when Combined to Tenofovir in HIV Infected Patients
with Multiple Treatment Failures: A Sub-study of Puzzle2-ANRS 107 Trial. Abstract 537 (poster).
KALETRA AND PHENYTOIN INTERACTION
Kaletra (lopinavir/ritonavir) inhibits CYP3A4 and Dilantin (phenytoin) is a substrate for CYP2C9 and CYP2C19; both drugs are
CYP450-inducers.Therefore, there is a significant likelihood of a drug interaction between these drugs.
In a study of 24 healthy volunteers, this interaction was assessed with one group of patients (n=12) started on Kaletra for the first 10
days with Dilantin added on day 11 and another group of patients started on Dilantin for the first 10 days followed by the addition of
Kaletra.The pharmacokinetic data for lopinavir (LPV) and Dilantin (PHT) at days 11 and 22 are shown in table 3:
Table 3
D11
D22
Ratio of Geometric Means
(D22 : D11) [90% CI]
p-value (paired t-test)
LPV AUC0-12h
70.89 ± 36.96
49.61 ± 25.09
0.67 [0.53 – 0.85]
0.011
LPV C0h
5.97 ± 3.17
3.55 ± 2.31
0.54 [0.42 – 0.70]
0.001
RTV AUC0-12h
3.08 ± 2.79
1.99 ± 1.09
0.72 [0.54 – 0.97]
0.074
RTV C0h
0.28 ± 0.33
0.14 ± 0.15
0.53 [0.36 – 0.78]
0.013
PHT AUC0-24h
191.00 ± 89.21
147.75 ± 104.54
0.69 [0.57 – 0.84]
0.009
PHT C0h
7.04 ± 4.02
5.31 ± 4.05
0.66 [0.49 – 0.89]
0.033
As shown by this table, Kaletra levels are reduced by Dilantin and vice-versa.The clinical significance of the decline in Kaletra in PInaïve patients is unclear since the inhibitory quotient (IQ) decreased from 85 to 50 (which is still very high), but in PI-experienced
patients which may not have a wild-type virus may need to increase Kaletra levels. Regarding Dilantin, patients on Kaletra and
Dilantin should have Dilantin levels monitored and Dilantin dosing adjusted as needed to maintain therapeutic levels.
ML Lim and others. A Two-way Drug Interaction Between Lopinavir/Ritonavir and Phenytoin. Abstract. 535 (poster).
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N E W A N T I R E T R OV I R A L S I N D E V E L O P M E N T
Brian Boyle, MD
Cornell University Medical College, New York, NY
PRELIMINARY STUDY OF AMDOXOVIR (DAPD/DXG)
Amdoxovir (DAPD) is a dioxalane guanosine analog nucleoside reverse transcriptase inhibitor (NRTI) that is deaminated to an active
metabolite (DXG).The results of DAPD 150, a 96-week, nonrandomized, open-label, Phase I/II study designed to evaluate the longterm safety, tolerability, and antiviral activity of DAPD, were reported by Thompson and colleagues. The trial enrolled 18 HIVinfected, heavily treatment-experienced (median of 10 prior antiretrovirals and 5 NRTI mutations) patients who were randomized to
receive either 300 mg BID or 500 mg BID of amdoxovir in addition to their background regimen that could be optimized at the
discretion of the investigator.
At the end of 12 weeks of therapy, the median decline in viral load was -0.90 log10 copies/mL, the median increase in CD4 count was
+55 cells/mm3 and 42% of the treated patients achieved at least a -1.0 log10 copies/mL decrease in viral load.While there were no
deaths, significant adverse events, or dose-related trends in adverse events, 10 patients discontinued the study: 2 due to virologic
failure, 3 for non-adherence with the protocol, and 5 due to the presence of lens opacities which did not impact visual acuity.
M Thompson and others. Preliminary Results of Dosing of Amdoxovir in Treatment-experienced Patients. Abstract 554 (poster).
RACIVIR: AN ANTIRETROVIRAL WITH A POST-ANTIVIRAL EFFECT?
Racivir is a nucleoside analog with potent and selective activity against both HIV and HBV in cell culture and in animal models. In a
Phase Ib/IIa study reported by Otto and colleagues Racivir was given orally once-daily for 14 days at doses of 200, 400, or 600 mg in
combination with Zerit (stavudine, d4T) and Sustiva/Stocrin (efavirenz) to HIV-infected, treatment-naïve volunteers. After the 14 days,
all antiretroviral therapy was stopped and patient plasma viral loads were monitored through day 35. In combination with Zerit and
Sustiva/Stocrin, the racivir doses resulted in a mean decline in viral load of between 1.13-1.42 log10 copies/mL by day 4.The mean
viral loads continued to decline, but at a slower rate, through the end of treatment on day 14 with mean drop in viral load at that time
ranging from 2.02-2.43 log10 copies/mL. After discontinuation of the therapy at day 14, viral levels remained suppressed for more than 2
weeks with mean viral loads ranging from 2.1-2.6 log10 copies/mL below baseline through day 28. By day 35, the viral loads had begun
to increase, but even at that point they remained more than 1 log10 copies/mL below baseline levels.The antiretroviral regimens were
well-tolerated and there were no significant adverse events noted regarding racivir during this very short study.
MJ Otto and others. Sustained Anti-HIV-1 Effect of Racivir Combined with D4T and Sustiva Following a 14-day Treatment of
Infected Volunteers. Abstract 552 (poster).
GSK BENZOPHENONE NNRTIS
GlaxoSmithKline investigators selected 3 compounds from 250 benzophenones that were synthesized and identified as potent
inhibitors of wild-type and NNRTI-resistant strains of HIV-1.These compounds are in phase I development with a focus was on
K103N resistance. GW4751, 3011, 4511 were found to be potent against wild-type with activity similar to Sustiva (efavirenz).They
were also potent versus K103N at <10nM.
4511 is active against many of the single mutations associated with the currently approved NNRTIs and some double mutations, but
has a decrease in efficacy with some single and double combinations, e.g., 106A (7 fold) [selected in vitro], 106A/ 181C, and
103N/190A.These compounds have a lower protein binding than Viramune (nevirapine) or Sustiva and appear to have low levels of
cytotoxicity and a wide safety margin.
J Chan and others. In Vitro Characterization of Novel Benzophenone Non-nonucleoside Reverse Transcriptase
Inhibitors. Abstract 6 (oral session).
ROCHE PROTEASE INHIBITOR
RO033-4649 is a substrate-based inhibitor of HIV-1 protease with potent antiviral activity against wild-type HIV-1. It is in phase I
development.The IC50 is 1nM.There are no Pgp or CYP 3A4 induction, but some CYP3A4 inhibition (inhibition falls roughly between
Norvir [ritonavir] and Fortovase [saquinavir]). It has lower protein binding than other PIs. It was effective against site-directed mutant
viruses that are resistant to available PIs (including viruses with combinations of 48V, 82A, 90M, 46I, 84V).Against 50 highly resistant viral
strains, 62% retained full susceptibility (<10 fold change) to RO033-4649 while the remainder had intermediate susceptibility.
N Cammack and others. RO033-4649: A New HIV-1 Protease Inhibitor Designed for Both Activity Against Resistant Virus Isolates
and Favorable Pharmacokinetic Properties. Abstract 7 (oral session).
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TMC-114
TMC-114 is a PI with potent in vitro antiviral activity against wild-type and PI-resistant HIV-1.This study evaluated the activity,
safety, and pharmacokinetics of TMC114 with low dose ritonavir (TMC114/r) in multiple PI-experienced patients currently failing
a PI-containing regimen at study entry.The treatment protocol involved 3 different doses of TMC 114 given in a liquid PEG
formulation at doses of 300mg, 600mg, and 900mg of all given with 100mg Norvir.The study enrolled 50 patients with prior
treatment with 2-4 PIs (excluding low dose RTV), resistance to a median of 3 PIs and mean viral load of 4.3 log10 copies/mL and 305
cells/mm3.The pharmacokinetic analysis showed drug levels similar at trough for all 3 but peaks proportionally increased with dose.
The viral suppression with the 3 different doses was +.02 (control), -1.24 (300mg), -1.13 (900), and -1.5 (600) log10 copies/mL.There
was no correlation between baseline resistance and virologic outcome and the mutation pattern of this drug is unknown.The primary
adverse events were GI and CNS with diarrhea (32%) flatulence, headache, and dizziness.There was 1 hepatotoxicity and 1 grade 4
rash, but few details were available regarding these toxicities.
K Arasteh and others. First Clinical Results on Antiretroviral Activity, Pharmacokinetics, and Safety of TMC114, an HIV-1 Protease
Inhibitor, in Multiple PI-experienced Patients. Abstract 8 (oral session).
T-1249: EFFECTIVE IN FUZEON FAILURES
Fuzeon (enfuvirtide,T-20) is likely to be the first entry inhibitor to be FDA approved for the treatment of HIV infection. Fuzeon
and a similar peptide,T-1249, act by inhibiting the interaction of gp41 with the human cell and block viral fusion and entry. In a
study, 54 patients failing a Fuzeon containing antiretroviral regimen, as reflected by 2 consecutive plasma viral loads between 5,000
and 500,000 copies/mL, discontinued Fuzeon and substituted T-1249 (192 mg per day) 10 days.The median baseline viral load and
duration of prior Fuzeon treatment were 5.0 log10 copies/mL and 70 weeks, respectively. Of the 25 patients that were reported, 24
patients had resistance testing available and all demonstrated Fuzeon-resistance mutations and/or decreased phenotypic susceptibility
to ENF. After 10 days of T-1249 therapy, the median decrease in viral load from baseline at day 11 was 1.12 log10 copies/mL, with 63%
of patients achieving at least a 1.0 log10 copies/mL decrease in viral load (Figure 6).The patients who had been on a failing Fuzeon
regimen for ≤48 weeks had a better response than those who had been failing for >48 weeks (–1.6 vs. –0.94 log10 copies/mL). Finally,
T-1249 was well tolerated and there were no serious adverse events attributed to T-1249.
(Figure 9, inside back cover)
GD Miralles and others. T-1249 Demonstrates Potent Antiviral Activity over 10 Day Dosing in Most Patients who Have Failed a
Regimen Containing Enfuvirtide (ENF): Planned Interim Analysis of T1249-102, a Phase I/II Study. Abstract 14lb (oral session).
CCR5 Inhibitors
A presentation by Y. Iizawa and colleagues provided information regarding TAK-220, a CCR5 antagonist.They reported that while
the development of TAK-779 has been terminated due to local injection site reactions,TAK-220 appears to be a highly potent
inhibitor of R5 HIV-1 replication and is orally bioavailable. Data derived from studies using several CCR5-expressing cell lines and
PBMCs showed that TAK-220 inhibited the binding of RANTES and MIP-1? to CCR5-expressing cells with an IC50 of 3.5 and
1.4 nmol/L, respectively, but did not inhibit the binding of MIP-1? even at a concentrations of 10 mumol/L.TAK-220 appears to have
a high specificity for the CCR5 receptor since it did not inhibit ligand-binding to CCR1-, CCR2b-, CCR3-, CCR4-, or CCR7expressing cells even at a concentration of 10 mumol/L. Further,TAK-220 selectively inhibited HIV-1 infection mediated by CCR5
in PBMCs with mean EC50 and EC90 of 1.1 and 13 nmol/L, respectively and this was unaffected by addition of high concentrations
of human serum. Finally,TAK-220 administered orally to fasted rats and monkeys at a dose of 5 mg/kg had bioavailability of 9.5%
and 28.9 %, respectively, with the concentration of TAK-220 in lymph fluid of rats was about twice as high as that in plasma.
Data regarding another CCR5 inhibitor, UK-427,857, was presented by P. Dorr and colleagues. In vitro models indicate that
UK-427,857 blocks viral replication at the point of membrane fusion by preventing the binding of the viral envelope gp120 to the
co-receptor CCR5. Thus far it appears that this compound has “excellent” potency against isolates that utilise CCR5 for entry, with
an IC90 < 10 nM against 43 isolates from clades A-G, J, and O in PBMCs; however, UK-427,857 has no activity against CXCR4tropic viral isolates. UK-427,857 is non-competitive with regards to chemokine binding and does not induce intracellular signalling
or trigger receptor internalisation. Finally, while UK-427,857 and binds the receptor reversibly, it has a long binding half-life, which
may lead to “advantageous” pharmacodynamics.
In a study by Maeda and colleagues, the development of one potential CCR5 inhibitor, AK602, a spirodiketopiperazine derivative,
was explored. In the study, AK602 was intraperitoneally administered to hu-PBM-NOD-SCID mice and tested for its in vivo antiHIV activity.The investigators found that AK602 exerted potent activity against a wide spectrum of laboratory and primary CCR5HIV isolates including a multi-drug resistant HIV, and that this activity was associated with its CCR5-binding affinity and potent
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inhibition of CCR5-gp120 binding.The investigators also found that while some other CCR5 inhibitors tested thus far have been
found to fully blocked HIV infection as well as CC/CCR5 binding, AK602 had high anti-HIV activity but only partially suppressed
other CCR5 interactions, even at the highest possible concentrations. In addition, due to its high affinity for the CCR5 receptor,
once bound to CCR52+ cells AK602 remained on the cell surface for > 9 hrs after thorough washing and continue to block R5HIV infection upon delayed HIV exposure. Finally, preliminary pharmacokinetics indicate that oral delivery of the drug is possible.
Y Iizawa and others. Anti-HIV-1 Activity of TAK-220, a Small Molecule CCR5 Antagonist. Abstract 11 (oral session).
P Dorr and others. UK-427,857, a Novel Small Molecule HIV Entry Inhibitor is a Specific Antagonist of the Chemokine Receptor
CCR5. Abstract 12 (oral session).
K Maeda and others. AK602: A Novel HIV-specific Spirodiketopiperazine CCR5 Inhibitor Potent Against a Wide Spectrum of R5HIV. Abstract 10 (oral session).
TNX-355
TNX-355 is a humanized IgG4 anti-CD4 domain which acts by binding to the CD4 receptor and blocking HIV from doing so. In
earlier studies, it had potent anti-HIV-1 activity in vitro and studies in rhesus macaques and human peripheral blood lymphocytes
indicated that it is not immunosuppressive. A study was performed by Kuritzkes and colleagues to determine the safety and
preliminary anti-HIV activity of a single dose of TNX-355 in HIV-infected subjects.
The study enrolled 5 sequential cohorts of 6 HIV-1-infected subjects who received single IV doses of TNX-355 in an open-label
dose-escalation study (0.3, 1, 3, 10, and 25 mg/kg).The enrolled patients had a mean baseline CD4 count and viral load of 354
cells/mm3 and 5.1 log10 copies/mL. All were HAART-experienced and almost 2/3 of the patients were on failing HAART at entry
into the study.
TNX-355 administration led to mean peak decreases in viral load of -0.2, -0.68, -1.48, and -1.09 log10, copies/mL that occurred on
days 2, 4, 14, and 21 for the 1, 3, 10, and 25 mg/kg dose cohorts, respectively. Duration of complete CD4 cell coating with TNX355, ranged from 1–2 days at 1 mg/kg to 15–27 days at 25 mg/kg and this correlated with the day of viral load nadir. Finally,TNX355 was well tolerated and no significant adverse events were reported.
DR Kuritzkes and others. Safety and Preliminary Anti-HIV Activity of an Anti-CD4 mAb (TNX-355; Formerly Hu5A8) in HIVinfected Patients. Abstract 13 (oral session).
H E PAT I T I S C O - I N F E C T I O N A N D L I V E R D I S E A S E
Brian Boyle, MD
Cornell University Medical College, New York, NY
Pegylated Interferon Associated with Eye Disorders
In an open-label prospective trial conducted at the National Institutes of Health (NIH), HIV-HCV co-infected patients were treated
with PEG-Intron (Pegylated-IFN alfa-2b) and Rebetol (ribavirin) for 48 weeks.These patients had ophthalmologic evaluations at
baseline and at least every 3 months, which included visual acuity, threshold visual field testing, color vision exam, and indirect
ophthalmoscopy.
The investigators found that 7 of the 16 patients enrolled in the study (44%) developed ophthalmologic pathology. Six (6) developed
cotton wool spots (CWS) on their 12 week follow-up funduscopic examination, which “waxed and waned” while PEG-Intron therapy
was continued. In addition to CWS, 1 of these patients was found to have bilateral cataracts at 12 weeks, while another patient
subsequently developed a unilateral cataract. Finally, 1 patient developed a 50% decrease in color vision requiring cessation of PEG-Intron
therapy.This patient’s color vision improved over the 4 weeks following PEG-Intron discontinuation, but did not return fully to normal.
The authors conclude, “The incidence of serious ocular pathology associated with treatment with anti-HCV therapy may be very
high and is likely associated with peg-IFN.While HIV, hypertension, and diabetes mellitus are associated with these ocular lesions,
incident cases of CWS and cataracts occurred in pts with high CD4+ T-cell counts and developed soon after beginning peg-IFN
therapy. As with patients treated with ethambutol, medications toxic to retinal ganglion cells can cause lesions such as optic
neuropathy and result in color blindness or loss of vision. Our findings suggest a need for increased vigilance in monitoring pts
treated with peg-IFN for visual changes. Color vision testing should be a routine component of the standard examination, as loss of
color vision may be a harbinger of serious optic neuropathy.”
C Farel and others. Serious Ophthalmologic Pathology with Visual Compromise in HIV/HCV Co-infected Patients Treated with
Pegylated Interferon Alpha-2b and Ribavirin. Abstract 844 (poster).
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HCV-related Liver Damage Worse in HIV-HCV Co-infected Patients
In a study, that involved multiple centers in Europe, 492 HIV-HCV co-infected patients were assessed. These patients had a median
age of 35 years, 78.5% were male, 86% had been intravenous drug users (IDUs), and 25% admitted high alcohol intake (> 80 g/d).
The median CD4 count was 463 cells/mm3, with 32% on HAART and 22.5% on mono or dual HIV treatment.The median
estimated duration of HCV infection in these patients was 14 years, the median ALT elevation was 2-fold, and approximately 63%
and 69% of patients were HCV genotypes 1 or 4 and had an HCV RNA > 800,000 IU/ml, respectively.
The investigators found that advanced liver fibrosis (≥F2) was present in more than 51% of these patients. In the multivariate logistic
regression analysis, the 3 factors that were the best predictors of severe liver fibrosis (F3-F4) included duration of HCV infection > 15
yrs (OR 3.6), age > 20 yrs at the time of HCV infection (OR 3.3), and a history of high alcohol (OR 2.5). Further, 46% of the
patients estimated to have been infected with HCV for more than 15 yrs had severe liver fibrosis. Finally, severe liver fibrosis in these
patients was not associated with the CD4 count, HCV genotype, HCV viremia, gender, or use of HAART.
The authors conclude, “More advanced stages of liver fibrosis are seen in HIV-HCV co-infected patients than in HCV-monoinfected patients. Overall, up to 1/3 of those with elevated ALT levels show severe liver fibrosis (F3-F4), but increases significantly
with duration of HCV infection mounting up to 50% after 15 years of carrying HCV.Thus, treatment of HCV infection should be
not delayed unnecessarily given that lower response rates are seen in cirrhotics.”
L Martin-Carbonero and others. Histological Damage in Liver Biopsy Specimens from 492 HIV-HCV Co-infected Patients: A
European Collaborative Study. Abstract 830 (poster).
HIV-HBV Co-infected Patients Are at Increased Risk of Hepatic Decompensation
In a study conducted in Taiwan, where vertical HBV transmission is hyperendemic, 126 HBV patients and 455 non-HBV patients, with
similar CD4 count and viral load characteristics, were enrolled between June 1994 and June 2002. After a median observation of 2 years,
126 of the 581 enrolled patients developed acute hepatitis: 34.2% of HBV patients versus 18.5% of non-HBV patients (p = 0.0002).
Further, 8.7% of patients with HBV or HCV infection developed hepatic decompensation versus 0.5% of the patients without (OR,
18.392). At 4 weeks of HAART, responses to HAART were similar between HBV and non-HBV patients and the adjusted OR for
death in HBV and non-HBV patients was also similar.
The authors conclude, “Our data indicated that HIV and HBV co-infected patients treated with ART, especially HAART, had a
higher rate of acute hepatitis and hepatic decompensation than non-HBV patients. Risks for HIV progression and mortality and
virologic and immunologic responses to HAART were similar.”
WH Sheng and others. Impact of Chronic Hepatitis B Infection on Outcomes of HIV-1 Infected Patients Receiving HAART in an
Area Hyperendemic for Hepatitis B Infection: An Eight-year Prospective Observational Study. Abstract 823 (poster).
Immune Reconstitution Is Not Associated with Liver Disease Progression
In a study to evaluate the impact of HAART and immune restoration (IR) on liver histological status in HIV-HCV co-infected
patients, 33 patients initiating HAART were enrolled. The patients had a median CD4 cell count of 278 cells/mm3 and median levels
of HIV and HCV RNA of 4.4 log10 copies/mL and 6.2 IU/mL, respectively. A liver biopsy was performed both at enrollment and at
month 12 of HAART in 25 of the enrolled patients.
Nine were started on a protease inhibitor (PI), 14 on a non nucleoside reverse transcriptase inhibitor (NNRTI) and 2 on Ziagen
(abacavir), in addition to 2 nucleoside analogues (NAs). Histological progression (HP) was defined as an increase of ≥ 2 units in the
Knodell score and ≥ 1 unit in the Metavir score between biopsies. IR was defined as an increase in CD4 count of 100 cells/mm3 or a
doubling of CD4 count in the first 12 months of HAART.
During follow-up, 13 patients had IR, 19 patients had a HIV RNA load < 1.70 log10 copies/mL at month 12, and there was no change
in HCV RNA load. Of the 25 patients that had both liver biopsies, 5 had HP. Of the 5 with progression, 4 were alcohol consumers.
No relationship was found between the patients’ baseline characteristics or IR and HP. However, elevation of transaminases occurred
in 5 patients, with 1 case considered drug-related, 2 alcohol-related and 2 HCV-related.Transaminase elevation was significantly
associated with HP (80% with TE, 5% without TE, p = 0.002).
The authors conclude,“These data suggest that IR following the initiation of HAART is not associated with a progression of liver lesions.
However, careful monitoring of liver enzymes and alcohol suppression are highly recommended in HIV-HCV co-infected patients.”
H Zylberberg and others. Progression of Liver Histological Status in HIV Hepatitis C Virus Co-infected Patients Started on HAART:
A Prospective Study. Abstract 831 (poster).
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OT H E R S T U D I E S O F I N T E R E S T
Editors’ Note: Due to space limitations, we were not able to include in this print report reviews of a number of studies of interest presented
at the 10th CROI. Following is a list of the abstracts of those studies, by category. In addition, we have created a supplemental section in the
PDF version of Highlights from the 10th CROI that contains reviews of these studies and links to the abstracts.Access to this supplement on
10th CROI studies is available on the HIV and Hepatitis.com web site at http://www.hivandhepatitsis.com/PDF/10CROI.pdf
WOMEN’S AND CHILDREN’S ISSUES
By Ross Hewitt, MD
Transmission of HIV Through Breastfeeding
Two presentations shed new light on the issue of the infectiousness of breastfeeding. Researchers at Stanford and University of
Zimbabwe studied the differences between HIV viral load in the blood (plasma) and in the breast milk (abstract 96). A single dose
of nevirapine (Viramune) given to pregnant women at the onset of labor has been shown to reduce mother to child transmission by
50%. Yet 20% of these women develop resistance mutations to nevirapine at 6 weeks.
Postnatal transmission has been shown to occur via breast milk, but in some countries it is the only way to provide the infant with
adequate nutrition. So, these researchers analyzed plasma and breast milk samples at 0, 2 and 8 weeks post-delivery. Infants also
received nevirapine (NVP) prophylaxis for the first 6 weeks of breastfeeding.They obtained left and right breast milk samples and
averaged the viral load results, and looked for common NNRTI mutations.
The viral load in plasma samples averaged 4.3 log10 copies and did not change over the 8 weeks. Breast milk viral load averaged 2.1
log10 copies at week 8, consistently remaining about 2 logs lower than plasma.There was a significant correlation between the plasma
and breast milk paired samples. In 20 clusters of paired samples, 9 had the same patterns (6 with wild type HIV), and 11 women had
different patterns (5 had K103N in breast milk but not in the plasma, 6 had divergent patterns).
There was no relationship between specific mutations and viral load in the plasma. Breast milk had 13/20 (65%) with mutations
whereas plasma had 8/20 (40%, p=0.09, a trend). Among 33 infants, 4 were HIV+ (2 PCR+ at birth, 1 turned positive between
weeks 2 and 8, the last one was negative at week 24 but positive at week 32).Thus HIV-1 was detected in the majority of women’s
breast milk and differential selection and expression of NVP resistance in breast milk and plasma.
In an effort to understand transmission via breastfeeding, researches at the NIH reported results of the Breastfeeding and International
HIV Transmission Study (abstract 97). They conducted an individual patient data meta-analysis of mother to child (MCT)
transmission by taking data from a variety of clinical trials of MCT.
These trials had to be conducted in a population where breastfeeding was common and have minimum schedule of HIV follow-up of
at least 2 tests in the first 3 months of life.They defined children as definitely or provisionally infected or indeterminate status.They
defined early MCT as a positive HIV test before 4 weeks of life and late postnatal MCT as a positive HIV test after 4 weeks of life.
There were children with unknown timing of MCT with a positive test after 4 weeks of life but no baseline test result available. They
defined the length of time of breastfeeding by the date of cessation or last study visit or midpoint between known yes and no visits.
Data were included from studies in South Africa, Cote D’Ivoire, Burkina Faso,Tanzania, Kenya and Uganda. In total, 5871 women
were enrolled in these trials, of which 5059 delivered singleton infant. 4085 had breastfed and had HIV results. 993 (24%) of infants
were definitely infected, 314 (32%) of these were early MCT,
225 (23%) were late postnatal MCT and 454 (46%) were unknown transmission status. 3028 children had negative HIV test at 4
weeks of age or later, of these 223 became infected by late postnatal MCT, while 2805 remained uninfected. Breastfeeding occurred
for a range of 4 weeks to 37 months. Cases of late MCT occurred throughout the duration of breastfeeding, up to 18 months of
observation.The cumulative probability of late MCT was 7.3% after 6 months, 11.3% after 12 months, and 15.6% after 18 months.
Clinical factors associated with increased late MCT through breastfeeding were maternal CD4 cell count at the time of delivery:
CD4 count < 200 had an 8 fold increased risk, while mothers with a CD4 cell count 200-499 had a 3.7 fold risk compared to
mothers with 500 or more CD4 cell counts (p<0.001). Girls were 40% less likely to become infected via breast milk.This surprising
result was not easy to explain.
There was no difference in duration of breastfeeding between boys and girls. However there was no data on length of time for
breastfeeding or number of times a boy versus a girl was offered a breast each day. Over time, the risk of late MCT was about the
same for every day of breastfeeding.These researchers found that MCT via breast milk occurred in 24% and possibly as much as 42%
of MCT transmission, treatment of breastfeeding women imperative.
E Lee and others. Breast Milk Shedding of Drug-resistant Subtype C HIV-1 and Among Women Receiving Single-dose Nevirapine. Abstract 96 (oral).
JS Read and others. Late Postnatal Transmission of HIV in Breastfed Children: An Individual Patient Data Meta-analysis (The Breastfeeding and HIV
International Transmission Study). Abstract 97 (oral).
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CO-INFECTION WITH HIV AND HUMAN HERPES VIRUS 8 (HHV-8)
Researchers from Zambia are studying HHV-8, the virus now shown to cause Kaposi’s sarcoma (KS) in immunodeficient people
(abstract 98). They studied trends in mortality among mother-infant pairs. In children, KS has grown 10 fold and is now 2nd most
common opportunistic cancer in children in Africa.
In Lusaka, Zambia, 3150 pregnant mothers were randomly tested (provided they were not in labor) once during a 2-year study
period. Standard serologic tests were done for both HIV and HHV-8. The overall incidence of HIV infection was 30.8% while the
overall incidence of HHV-8 was 39.4%. Co-infection occurred in 13.9%, while neither infection was detected in 43.7%. There were
36 months of follow-up a subset of 1431 mother infant pairs with a co-infected incidence of 15.5%.
Among these pairs, there were 124 deaths, 51% were co-infected and 46% were HIV+ but HHV-8 negative. Compared a death rate
of 20.5/1000 children in controls (women negative for both), there were death rates of 230 deaths/1000 children in the co-infected
infants (11 fold higher rate) and 158 deaths/1000 children (7.7 fold higher rate) in the HIV+ infants. Infants who were HHV-8+
but HIV negative had the same death rate as the double negative infants. In the initial 6 months of follow-up few deaths occurred,
but then the death rate was steady from 6 to 36 months.
In co-infected infants, worsened mortality started to occur at 18 months but the cause is not clear. It does not appear to be due to
cessation of breastfeeding, or to be due to maternal deaths and orphaned children, as only 19 mothers died.The cause of death for 74
babies was known or estimated. 60% were due to respiratory tract infection, which was the highest. Other causes were malaria,
gastroenteritis, malnutrition and febrile illness. Co-infection with HHV-8 resulted in higher infant mortality for reasons that are not
yet understood, but could be the result of greater HIV replication in the presence of HHV-8. Analysis of HIV viral loads is
underway in this cohort.
M Mulindi and others. Trends in Mortality among HIV-1 and HHV-8 affected Mother-infant Pairs in Zambia. Abstract 98 (oral).
IMMUNE RESPONSES TO AN HIV VACCINE IN INFANTS BORN TO HIV-INFECTED MOTHERS
Researchers conducted a small phase I/II study of the HIV-1 ALVAC vaccine in the PACTG protocol 326 (abstract 99). This
abstract presented results from part 1 of the study, abstract 404 from part 2 (which used a different vaccine). As MCT is so rare now
in the US as a result of AZT use, the main goals were to see if immune responses from the vaccine could be seen in infants.
Whether such immune responses would actually be protective would have to be studied in a population where prenatal or perinatal
treatment is not available.
They used an attenuated canary pox virus that expresses HIV gag, envelope and protease proteins (p55, gp41, gp120, and p15). There
were 3 groups: low dose vaccine, high dose vaccine, and placebo.The vaccine was given at birth, 4, 8 and 12 weeks. 28 infants were
enrolled at 7 clinic sites, but there were only 9, 9 and 5 evaluable patients in groups, respectively. There were no grade 3 or 4 vaccine
associated adverse events. 2 infants had grade 2 fevers or fussiness in the high dose arm. In total 10% of doses wee associated with
fussiness but this occurred in the placebo group as well. Grade 3 anemia occurred in 11, 27 and 14% of the groups respectively but
was due to ZDV and intensive phlebotomy.
Proliferative immune to the vaccine responses in infants were seen as early as 6 weeks. Interesting the low dose vaccine group had
better immune responses than the high dose vaccine group, as well as better than placebo.3 placebo recipients had isolated positive
responses that were not repeated or consistent from weeks to week. The majority of responders were positive after 2 doses of vaccine.
Salivary IgA antibodies were also measured. At week 12, 33% were positive in the high dose vaccine group only. While conclusions
are restrained by small number of subjects and samples in immune response assays, these results are encouraging and warrant a trial in
a population to assess the ability to prevent MCT in the absence of antiretroviral therapy if it is not available.
E Mcfarland and others. A Phase I/II Study of the Safety and Immunogenicity of an HIV-1 ALVAC Vaccine in Infants Born to HIV-infected
Mothers. Abstract 99 (oral).
D Johnson and others. PACTG 326: A Phase I/II Study to Evaluate the Safety and Immunogenicity of Alvac HIV Vaccines Alone and with AIDSVax
B/B in Children Born to HIV-infected Mothers: Preliminary Results. Abstract 404 (poster).
GENETIC VARIATION AND NELFINAVIR LEVELS IN CHILDREN
Host genetics play an important role in metabolism of drugs.The gene MDR1 codes for p-glycoprotein (pgp), which is known to bind
to drugs and prevent them from being active.The genetic variation of MDR1 was studied in 71 children receiving nelfinavir (abstract
100) via PACTG protocol 382.
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Possible genotype results were C/C or C/T or T/T. 31 children were C/C (44%), 33 were C/T (46%) while 7 were T/T (10%).
African American children had a lower frequency of the T allele. The C/C genotype leads to normal pgp on the surface of cells
which in turn leads to lower drug concentration in plasma.The C/T genotype leads to low pgp on the surface of cells, which in turn
leads to higher drug concentration in plasma and in lymphocytes. Similar results have been seen in another study in HIV+ adults
and in cancer studies.
The levels of nelfinavir were twice as high in the C/T genotype compare to the C/C genotype (2.8 vs. 1.4 mg/ml, P<0.05). Even
more striking was the difference in viral suppression: 91% of C/T achieved HIV RNA < 400 copies vs. 59% of C/C genotype
patients. T/T genotype had weaker effects but small numbers precluded meaningful analysis. Having the T allele led to higher
plasma concentrations and lower clearance of Nelfinavir.This could be an explanation for ethnic differences observed in some studies,
since the T allele was highest in whites and Hispanics and lower in African Americans.
K Singh and others. Allelic Variants of MDR1 Alter Pharmacokinetics of Nelfinavir Resulting in Higher Drug Levels and More Rapid Decline in
Plasma HIV-1 RNA in Children. Abstract 100 (oral).
INFLAMMATION IN THE FEMALE GENITAL TRACT AND VAGINAL HIV VIRAL SHEDDING
Researchers at Emory University are conducting the Vaginal Ecology Study, which assesses the impact of various infections on vaginal
HIV viral load (abstract 101).Vaginal and plasma viral loads do correlate (r=0.64), and HIV is produced in vaginal secretions.
Surgically induced cervical inflammation increases HIV viral load in vaginal secretions temporarily without affecting plasma viral
load. In addition, there is variability of vaginal viral load that is not seen in plasma viral load over time. To ascertain why this
difference occurs, the studied inflammation in the vagina by measuring levels of cytokines in women without evidence of genital
tract infection.
They collected 1000 samples from 135 women.The samples were 10 ml vaginal lavages and they also did pap smears and colposcopy
and looked for genital pathogens (gonorrhea, chlamydia, bacterial vaginosis, candida, trichomonas, and herpes simplex virus).
They selected 54 samples where no genital infection was detected. 20 samples with plasma and vaginal viral loads were within 90%
correlation, 16 samples with high plasma viral load with undetectable vaginal viral load, and 18 samples had higher vaginal viral load
than plasma. In these women, their plasma viral load was the same between the groups, while the CD4 cell count was higher in
women with vaginal viral loads higher than plasma (344 vs. 188).
Interleukin 1-beta, tumor necrosis factor alpha and leukocyte scores (numbers of white bloods cells present) were all statistically
significantly lower in patients with lower than expected vaginal viral loads compared to the other two groups. Commonly diagnosed
genital tract infections did not explain higher or lower than expected vaginal viral loads based on plasma viral loads.They concluded
that subclinical (asymptomatic) inflammation is associated with vaginal viral load.They did not study the effect of the use of topical
products such as douching, however.
J Lennox and others. Subclinical Inflammation in the Female Genital Tract is Strongly Associated with Vaginal Viral Shedding Independent of Plasma
Viral Load. Abstract 101 (oral).
BONE DENSITY IN HIV-INFECTED WOMEN
Loss of bone during a woman’s life is an important health issue. Development of decreased bone mineral density (BMD) can result in
either osteopenia (mild loss) or osteoporosis (severe loss), increasing the risk of bone fractures in older age. Now that women with
HIV are expected to live much longer as a result of antiretroviral therapy, how are their bones affected? Two presentations sought to
address this issue.
There have been several reports of low BMD in HIV+ patients, and most of these studies have been in men. In addition, there are
many risk factors for osteopenia/osteoporosis in the general population, including smoking. Researchers at Tufts University are
studying BMD over time in HIV+ women (abstract 102).They presented results of the first baseline DEXA scans for 132 women.
The mean age was 39.6, and 84% smoked (compared to 20% in the general population of Massachusetts). Change in BMD was
analyzed for 42 women followed for 2 years. Absolute change in BMD was only – 0.5% (marginally different). Age, race or current
smoking was not associated with a change in BMD. There were only three significant factors: greater than 100 CD4 cell increase
(–0.35%, p=0.03), increase in albumin (+1.85%, p=0.05) and loss of >5% body weight before the 2 year interval (-1.8%, p<0.05) in
multivariate analysis.
When measuring T scores from DEXA scans (osteopenia –1 to –2.5, and osteoporosis <-2.5), 30% had osteopenia at baseline and 4
new cases developed over the two years. Recent smoking was marginally associated (p=0.06) when baseline and new cases were
combined. Osteopenia was 10-20 years faster in HIV+ women than seen in the general population. One third of Caucasian HIV+
women have osteopenia or osteoporosis, as they tended to have lower body weight. HAART use was varied in the study, and the
researchers were unable to look at specific drugs in relation to osteopenia in the study.
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Researchers from Montefiore Hospital in the Bronx studied protease inhibitor use and bone mineral density in older HIV-infected
women (abstract 103). As more HIV+ women experience menopause, reduced bone mineral density will likely become an
important clinical issue.
Women achieve peak bone density during age 30 to 40 and then lose bone (0.5% per year) in the 4th and 5th decades and increase
their loss to 2-5% per year after menopause. A variety of predictors of osteopenia in HIV are based mostly on men: elevated lactate
levels, lower weight, abdominal fat, HAART duration and use, lean body mass, NRTI duration, smoking, weight loss and steroid use.
DEXA scans were done in 200 HIV+ women and 205 HIV- women. Overall, many of the women in their population had very
high body mass index (BMI). In other words they were overweight or obese. HIV+ women, while still overweight, weighed 9 kg
(about 20 pounds) lower that HIV- women.The median CD4 count was 446 and median duration of antiretroviral therapy was 27
months. A difference of 0.03 g/cm2 or 3% (p=0.02) was observed but it is not clinically significant in terms of risk for fracture. 30%
of HIV+ women had osteopenia vs. 24% of HIV- women, but this was not statistically different.
Older age, white race, Hispanic ethnicity, low BMI and steroid use were assoc with osteopenia. Women who had used PIs for more
than one year had higher bone density (0.04 g/cm2, p=0.03) but this difference may not be clinically significant. Why use of PIs
was protective is not clear, since there are studies linking avascular necrosis of the femoral head to PI use.
D Jacobson and others. Low Bone Mineral Density in HIV-infected Women. Abstract 102 (oral).
J H Arnsten and others. HIV Infection and Protease Inhibitor Use are Not associated with Reduced Bone Mineral Density in Older HIV-infected
Women. Abstract 103 (oral).
POTENTIAL MICROBICIDES FOR USE IN VAGINAL PROTECTION AGAINST HIV INFECTION
Two presentations also focused on the growing field of microbicide research. To help prevent HIV transmission, a microbicide that can be
used and controlled by women would provide an important tool to reduce HIV infection beyond or in addition to the use of condoms.
Dutch researchers have identified mannose-specific lectins as potential novel microbicides against HIV (abstract 104). Plant lectins
are small proteins are able to bind carbohydrate structures—they are carbohydrate or sugar-specific. Lectins cause agglutination of red
blood cells due to the sugar coating that normally occurs. HIV is also sugar coated, with sugars attaching to gp120, its outer envelope
protein. Mannose-specific lectins demonstrate potent anti-HIV and anti-CMV activity.
These researchers studied two different lectins, GNA (derived from snow drop plants) and HHA (derived from amaryllis plants). In
vitro, both inhibit HIV-1, HIV-2, SIV and FIV (feline immunodeficiency virus).They inhibit X4 and R5 type HIV viruses and are
able to prevent fusion between HIV-infected and uninfected cells. When combined with other anti-HIV agents, they were additive
to synergistic as well as being active versus multi-drug resistant strains, including entry inhibitor resistance.
Lectins inhibit HIV at the level of virus entry but do not interference with cell surface binding of HIV receptor specific monoclonal
antibodies. Lectins bind to the mannose residues in gp120, have no effect or DNA, RNA or protein synthesis, do not cause
agglutination of RBCs and no stimulation of lymphocyte activation (not mitogenic) and are odorless and colorless.These
characteristics expect to make them quite safe for human use.
There are some lectin resistant strains that have to do with glycosylation sites on gp120. Systemic use would be problematic because
of development of antibodies to lectins. Lectins are very stable.They are not susceptible to proteases, but whether they are absorbed
is unknown. These researchers have not worked yet with HIV in the lower pH conditions seen in the vagina. Manufacturing lectins
will also be a challenge, as they cannot be produced recombinantly because of the mannose residues in bacterial systems used to
produce synthetic proteins such as insulin.
Researchers studied another novel microbicide that prevents intravaginal transmission of SIV in rhesus macaque monkeys (abstract
105).The compound is 2-hydroxy-propyl-beta-cyclodextrin (BCD), a large ring shaped starch molecule that removes cholesterol
from the cell membrane and from the viral membrane, rendering the viral particle noninfectious.
It has been shown to be safe in humans given up to 16 gm/day intravenously. In human cell lines, the 50% toxic dose was 8-12%.
BCD at 5% inhibited viral infection using X4 and R5 HIV isolates as well as SIV in these cell lines.When they cultured from the
BCD treated cell lines looking for residual viral infection, none was detected.They then studied intravaginal infection in the
monkeys. They premixed pathogenic SIV with BCD before inoculation and challenged 6 animals, 3 with BCD and 3 without BCD.
All 3 without BCD became infected, where as the treated animals did not.
They then pretreated some animals with BCD gel: 4 controls, 6 gel alone without BCD, and 6 with BCD gel. Only BCD: 1/6 BCD
gel animals became infected vs. 8/10 controls (p=0.0134).They then challenged the BCD treated animals a second time with BCD
and premixed SIV, and all 3 became infected—but it is not clear why.They are investigating this further.
D Schols and others. Mannose-specific Lectins as Novel Microbicides against HIV? Abstract 104 (oral).
Z Ambrose and others. A Novel Microbicide that Prevents Intravaginal Transmission of SIV. Abstract 105 (oral).
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CLINICAL TRIALS AND COHORTS
By Ronald Baker, PhD
Coviracil (emtricitabine) Maintains HIV Suppression in Once Daily Protease-Sparing Regimen
The experimental once daily NRTI Coviracil (emtricitabine; FTC) suppresses HIV to undetectable levels (< 400 copies/mL) when
taken as part of a once daily, protease inhibitor (PI)-sparing anti-HIV regimen. French researchers presented the new 48-week data at
the 10th Retrovirus Conference from the ANRS Alize trial, a Phase III clinical study.
The ANRS 099 Alize trial is an ongoing three-year, open-label, multicenter study involving 355 patients who at baseline had HIV
RNA less than 400 copies/mL while receiving PI-based antiretroviral therapy. The median duration of PI therapy was 35 months,
and the median CD4 cell count was 540 cells/mm3. Patients were randomized (1:1) to continue their stable PI-based regimen or
switch to an entirely once-daily regimen of Coviracil, the NRTI Videx (didanosine; ddI) and the NNRTI Sustiva (efavirenz).
“These data suggest that switching to a once-daily, PI-sparing antiretroviral regimen including emtricitabine is effective in
maintaining suppression of HIV infection,” said Dr. Jean-Michel Molina, who presented the data. “While both arms of the study
demonstrated comparable and durable antiviral response, the data may be of particular interest to physicians and patients who now
have the alternative to use a convenient once-daily HAART regimen with a low pill burden.”
Study Results
At 48 weeks, 94 percent of patients receiving the once-daily regimen of Coviracil,Videx and Sustiva had HIV RNA levels (viral load)
less than 400 copies/mL, compared to 92 percent randomized to continue therapy in the PI-based arm.
When all the samples were analyzed with a more sensitive assay at a central laboratory, the proportion of patients with HIV RNA less
than 50 copies/mL at week 48 was significantly higher in the once-daily treatment group.
Ninety-five percent of patients in the once-daily group achieved this result, compared to 87 percent in the PI-based arm.The median
CD4 cell count increase was comparable in both arms, with an increase of 21 cells/mm3 for patients on the once-daily regimen and
13 cells/mm3 for those in the PI-based group.
Patients switching to once-daily therapy with Coviracil,Videx and Sustiva experienced an increase of 7.7 mg/dL in fasting highdensity lipoprotein cholesterol (HDL – or “good” cholesterol), as compared to no change in the PI-based arm (p<0.0001).
Coviracil is being developed by Triangle Pharmaceuticals, which was acquired by Gilead Sciences in January 2003. Triangle
submitted applications for marketing approval of Coviracil for the treatment of HIV to U.S. and European regulatory authorities in
September and December of 2002, respectively.
JM Molina and others. Once-daily Combination of Emtricitabine, Didanosine, and Efavirenz vs Continued PI-based HAART in HIV-infected Adults
with Undetectable Plasma HIV-RNA: 48-week Results of a Prospective Randomized Multicenter Trial (ALIZE-ANRS 99). Abstract 551 (poster).
NEW DATA ON EXPERIMENTAL PI ATAZANAVIR
Atazanavir (ATV) is a once daily investigational protease inhibitor (PI) from Bristol-Myers Squibb that is now in Phase III
development for the treatment of HIV/AIDS. The FDA has granted priority review status to ATV, which will result in a decision on
approval of the drug on or before June 20, 2003.
The new data released at the 10th CROI in Boston suggest that I50L is the signature mutation. In addition, the Company presented
data suggesting that long-term therapy with atazanavir resulted in sustained virologic suppression and that patients switching to
atazanavir from the PI Viracept (nelfinavir) exhibited improved virologic suppression and a significant decrease in serum lipid levels.
Safety and Efficacy of Atazanavir in Patients Previously Treated with Viracept or ATV
ATV is a potent, well-tolerated azapeptide protease inhibitor (PI) in Phase III development that does not produce clinically relevant
elevations in serum lipids.
The objectives of the Phase II trial BMS AI424-044 are to assess the long-term efficacy and safety of ATV beyond 72 weeks and to
assess efficacy and safety in patients switched from NFV?ATV.
Three hundred sixty-nine patients completing a Phase II dosing trial (BMS study AI424-008) were eligible for the open-label switch
trial (BMS study AI424-044), which looked at the safety and efficacy of atazanavir. After 72 weeks, patients were eligible to switch
from a nelfinavir-based regimen to one containing atazanavir (400 mg once-daily), ZERIT® (stavudine) (40 mg twice-daily) and
3TC (150 mg twice-daily). Sixty-three subjects were switched from nelfinavir to atazanavir, and patients who were previously on
atazanavir in the Phase II study remained on treatment.
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Twenty-four weeks following a switch from nelfinavir to atazanavir, 86 percent of the 63 subjects had HIV-RNA less than 400
copies/mL, compared to 71 percent prior to the switch at study entry (ITT analysis). In addition, 59 percent of patients in the
nelfinavir/atazanavir switch arm had HIV-RNA less than 50 copies/mL, compared to 50 percent of patients at study entry (ITT analysis).
Patients in the nelfinavir/atazanavir switch arm also experienced significant decreases in total cholesterol, LDL-C and triglyceride
levels toward pre-antiretroviral treatment levels. Patients switched from nelfinavir to atazanavir experienced median reductions in TC
from 202 mg/dL to 169 mg/dL; reduction in fasting LDL from 132 mg/dL to 99 mg/dL and reduction in fasting TG from 127
mg/dL to 102 mg/dL.
ATV 400 mg
(n=139)
044 Entry
Response Criteria†
<400 c/mL
As treated
ITT
<50 c/mL
As treated
ITT
NFVkATV
(n=63)
Week 24
044 Entry
Observed/Evaluable (%)
Week 24
101/129 (78)
111/133 (83)
44/60 (73)
54/62 (87)
—
111/139 (80)
—
54/63 (86)
63/129 (49)
80/133 (60)
30/60 (50)
37/62 (60)
—
80/139 (58)
—
37/63 (59)
Median cells/mm3
CD4
TC
Fasting LDL-C
Fasting TG
472
180 [129]
110 [60]
105 [103]
556
543
Median mg/dL [n]
176 [128]
202 [56]
105 [86]
132 [33]
104 [110]
127 [47]
584
169 [56]‡
99 [40]‡
102 [52]‡
TC = total cholesterol, LDL-C = low-density lipoprotein cholesterol,TG = triglycerides
† = As treated analysis, results maintained through 108 weeks from start of AI424-008. ITT analysis for 008/044 selected cohort
‡ = P<0.0001, NFVkATV, mean % change, week 24 vs entry
150L Is the Signature Mutation for Atazanavir and Results in Increased Susceptibility to Other PIs
Prior studies have shown that ATV displays a distinct resistance profile relative to other PIs using a panel of 950 clinical isolates. This
study confirms the identity of I50L as the signature change for ATV and characterizes its impact on susceptibility to ATV and other PIs.
Overall, ATV resistance was infrequently observed in all studies. Of the 19 isolates recovered from patients experiencing virologic
failure on regimens containing ATV as the sole PI, all (100%) contained the unique substitution I50L.
Of these 19 isolates, 11 (58%) also contained an A71V substitution, 5 (26%) had a G73S and 4 (21%) had K45R changes. Isolates
were from patients treated 24-81 wk and the median Fold Change (FC) in ATV susceptibility among these isolates was 8.8 (range 3.5
to 36.6).
Resistance appears to be specific for ATV, since the susceptibility to all 6 marketed PIs increased and virtually all had FCs of <1. Of
particular interest were those isolates that were resistant to multiple PIs upon treatment initiation and exhibited increased
susceptibility or resensitization coincident with the emergence of the I50L substitution.
The distinct resistance profile of atazanavir may help preserve future treatment options with other marketed protease inhibitors,” said
Richard Colonno,Vice President, Infectious Diseases Drug Discovery, Bristol-Myers Squibb. “If approved, atazanavir could provide
physicians with additional flexibility in treating their patients should resistance to atazanavir occur.”
Studies on recombinant viruses also showed that the I50L substitution was indeed responsible for this unique resistance phenotype.
In contrast, isolates resistant to atazanavir at study entry failed to induce an I50L change and, subsequently, displayed higher resistance
levels to both atazanavir and other protease inhibitors.
R Colonno and others. Emergence of Atazanavir Resistance and Maintenance of Susceptibility to Other PIs is Associated with an I50L Substitution
in HIV Protease. Abstract 597 (poster).
R Murphy and others. Long-term Efficacy and Safety of Atazanavir with Stavudine and Lamivudine in Patients Previously Treated With Nelfinavir or
ATV: 108-week Results of BMS Study 008/044. Abstract 555 (poster).
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LIPODYSTROPHY, METABOLIC COMPLICATIONS AND ADVERSE DRUG REACTIONS
By Ronald Baker, PhD
Body Composition and Antiretroviral Use in Older HIV Positive Women
Fat loss (lipoatrophy) and fat accumulation (lipohypertrophy), are complications in HIV positive patients. Abnormal body fat
distribution may result from the use of antiretroviral drugs, but could also be due, at least in part, to non drug-related factors.
Most studies of fat distribution in HIV positive patients have relied on subjective criteria and have focused predominantly on men. In
the current study, researchers at two medical centers in New York City analyzed regional body composition in 105 HIV positive and
120 HIV negative women, and assessed the impact of antiretroviral use and non drug-related factors on regional adiposity.
T-tests were used to compare measurements between groups, and linear regression was performed to assess factors independently
associated with fat distribution. Mean age was 45 ±5 yrs; 45% were African American, 36% Hispanic and 15% white. Among HIV
positive women, median CD4+ count was 464 cells/mm3; 68% reported protease inhibitor (PI) use and 61% stavudine (D4T) use.
Body composition measurements are shown in the table below. Body mass index (BMI) and percentage body fat were decreased and
percentage lean body mass increased in the HIV positive women compared with HIV negative women.
Among HIV positive women, percentage truncal fat and truncal fat/extremity fat ratio were increased and percentage extremity fat
decreased in women with PI use compared with PI-naive women, and in women with D4T use compared with no D4T use.
African Americans had decreased percentage truncal fat and truncal fat/extremity fat ratio and increased percentage extremity fat
compared to non-African Americans.
D4T use and African Americans race remained significantly associated with African Americans truncal fat, African Americans
extremity fat, and truncal fat/extremity fat ratio after controlling for age, CD4 count, and PI use on multivariate analyses.
Conclusions: HIV is associated with decreased BMI and African Americans body fat, but not with fat distribution in older women.
Among HIV positive women, D4T use and non-African Americans race are independently associated with increased truncal fat and
decreased extremity fat, while PI use is not.
HIV- (120)
HIV+ (105)
HIV+ PI- (33) HIV+ PI+ (72) HIV+ D4T- (40) HIV+ D4T+ (64)
BMI (kg/m2)
31.7 ±7.3
28.4 ±6.3*
28.5 ±7.6
28.3 ±5.6
28.6 ±8.1
28.2 ±4.9
Body fat (%)
40.1 ±8.4
35.8 ±8.7*
35.3 ±12.1
36.0 ±6.8
36.1 ±10.1
35.7 ±7.9
Lean body mass (%)
56.7 ±7.9
60.8 ±8.4*
61.2 ±11.6
60.6 ±6.5
60.4 ±9.6
61.0 ±7.6
Truncal fat (%)
50.9 ±5.6
52.0 ±7.6
49.7 ±8.0
53.1 ±7.2*
48.6 ±6.6
54.0 ±7.4*
Extremity fat (%)
46.0 ±5.5
44.6 ±7.4
46.8 ±7.6
43.6 ±7.2*
48.0 ±6.2
42.6 ±7.4*
Trunk fat/extremity fat
1.1 ±0.3
1.2 ±0.4
1.1 ±0.4
1.3 ±0.4
1.0 ±0.3
1.3 ±0.4*
A A Howard and others. Body Composition and Antiretroviral Use in Older HIV-infected Women. Abstract 735 (poster).
Ultrasound-Assisted Liposuction for Treatment of HIV-related Buffalo Humps
The incidence of fat accumulation and fat loss among patients with HIV on HAART continues to increase.These often disfiguring
body shape changes may cause feelings of low self-esteem and other emotional problems.
In cases of the so-called “buffalo hump” (BH), an enlargement of the dorsocervical fat pad, neck pain and sleep apnea may
accompany the depression and anxiety resulting from the disfigurement.
The cause(s) of BH are not known and no therapeutic intervention has proven universally effective. Ultrasound-assisted liposuction
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(UAL) is one treatment option for BH.The current study retrospectively evaluates the outcomes of UAL in a US urban clinic.
The charts of 10 patients with the following characteristics were reviewed: 6 men, 4 women; 8 Caucasians, 2 African-Americans;
mean age 46 yrs; mean duration of HIV diagnosis prior to BH: 8.1 yrs; CDC class C (5), B (3), (2).
All the patients were ARV-experienced for a mean of 5.4 yrs prior to BH; mean number of prior agents: 3.3-NRTIs, 1-NNRTI, and
1.3-PIs.
The mean CD4 nadir was 139 cells/mm3 (8-497) with 7 being < 200 cells/mm3; mean current CD4 count 400 cells/mm3 (111,044); mean current viral load 10,445 copies/ml (< 50-95,561) with all but one < 5,000 copies/ml; 9/10 of the patients were
receiving NRTIs at the time their BH was diagnosed, 5 were receiving a PI or boosted PI, and 3 were receiving Sustiva (efavirenz).
Metabolic complications present included dyslipidemia (n = 9) and dysglycemia (n = 4). Eight (8) pts had other manifestations of fat
maldistribution in addition to their BH.
Treatment Outcomes
All 12 UAL procedures were well tolerated. BH did not fully resolve in any of the 10 patients, but all had at least partial reduction in
BH size. However, BH recurred in 5, and 2 underwent the procedure again. Following the procedure, two of the patients developed
pneumococcal bacteremia at 1 and 3 months post UAL.
PJ Piliero and others. Ultrasound-assisted Liposuction of HIV-related Buffalo Humps. Abstract 724 (poster).
Protease Inhibitors May Increase Risk of Cardiovascular Disease in HIV-infected Patients
Results of numerous prior studies conclude that protease inhibitors (PI) are associated with hyperlipidemia, insulin resistance, fat
redistribution, hypertension (HTN), and diabetes mellitus (DM).These risk factors in turn are established risks for cardiovascular
disease (CVD).
The aim of the current retrospective analysis was to quantify the association between PI exposure and subsequent CVD events.The
study population was derived from a prospectively collected database of HIV positive patients from eight clinical sites in the US.
Patients were followed to the first CVD event (myocardial infarction, angina, coronary artery disease, PTCA/CABG, Stroke,TIA,
PVD) or censored at end of study follow-up.
Co-variates included age (18-34, 35-49, 50-64, 65+) gender, race (white, black, other), weight, PI exposure (ever vs never),
hyperlipidemia, CVD, DM, HTN, smoking (current, past, never), IV drug (IVDU), and cocaine use. Hyperlipidemia was defined
according to current ATPIII guidelines, diagnosis of hyperlipidemia, or use of lipid lowering therapy. Diagnoses or treatment defined
DM and HTN.
A total of 6,711 pts were studied with a median follow-up of 2.8 yrs. Baseline demographic and risk factor distributions were as
follows: males 86%, whites 59%, blacks 28%, mean age 39 yrs, mean weight 169 lbs, PI use 77%, current smokers 37%, past smokers
14%, cocaine use 1.9%, HTN 5.2%, DM 1.1%, pre-existing CVD 0.1%, and pre-existing hyperlipidemia 6.5%.
The CVD-event rate was 1.64% for pts in the PI group and 0.52% for non-PI pts. Unadjusted hazard ratio (HR) for PI exposure was
2.1.The adjusted HR for PI use was 2.
When only CAD events (AMI, Angina, coronary heart disease, PTCA/CABG) were modeled, the event rates for PI and non-PI use
were 1.31% and 0.39%, respectively; unadjusted HR was 2.3; and adjusted HR for PI exposure was 2.1.
Conclusions: PI exposure was consistently found to double the risk of developing both CVD and CHD events in this analysis.
Longer-term follow-up data will be needed to confirm these findings. Physicians should consider use of HAART regimens that
minimize this risk.
U Iloeje and others. Protease Inhibitors May Increase Risk of Cardiovascular Disease in HIV-infected Patients. Abstract 746 (poster).
Fat Redistribution and Metabolic Abnormalities in HIV-infected Children and Adolescents in Europe
Little is known about the characteristics and prevalence of and risk factors for lipodystrophy in children and adolescents. Researchers
in the UK and Italy sought to estimate the prevalence of both clinical and biochemical signs possibly relating to lipodystrophy in
HIV-infected children in Europe.
Over a 2-3 month period, data on all infected children aged 3-18 yrs attending the participating 23 pediatric HIV clinics was
collected including socio-demographic, clinical, immunological and antiretroviral therapy (ART) variables and laboratory assessments
of metabolic function.
The analysis included 374 children (196 female, 176 male), with a median age of 5 yrs. Most (276, 74%) children were currently on
triple combination antiretroviral therapy.
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A total of 106 (28%) children had 1+ clinically determined sign of fat redistribution, of whom 24 (23%) had signs of peripheral
lipoatrophy alone (fat wasting of the face, arms, legs or buttocks), 39 (37%) signs of central obesity alone (fat accumulation in the
abdomen or dorsocervical spine, or breast enlargement), and 43 (41%) combined lipodystrophy.
The most common sites of fat redistribution were the abdomen (21% of 374 children), face (12%), legs (12%), and arms (11%).
Dyslipidemia was present in 37% (101/270) children, of whom 42% (42/101) also showed fat redistribution. Female gender, CDC
clinical stage C and current use of triple combination ART were significantly and independently associated with any fat redistribution
(and also for lipoatrophy and central obesity individually. Additionally, age > 12 yrs was significantly associated with development of
central obesity.
Children on triple combination ART were at a substantially increased risk of both fat redistribution and dyslipidemia compared with
all other children. Duration of any ART was not significantly associated with fat redistribution or metabolic abnormalities.
Conclusions: The investigators conclude, “We show that between a 1/4 and a 1/3 of children could be taken to have signs of
lipodystrophy. Our broad approach allowed us to describe the full range of signs of fat redistribution and metabolic abnormalities and
their risk factors in children and adolescents and will be helpful in informing the development of a clinical definition.”
A Vigano and others. Fat Redistribution and Metabolic Abnormalities in HIV-infected Children and Adolescents in Europe. Abstract 774 (poster).
Increased Healthcare Costs for HIV Patients with Lipodystrophy
Patients without HIV infection who have diabetes and hyperlipidemia experience higher healthcare costs. In this retrospective study
presented at the 10th CROI, the researchers evaluated whether HIV positive patients who develop similar disorders on HAART also
incur higher healthcare costs.
The investigators looked at patient records from an ongoing observational database at the HIV clinic at the University of Alabama at
Birmingham.
Patients were included if they were seen between 3/1/00-3/1/01, had a CD4 count on 3/1/00 ±90 days, and had at least one
follow-up visit or hospitalization between 6/1/00-3/1/01.
Patients who developed lipodystrophy (LD) during the year (n = 35) were excluded. LD was defined as: LD, diabetes mellitus,
hypercholesterolemia, hypertriglyceridemia, or hyperlipidemia on problem list; or non-fasting serum glucose > 200 mg/dL,
cholesterol > 240 mg/dL, or triglycerides > 400 mg/dL.Those meeting any of these criteria before receiving HAART were
excluded.
N = 551. 77% Male, 58% Caucasian, 62% MSM. Median age 40 years, median baseline CD4+ cell count 365 cells mm3, viral load
287 copies/mL.
Mean costs were determined using 2001 Medicare reimbursement rates by CPT and DRG codes. Medication costs were based on
average wholesale price.
Cost Category
LD (n=299)
NonLD (n=252)
P value (ANOVA)
Hospitalization
$2,150
$3,668
0.41
Home Health
$125
$9
0.47
Physician
$379
$312
0.01
Imaging
$105
$69
0.13
Procedures
$240
$165
0.10
Laboratory
$876
$722
<0.0001
ART
$11,369
$9,222
<0.0001
NonART
$4,855
$3,532
0.0019
Total
$20,099
$17,698
0.05
After adjusting for CD4 count, patients with LD have significantly increased healthcare costs compared to those without LD due to
increased physician, laboratory, ART, and non-ART costs.
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Conclusions: Total healthcare costs of HIV pts with LD significantly exceed those without LD primarily due to greater physician,
laboratory, and medication costs.
M Mugavero and others. Increased Cost of Lipodystrophy in HIV Patients Due to Higher Physician, Laboratory, and Medication Costs. Abstract 740
(poster).
Bone Loss and Fat Loss Are Closely Related in HIV Patients on HAART
A number of previous studies have demonstrated that HIV positive individuals on HAART regimens are at increased risk for
developing lipoatrophy (fat loss) and bone loss.The aim of the present longitudinal cohort study was to determine whether there is a
direct association between the fat mass and bone changes.
The study population consisted of 86 HIV positive patients (73 males, 13 females; 44 PI-experienced, 42 PI-naive) aged 37.3 ±8.6
years.Whole body composition was determined by DEXA; bone mineral content (BMC), fat (FAT), and lean body mass (LEAN)
were evaluated for whole body as well as regionally.Two (2) body-composition analyses were obtained for each patient.The second
measurement was performed 30 months after the first.The degree of association between the bone and fat mass changes was tested
using the Pearson’s correlation coefficient.
Mean BMI on study entry was 24.40 ±3.17 kg/m2, and mean CD4+ count was 362 ±228 cells/mm3. Patients exhibited a significant
decrease in their body weight.Weight loss was due exclusively to FAT, while LEAN was not affected. Fat loss was statistically
significant in the arms and legs, but not in the trunk. A significant decrease in the whole body BMC was also evident. Analysis
showed a statistically significant positive correlation between the fat and bone mass changes (r = 0.357, p < 0.001).
Conclusions: “In a cohort of HIV-infected individuals receiving antiretroviral treatment, a positive correlation between the bone and
fat mass loss was observed.This finding possibly suggests that common pathogenetic mechanisms contribute to lipoatrophy and
osteopenia/osteoporosis in HIV-infected patients.”
G Tsekes and others. Bone Loss Is Closely Related to Fat Loss in HIV-infected Patients Receiving Antiretroviral Treatment. Abstract 764 (poster).
HEPATITIS B, HEPATITIS C AND HEPATITIS CO-INFECTION WITH HIV
By Ronald Baker, PhD
Hepatitis C Virus Load Measured Prior to HIV Seroconversion Is Not Associated with Subsequent HIV Disease
Progression in Injection Drug Users
In some studies, the HCV RNA level determined following HIV seroconversion has been associated with progression to AIDS
and/or death. However, the relationship of the HCV RNA level prior to HIV seroconversion (SC) and subsequent HIV disease
progression is unknown.
HIV disease progression and survival were analyzed prospectively in the ALIVE cohort of active and former injection drug users
(IDUs). HCV-antibody-positive, HIV antibody-negative persons who acquired HIV infection before 1/1997 were studied. Using
longitudinal data, including blood tests, clinical outcomes (e.g., AIDS and death), the researchers analyzed 225 HCV seropositive, HIV
seroconverters: male, 76%; median age at HIV SC, 35.9 yrs; Black, 94%.
The median duration of follow-up was 4.9 yrs during which time only 11% received HAART. Progression to AIDS, AIDS-related
death, and CD4 cell count < 200 cells/mm3 was observed in 53 persons (24.6%), 31 persons (13.7%), and 104 persons (46.6%),
respectively. HCV RNA level determined before HIV SC was not associated with progression to AIDS, AIDS-related death, or CD4
cell count < 200 cells/mm3.
The authors conclude, “In this cohort, the HCV RNA level measured prior to HIV seroconversion was not associated with
subsequent progression to AIDS, AIDS-related death, or CD4 cell decline. Further research is needed to determine the relationship of
hepatitis C infection and HIV disease progression.”
M Sulkowski and others. Hepatitis C Virus Load Measured Prior to HIV Seroconversion is not Associated with Subsequent HIV Disease Progression
in Injection Drug Users. Abstract 833 (poster).
Final Results of 68-Site Trial of Daily vs Weekly Interferon Plus Ribavirin in Treatment-Naïve Patients Co-infected with HIV
Hepatitis C virus (HCV) infection may cause substantial morbidity and mortality in individuals with HIV infection. Few studies have
evaluated the safety and efficacy of combination interferon (IFN)/ribavirin (RBV) in HIV-HCV co-infected patients.
In this multicenter (68 sites), randomized, controlled trial, researchers assessed the efficacy and safety of RBV in combination with
daily (QD) or 3 times weekly (TIW) IFN for chronic HCV in HIV co-infected patients.The final (48 week) results were presented
at the 10th CROI in Boston.
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The trial compared IFN 3 mIU QD vs TIW + RBV (800 mg/d) for 48 wks in 180 IFN/RBV-naïve, HIV-infected pts with
compensated liver disease on stable antiretroviral therapy (ART).
Those with active OIs, active substance abuse, severe psychiatric disease, or CD4 < 100/mm3 were excluded. Efficacy (HCV RNA)
was assessed at treatment (Tx) wks 12, 24, and post-Tx wk 24. Safety assessments included incidence of AEs, rate of dose
modification/discontinuation. CD4 count and HIV RNA levels were monitored.
Patient characteristics (QD/TIW) were as follows: mean age, 44/44 yrs; male, 78/74%; Caucasian, 58/44%; genotype 1, 78/80%; ART,
89/82%, mean CD4, 551/533/mm3, mean HIV RNA, 1,531/3,698 c/mL.
A total of 162 pts (79 QD/83 TIW) were eligible for the intent-to-treat (ITT) analysis.
Discontinuation for AEs was similar in both groups; however, more pts taking QD IFN completed 48 wks of Tx (30.0% QD vs
12.0% TIW, p = 0.0003) since 43.4% of pts taking TIW IFN stopped due to virologic failure compared to only 20.2% of those taking
QD IFN.The trial participants were administered interferon alfa-2b (Intron A) plus ribavirin (Rebetol) from Schering-Plough.
HCV RNA response (undetectable < 600 IU/mL) was assessed at week 12 (EVR) and wk 24 post-Tx (SVR).
On-treatment results: EVR QD 44.3%/TIW 17.1% (p = 0.004); SVR: QD 42.9%/TIW 28.% (p = 0.03). Intention to treat results:
EVR: QD 32.9% /TIW 13.3%; SVR: QD 9.3%/TIW 4.3% (note: missing data = failure).
No significant effect was seen on HIV RNA levels; absolute CD4 fell in both groups (QD > TIW), but no decrease in CD4% was
observed. EVR was a strong predictor of SVR (90.9% sensitivity, NPV 93.9%).
Conclusions: Both EVR and SVR were significantly greater in HIV-infected pts taking QD IFN/RBV than in those taking TIW
IFN/RBV.The adverse event rate was similar in both groups; however, more pts taking QD IFN completed treatment. However, the
attrition rate for both Treatment arms was substantial, and the intention-to-treat SVR rates observed were low.
M Sulkowski and others. Final Results of Daily vs 3-times Weekly Interferon alpha-2b plus Ribavirin for the Treatment of Hepatitis C Infection in
HIV-infected Persons: A Multi-center, Randomized Open-label Study. Abstract 841 (poster).
Prior HBV Infection Protects Against Fibrosis in HIV-HCV Co-infected Patients with CD4 Counts Less Than 200 Cells/mm3
Individuals co-infected with HIV-HCV will often have antibodies to the hepatitis B core antigen, indicating their prior exposure to
HBV. A persistence of HBV in these patients may produce a harmful effect on liver histology.
In the current study, conducted researchers at the Groupe Hopital Pitie-Salpetriere in Paris, France, researchers evaluated the
relationship between anti-HBc status and histologic lesions in HIV-HCV co-infected patients.
The investigators evaluated liver histology in 145 treatment-naïve, hepatitis B surface antigen-negative, HIV/HCV co-infected pts.
They then determined the impact of anti-HBc-positivity on necro-inflammatory activity and progression to septal fibrosis (F2-F4) via
multivariate analyses.
The median age was 36 yrs, 75% were male, and 78% were anti-HBc-positive. Serum ALT and necro-inflammatory activity did not
differ between anti-HBc-positive and negative patients. However, progression to septal fibrosis was slower in anti-HBc-positive
patients, particularly those with CD4 counts less than 200 cells/mm3.
After controlling for alcohol consumption, necro-inflammatory activity, steatosis, CD4 count, and HCV genotype, Cox proportional
hazards analysis identified anti-HBc-positivity as an independent protective factor against progression to septal fibrosis.The protective
effect of anti-HBc positivity persisted when adjusted for lamivudine therapy, suggesting the involvement of mechanisms independent
of HBV replication.
Conclusions: Prior HBV infection does not have a detrimental impact on histologic lesions in HIV-HCV-co-infected pts. “A
potential protective effect of anti-HBc positivity on fibrosis progression, particularly in those with advanced immunosuppression,
warrants confirmation,” concluded the investigators.
Y Benhamou and others. The Impact of Prior Hepatitis B Virus Infection on Histologic Lesions in HIV and Hepatitis C Virus Co-infected Patients.
Abstract 822 (poster).
12-Week Response Predicts Which HIV-HCV Coinfected Patients Will Not Benefit from Continued Pegylated Interferon + Ribavirin
Treatment with pegylated interferon plus ribavirin is producing an average 60% “cure” rate among HCV-monoinfected individuals.At the
same time, liver disease caused by HCV infection is a growing cause of concern among HIV-HCV coinfected patients and their caregivers.
The response rates to combination therapy with pegylated interferon/ribavirin appears to be lower in HIV-HCV coinfected patients,
while the side effects of treatment are more frequent.This may be due to the interaction between ribavirin and the nucleoside
analogue drugs.
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In HCV-monoinfected patients, the treatment response at 12 weeks or “early virological response” (EVR) predicts which patients will
not benefit from continued therapy with pegylated interferon/ribavirin. A reduction in HCV RNA > 2 logs at 12 weeks predicts a benefit
of continued benefit. No data among coinfected patients are available on the validity of this approach.
In the present study, investigators evaluated 89 HIV-HCV coinfected patients who completed a course of anti-HCV therapy.
Pegylated interferon was administered to 63 and standard interferon to the remaining patients, all at standard doses. All received
ribavirin 400 mg twice daily.
Overall, sustained virological response (SVR) occurred in 29 patients. End-of- treatment response with further relapse was seen in 15.
The remaining 45 were non-responders.
A drop in HCV RNA > 2 logs occurred in 38 (43%) and 52 (58%) of patients at 4 and 12 weeks, respectively. Of those subjects, only
18 (48%) and 29 (56%), respectively, reached SVR. In contrast, SVR occurred in 11 (38%) and 0 patients who did not show a > 2 log
drop In HCV RNA at weeks 4 and 12, respectively.
Thus the negative predictive value (NPV) was 100% at week 12. There were no significant differences between HCV genotypes, baseline
HCV RNA and use of either pegylated or regular interferon.
In patients with HCV genotype 2-3, a high rate of relapse in early responders was noted, which suggests that extending treatment
beyond 6 months might have provided a higher SVR rate for them.
The investigators conclude, “The use of an early time decision point at 12 weeks to identify which subjects will not benefit from
continuing anti-HCV treatment is valid for HIV positive patients. However, a delayed clearance of HCV RNA in early responders
with HIV might account for a higher relapse rate when treatment is stopped prematurely -e.g., 6 months in genotypes 2-3.”
M Perez-Omeda and others. Predictive Value of Early Virological Response (12 Weeks) to Pegylated Interferon plus Ribavirin in HIV-HCV Coinfected Patients. Abstract 842 (poster).
Tenofovir and Lamivudine Combination Therapy Compared to Lamivudine Alone for HBV in Therapy-naive
HIV/HBV Co-infected Patients: 48-week Interim Results
Tenofovir DF (TDF) shows strong activity against both wild type and lamivudine (LAM)-resistant hepatitis B virus (HBV). Study 903
is an ongoing, randomized, double-blind, active-controlled 144-wk trial of TDF 300 mg qd vs stavudine 40 mg bid in combination
with efavirenz 600 mg qd and LAM 150 mg bid in 600 HIV treatment-naive adults. Stavudine and efavirenz have no reported antiHBV activity.
Eleven (11) HIV/HBV co-infected patients (pts) from Study 903 (5 TDF + LAM and 6 LAM) with baseline serum HBV DNA ≥ 6
log10 copies/mL and with wk 48 data, were included in this as-treated analysis.
Baseline mean characteristics: age 38 yrs; plasma HIV RNA 4.8 log10 copies/mL; CD4 count 204 cells/mm3; serum HBV DNA 8.6
log10 copies/mL; serum ALT 86 IU/L (2.0 x ULN).There were no significant differences in baseline characteristics.Ten (10) pts
were HbeAg+ and male.
Serum HBV from pts with detectable (> 1000 copies/mL) HBV DNA at wk 48 were genotypically analyzed for the development of
LAM-resistance mutations (LAMR).The 4 pts who developed the LAMR showed a mean increase in HBV DNA of 2.3 log10 from
their response nadir.
Results
At week 48
TDF + LAM n = 5
LAM n = 6
Mean change HBV DNA (log10 copies/mL)
-4.70
-2.95
HBV DNA < 1000 copies/mL
4
1
LAMR (YMDD mutant)
0/1
4/5
HBeAg seroconversion
1
1
Mean change ALT level (IU/L)
-55
-22
ALT > 5x ULN (weeks 0–48)
2
4
p > 0.05, for all comparisons
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The investigators conclude, “The combination of TDF + LAM appears to more effectively suppress both HBV replication and
LAMR development compared to LAM alone. Further study will be needed to clarify the role of TDF + LAM combination antiHBV therapy in HIV/HBV co-infected patients.”
D Cooper and others. Tenofovir Disoproxil Fumarate and Lamivudine Combination Therapy Compared to Lamivudine Alone for HBV in Therapynaive HIV/HBV Co-infected Patients: 48-week Interim Results. Abstract 825 (poster).
Active and “Occult” Hepatitis B Infection in a US Cohort of HIV Positive Patients
Hepatitis B has emerged as a significant cause of morbidity and mortality in HIV positive patients in the US. No studies have yet
described the prevalence of HBV infection in a nationally representative HIV patient cohort.
In the present study, investigators at Harvard and Johns Hopkins sought to determine the prevalence of both active HBV and “occult”
HBV infection in an AACTG HIV cohort.There is considerable ongoing debate about the significance of occult HBV (anti-HBc+,
HBV DNA HBV).
The researchers randomly selected sample subjects from the cohort for an evaluation of HBV markers that included anti-HBc, antiHBs, HbsAg, and HBV DNA.The samples were collected before the subjects started anti-HIV therapy.
Of the 240 representative samples, 156 (65%) showed evidence of either past hepatitis B exposure or active hepatitis B infection. Of
these, 92 samples (38.2%) demonstrated typical markers of HBV infection and clearance (anti-HBs+, anti-HBc+, anti-HBsAg-).These
samples were all HBV DNA -. Seventeen were (7.1%) samples were consistent with acute or chronic hepatitis B (anti-HBc+ and
HBsAg+).Ten of these were HBV DNA+.
Thirty-eight (15.8%) subjects had an “occult” marker pattern characterized by only anti-HBc reactivity. Only one occult sample had
detectable HBV.
The investigators conclude that the majority of HIV-infected patients in a nationally distributed cohort have evidence of current or
past HBV infection. ACTIVE HBV INFECTION IS MORE PREVALENT IN THIS COHORT THAN IN THE GENERAL
POPULATION AND IS CHARACTERIZED BY HIGH VIRAL LOADS IN ALMOST 60% OF HBsAg+ INDIVIDUALS.
The prevalence of HBV anti-core alone is lower than that seen in European cohorts. Only 2.6% of the US subjects showed any
evidence of highly replicative HBV infection.
KE Sherman and others. Prevalence of Occult Hepatitis B Infection in HIV-infected Patients: Analysis of a Geographically Distributed ACTG Cohort.
Abstract 820 (poster).
Viread Is Effective Against Epivir-HBV-Resistant Hepatitis B in HIV-HBV Co-infected Patients
Long-term use of Epivir-HBV (lamivudine) often results in the development of YMDD mutations in the hepatitis B virus.This, in
turn is associated with the progression of liver disease and clinical decline.The incidence of the YMDD mutations in HIV-HBV
coinfected patients may be as high as 91% after four years of treatment with Epivir-HBV.
The nucleotide analog Viread is active against both HIV and HBV.The current small study explored whether Viread might be an
effective alternative therapy for HIV-HBV coinfected patients with lamivudine-resistant HBV infection.
Ten HIV-HBV coinfected patients treated with lamivudine and HAART added Viread to their regimen, and then were monitored on a
monthly basis for the first 3 months and every 3 months thereafter for HIV and HBV viral load, transaminases and CD4 T cell count.
After 12 months of treatment, there was no significant change in HIV viral load or transaminase levels, but there was a dramatic mean
decrease in HBV viral load (4.55 +/- 1.21 Log).Viread treatment was not associated with any HIV or HBV specific resistance mutations.
These encouraging results suggest that Viread is an effective alternative therapy for lamivudine-resistant HBV in HIV-HBV coinfected
patients who are on an effective antiretroviral regimen.
AG Marcelin and others. Long-term Tenofovir Treatment of Lamivudine-resistant Chronic Hepatitis B in HIV Co-infected Patients. Abstract 824 (poster).
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TUBERCULOSIS CO-INFECTION WITH HIV
By Ross Hewitt, MD
Treatment of HIV and Tuberculosis (TB) in Co-infected Patients
Three abstracts highlighted issues regarding this important worldwide issue: how to treat TB and HIV at the same time? The goal of
HIV treatment is viral suppression but the goal of TB treatment is cure and prevention of recurrence or relapse.
The key issue is the use of the rifamycin drugs rifampicin (RIF) and rifabutin (RBT). RIF is the standard for treatment of TB in
patients without HIV, but it greatly reduces the blood levels of all PIs and NNRTIs except full dose ritonavir. RBT appears safer to
use in HIV+ patients because its reductions in blood levels is much less except with delavirdine.
American researchers conducted a prospective single arm study of a largely twice-weekly RBT based regimen for HIV-related TB
(abstract 136). For the first 2 months, patients received RBT, isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB) daily,
three times weekly or twice weekly, then RBT + INH were given twice weekly.
The entire TB treatment medications were given via directly observed therapy (DOT).
The choice of HAART was left up to primary care physicians except delavirdine was not allowed. The enrolled 169 patients, 79%
were male, 50% were African American, 34% were Hispanic, the median CD4 count at baseline was only 90 cells, and the baseline
viral load was 5.3 log10 copies (>100,000).
This study had a rate of culture positive treatment failure or recurrence 4.6% and was stopped early, as this is higher than the general
population. In all 7 cases, patients had acquired rifamycin resistance. In these patients, their CD4 count < was 75 and they had low
INH blood levels. Patients with HIV can be successfully treated with HAART during TB treatment as evidenced by CD4 counts
that doubled and viral loads that declined 3 log10 by the end of TB treatment.
In ACTG 223, a TB treatment trial in a pre-HAART cohort, the treatment failure was 20%. Twice weekly RBT-based TB treatment
was associated with resistance and should be avoided in HIV+ patients.
Researchers in Baltimore studied the issue of rifamycin resistance in HIV patients (abstract 137).TB recurrence after short course 6month TB therapy is low in HIV+ and HIV- persons. Once weekly rifapentine was associated with rifamycin resistance and is not
recommended, and neither is RBT twice weekly as noted above.
They studied patients and compared RBT to RIF-based regimens in an observational cohort study for the period Jan 1993 to Dec
2001 with follow up through Dec 2002. They excluded people with prior rifamycin resistance, non-completion of therapy or those
lost to follow up. They administered 2 weeks of 4-drug therapy (similar to above) then 2-drug therapy.
Relapse was verified by genetic testing (RFLP)—the same pattern had to be present between the baseline and the relapse isolate.
618 cases of culture-confirmed TB occurred, 187 of which were excluded (the majority due to death, <20 due to no DOT of TB
meds). 109 (25%) of cases were known to be HIV positive. 322 were HIV negative or unknown (most of these declined HIV
testing) and were combined in the analysis.
The TB recurrence rate was 3.7% (16 cases). 9/109 (8.2%) in HIV+ and 7/322 (2.2%) in HIV- yielding a relative risk 2.3 in HIV+
patients. There were 3 cases of acquired rifamycin resistance vs. none in the HIV- group yielding a risk of 4-fold increase. The
median CD4 count of recurrence and acquired rifamycin resistance was 51.
The only difference between HIV+ patients who relapsed and those who didn’t was the initial CD4 count (51 vs. 137, p=0.02).
Researchers from India, which has 30% of the TB in the world and 2 million HIV co-infected with TB, studied the use of RIF and
efavirenz (EFV) in ARV naive patients (abstract 138).
RIF decreases EFV by more than 20%, and even greater in people with higher body weight. In this observational cohort, they
looked at CD4 count at 9 months (the end of TB treatment). 211 naïve subjects with CD4 count <200 initiated 2 NRTIs + EFV
600mg QD (the standard dose).
The NRTIs prescribed were d4T/3TC in 176 patients and AZT/3TC in 35 pts. A standard 4-drug combination of INH, RIF, EMB,
and PZA was used with streptomycin added for disseminated disease. After 3 months, they used only RIF and INH. There were
107 patients with HIV and TB and 104 patients with HIV but no TB. They used ultrasound of the spleen, which gives echogenic
masses in combination with abdominal lymphadenopathy to make a presumptive diagnosis.
197 patients completed 9 months of follow up, yielding 98 HIV+TB vs. 99 HIV+ alone. There were 79 males, age 35 years in the
HIV/TB group and 67 males, age 38 years in the HIV+ alone group. This was an underweight population, ranging between 40 and
60 kg (90 and 132 pounds). 50% had lymph node TB and 19% had pulmonary TB and thrush was seen in 44 patients.
They cured TB in 62.2% and improved TB but extended treatment in 37.8%. There was no difference in side effects between
groups. Raised liver enzymes occurred in 10.2% of HIV/TB group but in none of HIV+ alone group. Paradoxical worsening of
TB was seen in 8.2% within one month except in one patient.
Overall, the CD4 count rose 104 to 247 in the HIV/TB and 130 to 273 in the HIV alone group after 3 months. In this study done
in a resource limited setting, EFV drug levels and plasma HIV viral load were not measured. Despite the fact that other PK data
recommends increasing EFV dose to 800 mg daily when using RIF, a positive immunologic response was observed.
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W Burman and others. Use of Antiretroviral Therapy During Treatment of Active Tuberculosis with a Rifabutin-based Regimen. Abstract 136 (oral).
R Nettles and others. Tuberculosis Relapse and Acquired Rifamycin Resistance in HIV-1 Infected Persons Is Associated with Low CD4 Count, But
Is Not More Common with Rifabutin than Rifampin. Abstract 137 (oral).
A Patel and others. To Study the Safety and Antiretroviral Efficacy of Concomitant Use of Rifampicin and Efavirenz in Antiretroviral-naïve
Tuberculosis Co-infected HIV-1 Patients in India. Abstract 138 (oral).
HIV VACCINES
By Ross G. Hewitt, MD
Challenges in Evaluating HIV Vaccine Candidates: A Symposium
Role of Animal Models in Vaccine Evaluation
Dr. Mark Feinberg addressed the important subject of the role of animal models in vaccine evaluation as a researcher working in this
field.Vaccines were developed for measles, mumps and poliomyelitis using animal models.
Animal models now play an unprecedented role in the vaccine development effort (abstract 106). Biological barriers to AIDS
vaccine development exist and need to be addressed. Animal models can help us in regards to safety and toxicity, immunogenecity,
derivation of effective vaccine schedules and elucidation of viral pathogenesis.
Animal studies have given us essential insights into disease pathogenesis, importance of cellular immune responses, antiretroviral
therapy during acute infection, pre-exposure and early post-exposure prophylaxis, pioneered “prime-boost” immunization strategies as
well as proven that vaccination can prevent viral infection. There are doubts in the field regarding drawbacks of current vaccine
development.
Animal models need be made to approximate HIV infection as much as possible.We don’t use chimpanzees because they are too
scarce and endangered—so macaques are usually used. SIV and SHIV (not HIV) are used to elicit appropriate responses.
SIV-2 viruses used in these studies have come from sooty mangabey monkeys that have tolerated this virus for thousands of years.
The same virus put into macaques causes a disease very similar to human AIDS. We also use SHIV virus, where a number of HIV
genes can be substituted for the SIV genes.These reproducible infections betweens animals give rise to a solid statistical basis for using
small numbers of animals.
SHIVs are based on CXCR4 use, cause rapid CD4 depletion, and tend to be more neutralization sensitive than SIV isolates.
The use of very aggressive challenges viruses may obscure important pathogenetic processes in HIV infection. Subtle differences in
monkey immune activation could lead to unexpected outcomes in vaccine trials. Escape mutants can occur in these trials that can
then be characterized and measured, giving insight into immune response separate from antibody responses.Vaccine studies done in
monkeys can define the measures of vaccine efficacy. Studies using a priming vector followed by a boosting vector have been shown
to be more protective of transmission in these animals.
Animals differ from humans because they are smaller, so the amount of vaccine given per kilogram of weight is higher in smaller
animals when compared to humans. Animals have also helped us to aim for preventing disease rather than infection and aiming for
lower viral set points.
Vaccine animal models could be biased toward making the vaccines look good or better than it would be once studied in humans.
Animal model studies also use very high inoculums of virus, much more so than in usual human exposures. So, low dose, repeated
exposure models are needed.
We still need to define to what extent what we see in monkeys will be what we see in humans. We need to prioritize how we use
animal models in pre-clinical development and which of the increasing number of vaccine candidates should be advanced. He
reiterated that it is important that all monkeys whose lives have been sacrificed have been so in the pursuit of an AIDS vaccine, even
though these intelligent animals may not have volunteered for the responsibility.
The Role of Neutralizing Antibodies in the Prevention of HIV Infection
Dr. Susan Zolla-Pazner discussed this field, in which she has worked for over 20 years (abstract 107). She started with an answer and
ended with a question.The answer that we should start with is broadly neutralizing antibodies (NA). The question is: what
immunogen will induce them?
Passive immunization experiments show that giving antibodies alone can provide immunity in chimps challenged with HIV,
macaques challenged with SIV or SHIV and scid-hu mice challenged with HIV. The antibodies must have the appropriate
specificity and be present in sufficient concentrations.
Why have recent vaccine efforts steered away from NAs? Yes, primary HIV isolates are relatively resistant to neutralizing antibodies,
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but HIV+ sera can neutralize them. High titers are thought to be needed, but in other viruses, low NA titers can be protective.
Antibodies that mediate primary isolate neutralization are hard to induce with existing immunogens—so let’s discover ones that will!
There are now 15 and 20 human monoclonal antibodies with broad neutralizing activity.They can be broken down into various
fields: CD4 binding domain (only 1 exists), CD4 specific to the bridging sheet of the protein with gp120 (but only Fab fragments
neutralize), gp120/carbohydrate epitope (poorly immunogenic region and rarely found in HIV+ persons),V3 loop of gp120 (highly
immunogenic and described originally as being highly type specific), gp41 clusters 1 and 2 (a region near the transmembrane
domain—poorly immunogenic and rarely found in HIV+ sera).
Antibodies to the V3 loop need re-examination.They are not all the same. Some are type-specific induced or selected with linear V3
peptides.Those specific for conformational V3 epitopes are broadly neutralizing (neutralization of 5 to 7 of 14 various isolates—as
broad as the standards of the past).
How is it that an antibody against a highly variable region of the virus can actually neutralize it? These antibodies must bind to
conserved conformational aspects of the V3 loop despite sequence variation. This loop is always fairly small (30 to 35 amino acids),
has a net positive charge, a conserved beta turn at the tip and a sulfide bond at its base.
Her team studied this interaction by looking at the structured of V3 when bound to a NA.The V3 loop displays two alternative
conformations: one mimics the structure in chemokines that binds to CCR5 and the other mimics a structure in the chemokine that
binds to CXCR4!
The antibody recognizes a beta hairpin turn structure at the tip of the loop. In four of the amino acids in the 14 amino acid
sequence were searched for homologues in the protein database. Only 7 proteins had the 4 amino acid motif: 4 were human, and 3
were immune system related—MIP-1alpha, RANTES and mid-RANTES—all ligands for the CCR5 receptor. These proteins have
the same beta hairpin turn in their structures. Only 1 protein had a similar structure to the X4 virus—SDF-1, the natural ligand for
the CXCR4 receptor!
When these two conformations are compared to each other—they are similar: one is a left hand turn and the other is a right hand
turn.They are mirror images of each other.There could be other conformations as well—these are under study.
The implication for vaccine development is that increased emphasis should be placed on development of neutralizing antibodies.
This means that rational immunogen design may be possible to elicit neutralizing antibodies. If these antibodies bind to human
RANTES and MIP1-alpha, will it have a deleterious effect? It remains to be determined.
Vaccine Clinical Trials Update
Dr. Scott Hammer, an investigator in the HIV Vaccine Network, presented an update on vaccine clinical trials (abstract 108). There
are many preparative steps for clinical trials, including political commitment, community participation and education, attention to
ethical and cultural consideration, seroprevalence and seroincidence data, molecular dynamism data, site preparation steps and strong
industry collaborations.
Datasets that drive the immunogenecity goals include: exposed but uninfected people have CTL responses to HIV, acutely HIV
infected persons where CTL responses correlate with viral load decline, long-term nonprogressors who have strong CTL and NA
responses and primate models with strong CD8 and NA responses.
Biologic targets of vaccines include CD8 cytotoxic lymphocytes, CD4 lymphocytes and NAs.We want protective immunity, viremic
control/amelioration of disease and reduction of HIV transmission in a population.
Vaccine approaches include protein subunit vaccines that induce antibodies, recombinant peptide based vaccines, DNA based vaccines
and vector based as well as viral-like particles.There is a long list of viral vectors, including adenovirus, canarypox, and vaccinia
Ankara. Also, bacterial and fungal vectors that target mucosal immunity and dendritic cells are under investigation.
Challenges to successful vaccination include definition of immune correlates of protection, induction of broadly reactive NAs, viral
diversity and complex molecular epidemiology, potential for viral escape, HIV co-infection and super infection, multiple candidate
immunogens (doses, regimens, combinations), influence of varied HLA backgrounds, and need for protection against mucosal and
blood challenges.
Viral diversity in HIV is great. There three groups: M, N, O.There are at lest 9 subtypes, many other sub-subtypes.There are
multiple epidemics around the world. There is B in the Americas, Europe and Australia versus C in Africa and E in Asia.
Circulating strains must be monitored as recombinants change and vaccines must keep up with the changes. It would be great if we
could take a single subtype and induce cross-subtype immunity. Other vaccines can be subtype specific for a particular region or
country. Other vaccines may have multiple antigens or looking back at ancestor viruses.
A DNA vaccine was recently shown to fail after 24 weeks in monkey model. There are now three separate reports of HIV superinfection with 3 published reports involving 4 patients reported in 2002, including one where type B was super-infected by another
type B virus.These are some of the challenges facing vaccine development.
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Phase I studies look at safety, phase II studies look at immunogenecity while phase III studies looks at efficacy. A few trials that are
ongoing will be featured.
One set is the canary pox vector vaccines. HVTN 203 was the most negative study that led to the decision not to move ahead with a
phase III study.The vaccine alone or with gp120 showed only cellular immune responses in only 16% vs. env or gag, with 7% for env
and gag 13%. This response was too low.
The Merck program to develop both a DNA and adenovirus type 5 vaccine is certainly promising.The higher doses of DNA vaccine
gained responses in about 50%. The adenoviral vaccine induced responses in the 56 to 78% range.The pre-existing immunity to
adenovirus can likely be overcome by increasing the dose of the vaccine. Merck will be doing a phase I study in five regions of the
world in conjunction with the AIDS Vaccine Network.
There is the Vaccine Research Program at the NIH.They are looking at immunogens that begin with a DNA primer followed by
adenoviral boost looking at 4 different clades. This strategy looks promising in animal models.
Phase III trials include Vaxgen 004 (5417 volunteers in the USA, Canada, Puerto Rico and the Netherlands), the Vaxgen 003 trial for
clade E in Thailand.There is also a US military trial that will start in 2003 with canary pox vector in Thailand as well. There are
several centers around the world looking at a variety of candidates in a variety of populations.
New Requirement for HIV Vaccine Efficacy Trials
Dr. Steve Self presented issues to consider in designing vaccine efficacy trials using CTL vaccines. These vaccines focus on cellular
immune responses, both T cell responses and antibody responses. Macaque studies show some protection, and some disease
amelioration.What will be seen in humans?
Trial designs with 2% incidence would need 125 infections out of a total of 2800 in each arm, or 5600 persons.Vaccine Efficacy (VE)
would be determined for reduction in population infection rate, reduction in rate of morbidity/mortality and reduction in rate of
secondary infection.We would want to distinguish 30% vs. 59% protection with 90% power or 0% vs. 37% with 90% power. We will
want to look at immunologic and virologic correlates of protection.
A trial of this size will have the magnitude to assess the degree of viral load set point differences (early effect).There will be a limited
assessment of durability of effect over the first 36 months of observation. The observation period once infection occurs needs to be
longer than the average of 18 months in such a trial.
Can combine data from natural history studies or treatment data to assess the impact on viral load might imply with respect to disease
progression. These biomarkers are not validated as surrogates in vaccine trials—but there will be a leap of faith in this regard. The
long-term clinical effects with access to clinical treatment and care will be complicated to discern.These effects will be dominated by
treatment rather than vaccine effect.
To assess prevention of secondary infections in a community, the vaccine trials will provide some data on effect on viral load.We can
also look at natural history data on discordant relationships with secondary transmission. 50% of secondary infections occur within
the first 5 months of the newly infected person. So, how many uninfected persons can we vaccinate in the population to slow
secondary infection as well? The vaccine cannot cover prevalent infection at all.Waning of a vaccine effect several years down the
road may also influence the impact of the vaccine in the population.
HIV transmission by source is defined by the number of infection events as a result of the probability of infection, the degree of
infection in the infected partner, knowledge of infection status and the number of susceptible individuals in the population. Multiple
interventions will be necessary to achieve coverage from a vaccination program.We will need voluntary HIV testing and counseling
after the vaccination period and treatment and care of identified HIV+ in the population as the vaccine effect wanes.
Will a community based vaccination program integrated in systems for voluntary testing and counseling and HIV treatment and care
result in better outcomes compared to communities without vaccination but have these other programs. Community randomized
controlled trials are needed to fully assess vaccine impact. Planning needs to begin now, and these should incorporate voluntary
testing and counseling as well as HIV treatment and care.
M Feinberg. Role of Animal Studies in Vaccine Evaluation. Abstract 106 (oral session).
S Zolla-Pazner. The Role of Neutralizing Antibodies in the Prevention of HIV Infection. Abstract 107 (oral session).
S Hammer. Vaccine Clinical Trials Update. Abstract 108 (oral session).
S Self. New Requirements for Efficacy Trials. Abstract 109 (oral session).
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GB VIRUS TYPE C (GBV-C) AND SENV
By Ronald Baker, PhD
There were a total of seven presentations—3 orals and four posters—on the hepatitis C-related virus GBV-C (a.k.a. HGV = hepatitis
G virus) at the 10th CROI.
GBV-C is an intriguing virus because scientists have discovered that it does not appear to cause disease, and in some clinical studies
(but not all), its presence is associated with a decreased risk of disease progression and death in individuals with HIV infection.
Following is a brief summary of six of the studies presented on GBV and its association with HIV infection at the Boston meeting:
Effects of GBV-C on HIV Replication and on Gene Expression in PBMC Cultures (Abstract 156)
Co-infection with HIV and GBV-C is associated with prolonged survival or clinical benefit in 8 clinical studies. In addition, GBV-C
/ HIV (R5 strain) co-infection of PBMC cultures resulted in decreased HIV replication.The mechanism by which GBV-C may slow
HIV disease progression is not known. In this study, the researchers characterized the effects of GBV-C infection on HIV replication
and on cellular gene expression in a PBMC co-infection model.
Study authors J Xiang and colleagues conclude, “GBV-C inhibits R5 and XR4 strains of HIV in vitro, with maximal inhibition
occurring 48 hrs post-infection. GBV-C infection of PBMCs appears to increase expression of the CCR5 chemokines RANTES,
MIP-1a, MIP-1b, and SDF-1. Survival benefits associated with GBV-C co-infection may reflect a direct inhibitory effect of GBV-C
on HIV replication. Additional factors may be involved, including effects on cytokine expression and decreased lymphocyte death.
GBV-C Viremia at Diagnosis Does Not Predict Viremia (Abstract 157)
Swedish researchers followed 230 HIV positive patients to assess whether GBV-C status at diagnosis of HIV-1 infection can be used
to predict the disease course in patients not receiving combination antiretroviral therapy, and whether longitudinal changes in GBV-C
status occur during the course of HIV-1 infection.
The patients were followed until either death or initiation of combination therapy.
The investigators conclude, “GBV-C status at diagnosis of HIV-1 infection does not predict the natural course of disease.The
decreased prevalence of GBV-C viremia in patients with AIDS, and the observed loss of GBV-C viremia without anti-E2
seroconversion in patients with progressive disease support an interaction between these two viruses.
“However, the GBV-C status in HIV-1 infection is probably a secondary phenomenon during disease progression rather than an
independent prognostic factor. “
GBV-C virus and Decreased Risk of Death in the Multicenter AIDS Cohort Study (MACS) (Abstract 159lb)
Stored plasma from MACS participants with HIV infection 1 - 1 1/2 years (early visit; N=271) and 5-6 years (late visit; N=138) after
HIV seroconversion were tested for GBV-C infection.
GBV-C RNA status at the early visit was not associated with a difference in survival. In contrast, GBV-C RNA at the late visit was
strongly associated with survival: compared to men who were RNA pos at both visits, men who were GBV-C RNA negative at both
visits were 2.43 times more likely to die and those who cleared GBV-C infection between visits were 5.87 times more likely to die.
The authors conclude, “GBV-C viremia assessed 5-6 years after HIV seroconversion was a strong predictor of survival, and loss of
GBV-C predicted a higher risk of death. Mis-classification of those who cleared GBV-C as “positive”, based on the early visit, proved
important, as there was an increased risk of death with the clearance of GBV-C [emphasis added].
“GBV-C infection has a high attributable benefit in HIV infection, since both the prevalence of GBV-C and size of its protective
effect were high. Understanding the mechanisms for the interaction between GBV-C and HIV may provide insights into ways to
control HIV disease progression.”
GBV-C Is Frequently Transmitted to HIV-infected Patients by Blood Transfusions (Abstract 846)
The results of several recent studies suggest that GBV-HIV co-infection may be clinically beneficial, and suggest a possible role for
GBV in HIV therapy. However, without definitive data on clinical benefit and/or risk, ethical concerns preclude intentional GBV
inoculation HIV-infected patients.
The VATS study followed 531 HIV-infected persons requiring blood transfusions to study the impact of transfusions on HIV,
immunological parameters, and clinical HIV disease progression. Samples analyzed were collected pre-transfusion, weekly for 4 wks
post-transfusion, and quarterly for up to 3 yrs.
These results demonstrate a high (22%) GBV transmission rate for HIV-infected persons after transfusion, with 2/3 of acutely infected
persons evidencing persistent viremia. In contrast, prior GBV infection/seroconversion was protective against re-infection, despite
anti-GBenv loss.
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GBV-C Viral Load Decreases During HIV-1 Infection (Abstract 848)
Recent HIV-1 seroconverters were identified and followed in the San Francisco Men’s Health Study from 1983-1993. Reposited
serum specimens from the first HIV-1 seropositive visit and subsequent visits were tested for GBV-C viral load.
One (1) to 3 serum specimens from each of 18 recent seroconverters, spanning a total of 102 person yrs of observation, were available
for testing. GBV-C viremia was detected in 7/18 (39%) of subjects at baseline. During the course of untreated HIV-1 infection, GBVC viral load decreased in all initially viremic subjects and reached levels that were not detected in the assay in 2/7 subjects.
The investigators conclude, “GBV-C viremia was common at baseline, but incident cases did not occur during follow-up of HIV-1
infected persons. Decreased detection of GBV-C viremia in subjects infected with HIV-1 for a longer time could confound
associations between these factors and the rate of clinical AIDS progression.
Slower Disease Progression and Greater CD4 Response to Antiretroviral Treatment in HIV Patients Co-infected with
GBV-C (Abstract 849)
The primary objective of the present study was to evaluate the effect of GBV-C infection on HIV DP in treatment-naïve HIV
positive individuals.To control for antiretroviral treatment (ART) received, the researchers studied HIV-GBV-C co-infection in a 3year randomized trial with clinical end-points.
A cohort of 326 untreated patients randomized to AZT alone or in combination with DDI or DDC was sampled from the Delta
trial (1992-1995).The presence of GBV-C was determined at baseline (BL) by 2 rounds of RT-PCR on RNA extracted from serum.
CD4, HIV RNA and clinical events were recorded every 2-4 months. GBV-C positive and negative patients were compared both at
BL and longitudinally.
During a 29-month median follow-up, 79 patients progressed either to AIDS (n = 40) or death (n = 39). Adjusted on BL CD4, BL
HIV RNA and sex, DP was slower in GBV-C positive compared to negative patients. Reduction in HIV RNA was identical in
GBV-C positive and negative pts.
In contrast, increase in CD4 cell count was greater in positive than in negative pts in particular at week 64 and week 80 with a trend
toward slower return to BL value.When adjusted on CD4 response, in addition to BL characteristics, DP was no longer significantly
different in positive and negative patients.
The researchers conclude, “In this cohort, GBV-C co-infected patients had a better CD4 response to ART than GBV-C negative
patients, which explained in part their slower progression to AIDS or death. Immunologic implications of GBV-C co-infection in
HIV should be further investigated.”
SENV INFECTION IS ASSOCIATED WITH INCREASED SURVIVAL IN HIV POSITIVE PATIENTS
SENV and Hepatitis
By Mark Nelson, MD
SENV is a sub virus of TTV (a small non-enveloped circular virus of the circoviridiae family), and may be associated with hepatic
disease.There are at least 8 members of the SENV family, with major variation between them (approximately a 25% difference in
nucleotide sequence). SENV-H and SENV-D have shown a close association with post transfusion hepatitis, although both are found
in low prevalence in volunteer donor populations (around 2%).
In studies prospectively following patients having undergone open-heart surgery, SENV was found in 30.1% of transfused individuals
compared to only 3.1% of identically followed surgical patients who were not transfused.This was highly significant (p < 0.001). A
positive donor could be identified in 70% of cases and donor recipient transmission was proven by sequence homology. SENV has
also been found in a high proportion (up to 60% of individuals) with established parental exposure.
New SENV infections have been found in 92% of individuals with transfusion associated non A-E hepatitis compared to 24% of
those who did not develop hepatitis. Clinical disease in such cases has been mild but 18% developed chronic hepatitis.The majority
of individuals cleared this infection within one year.
SENV has also been reported to occur as an acute co-infection in 41% of individuals developing hepatitis C, although the presence of
this agent did not appear to affect the severity or persistence of hepatitis C.
SENV and HIV Infection at the 10th CROI
Co-infections with HIV are an emerging problem that could adversely or beneficially affect HIV clinical course. Presented at the
10th CROI in Boston, MA, the current study was aimed at characterizing SENV epidemics and exploring whether SENV can impact
on survival in HIV patients.
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In an Italian cohort, 165 HIV-infected patients (pts) have been tested by PCR on a portion of ORF-1 gene that is specific for
SENV-A, B, D, and H subtypes. Clinical and laboratory data were collected at least every 4 months (mos) for a mean of 49.1 mos.
Prevalence of SENV infection was 85/165 (51.5%). Intravenous drug use (IVDU) as risk factor for HIV acquisition was associated to
increased risk of SENV infection, while female gender resulted to be protective. Interestingly, IVDU was also associated to the
patients’ risk of being super-infected with more than one SENV variants.
Multi-variate stepwise Cox regression model included the following covariates: age, gender, risk factor for HIV acquisition, HCV-Ab,
HBs-Ab reactivities, CD4+ and HIV-RNA at the time of testing for SENV, C stage of HIV infection (CDC ’93), exposure to
HAART, duration of undetectable HIV-RNA and SENV infection.
Among these co-variates, IDVU and HAART exposure were associated with increased survival, while C-stage of HIV infection and,
at borderline significance, absent SENV infection increased the risk of death.
The investigators conclude, “High prevalence, super-infection and broad subtype diversification of SENV infection have been
demonstrated in this cohort of HIV positive patients, especially as far as patients who acquired HIV through IVDU are concerned.
Infection with SENV does not seem to have any negative impact, and a possible positive relationship with survival needs further
investigation.”
J P Aboulker and others. Slower Disease Progression and Greater CD4 Response to Antiretroviral Treatment in HIV Patients Co-infected with
GBV-C. Abstract 849 (poster).
P Björkman and others. GB Virus C Viremia During the Natural Course of HIV-1 Infection:Viremia at Diagnosis Does Not Predict Mortality.
Abstract 157 (oral).
M Busch and others. GBV (HGV) Is Frequently Transmitted to HIV-infected Patients by Blood Transfusions. Abstract 846 (poster).
R Grant and others. GB Virus C Viral Load Decreases During HIV-1 Infection. Abstract 848 (poster).
C Williams and others. Persistent GBV-C virus Type C (GBV-C) Infection is Associated with Decreased Risk of Death in HIV-seroconvertors in the
Multicenter AIDS Cohort Study (MACS). Abstract 159lb (oral).
J Xiang and others. GBV-C Infection Inhibits CCR5 and CXCR4 HIV Strains and Alters Chemokine and Cytokine Gene Expression in PBMC
Cultures. Abstract 156 (oral).
M Nelson. Other Viral Infections. Selected Highlights from Drug Development for Antiretroviral Therapies 2001 (Hep DART 2001). December 16-20,
2001. Maui, Hawaii.
E Quiros-Roldan and others. SENV Infection in HIV+ Patients: Prevalence, Subtype Characterization, and Impact on the Clinical Outcome.
Abstract 850 (poster).
GENETICS
By Ross Hewitt, MD
The Impact of Host Genetic Factors on Clinical Outcomes: A Symposium
Susceptibility of humans to HIV infection and progression to symptomatic disease once HIV infection has occurred is clearly the
result of the interaction between the virus and the host.The virus presents various pieces of itself to our immune system. Genetic
differences within people that exist still comprise a system that is able to respond, but HIV expoits subtle differences in response to its
advantage.These differences may have implications for when to start antiretroviral therapy, mother to child transmission and vaccine
development.
Genetic Variation of CCR5 Receptor and Its Ligands
CCR5 Receptor Genotype and Risk of HIV Infection
Dr. Sunil Ahuja began his review of work in this field by reminding us that the viral set point—the amount of HIV replication that
levels after infection—is the result of both viral and host interaction.The level of viral set point ultimately influences how fast a
person progresses to symptomatic HIV disease.Wide variation in set points has been described leading to the question why do some
people have very low or very high viral set points?
CCR5 receptor protein binds several chemokines that are important in immune signaling. Every person has one copy of the gene for
CCR5 and there are two alleles—one inherited from each parent.There are several polymorphisms, classified as Human Haplotypes
A, B, C, D, E, F, and G. F and G also have subtypes 1 and 2.The G2 allele is always associated with the delta32 deletion mutation.
Combinations of alleles occur to yield various genotypes such as C/G2 or E/E.
Dr. Ahuja studied a cohort of 649 children born to HIV+ women, 466 of which never received AZT to prevent transmission. A
genotype of G2/G2 (homozygosity) was highly protective from HIV infection in the infants, and a genotype of C/G2 was partially
46
10th Conference on Retroviruses and Opportunistic Infections
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protective. Other genotypes such as C/E, E/E and E/G2 increased the risk of infection.
CCR5 genotypes vary according to ethnicity. Clear differences are seen in European adults in whom a C/G2 is protective compared
to Africans and African-Americans in whom a A/F2 genotype is protective. Japanese hemophiliacs have a unique genotype of A/G
that is not seen in the other populations that is associated with increased risk of HIV infection
Genetic Variation of MCP-1 and HIV Disease
HIV-infected monocytes and macrophages arrive in the brain, drawn there via a gradient of MCP-1 (monocyte chemoattractive
protein). MCP-1 levels in cerebral spinal fluid (CSF) correlate well with development of HIV-associated dementia. CCR2 is the
receptor for MCP-1. Researchers have identified two polymorphisms in MCP-1 gene, thus yielding three possible alleles: AA, GA,
and AT. Genotypes for MCP-1 also vary significantly between ethnic groups.
GA/GA genotype reduces the risk of HIV infection. However, once a person is HIV-infected, the GA/GA genotype actually results
in faster progression to AIDS and death. In a cohort of HIV-infected patients, the risk of dementia for GA/GA was increased by
4.52 fold (p=0.017). There was also an increased risk for disseminated mycobacterium avium complex infection (4.41 fold risk,
p=0.005) but no increased risk for Pneumocystis carinii pneumonia or cytomegalovirus infections.
Is the genetic variation really more than just a chance association? Two lines of evidence suggest it is a direct effect. First, people with
the GA/GA genotype have higher levels of MCP-1 in their CSF. Second, kidney biopsies showed increased recruitment of HIV
infected monocytes in people with the GA/GA genotype. A possible application of this information is whether knowledge of this
genotype would result in the use of antiretrovirals with better penetration into the CSF and the brain.
The Influence of KIR Genetic Variation on HIV-1 Disease
Dr. Mary Carrington reviewed her work on this new area of research (abstract 55). Natural killer (NK) cells are specialized
lymphocytes that can directly kill infected cells once stimulated to do so. The signals for killing are mediated by receptors on the
surface membrane of NK cells. One such family of receptors is KIR (killer immunoglobulin-like receptor) proteins. Class I human
leukocyte antigens (HLA proteins) are the ligands (what binds to it) for the KIR receptor. Infected cells bear these HLA proteins on
their surface and when they contact an NK cell, send a signal to the NK cell whether or not to kill this infected cell. Activating
signals tell the NK cell to kill, while inhibitory signals tell the NK cell not to kill.To help avoid this destruction of infected cells (and
thereby reducing IV replication overall), HIV-1 reduces the number (down regulates) of HLA class I proteins on the cell surface of
the infected cell.
KIR genes are located on chromosome 19 at the 13.4 position. KIR proteins are molecules with 2 or 3 extracellular domains and
long or short tails. Long tails send inhibitory signals and short tails send activating signals within the NK cell. KIR genes are the
only other collection of genes to rival HLA genes in variation (polymorphic content).The KIR locus is comprised of many genes
(polygenic). KIR are classified into two haplotypes, A and B. Haplotype A is the most common, occurring in about 50% of people
tested, where one allele is activating and the other is inhibitory. The rest of them, called B, have two activating alleles. This might
be a bad thing for some diseases (like autoimmune) but is probably a good thing for dealing with infectious diseases.
Her team identifies two alleles called 3DL1 and 3DS1, which differ in function. 3DL1 will send inhibitory signal (it has a long tail,
thus the “L”) when it contacts the HLA B Bw4 protein and tell the NK cell not to kill. 3DS1 is activating (tells the NK cell to kill)
but the ligand is unknown. Does 3DS1 recognize aberrant HLA Bw4 protein, and then send the signal to kill the infected cell?
HLA Bw4 is protective for progression to AIDS (slightly) with 1 allele and slightly more so when 2 alleles are present in the HLA
Bw4 gene. In a cohort of HIV patients with varying progression to AIDS, her team found that a mutations in Bw4 at position 80 for
isoleucine is more protective that normal HLA Bw4, with relative hazard of 0.8 (a 20% reduction in progression) that is statistically
significant (p<0.02).
Are these two things related? Does bw4-Isol80 interact with KIR3DL1/3DS1 to kill infected cells? When the effects of progression
are studied inpatients with both, the combination of the two together results in an even lower risk with a relative hazard of 0.56-0.58,
p=0.0009. What is interesting is that these two pairs of gene systems are located on different chromosomes: 6 and 19. Furthermore,
there are differences by ethnicity. 3DS1 is more common in Caucasians than in African-Americans. Her team has identified new
alleles in African Americans that are still being characterized. In one example, subtype 007 of 3DL1 occurs at a rate of 7% in African
Americans and 3% in Caucasians.
The higher incidence is also associated with more rapid progression to AIDS in African American patients, with a relative hazard of
1.7 to 2.5 fold (p<0.001). Those patients with Bw4 increase their relative hazard from 2.11 fold to 2.44 fold. Thus, it is likely that a
direct relationship between the genetic variation of the KIR receptor and its HLA Bw4 ligand (“epistatic interaction”) plays a role in
HIV pathogenesis.This work provides evidence that in individuals with certain genetic variation, activation of NK cells leads to
elimination of HIV-1 infected cells and results in delayed progression to AIDS.
10th Conference on Retroviruses and Opportunistic Infections
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HIV and Hepatitis.comTM
Human Genetic Variation and Its Effects on HIV Infection and Disease Progression
Dr. Richard Kaslow presented a summary of the state of knowledge of human genetic variation and susceptibility to HIV infection as
well as HIV disease progression (abstract 56). This is a rapidly evolving field with much information having come to light over the
past 7 years. The CCR5 G2 allele (with the delta32 mutation) and the KIR-HLA Bw4 interactions described above are two
detailed examples of this growing body of research. Dr. Kalsow listed the evidence from well-designed and controlled studies for
other genetic variations and their effects on HIV susceptibility and disease progression.
Because of the availability of natural history of HIV cohorts, studying the effects of disease progression is actually fairly
straightforward. This is more difficult with susceptibility to HIV infection, where one can study mother-to-child (“vertical”) HIV
transmission or sexual partners who are discordant for HIV (one is negative and the other positive) and correlate new HIV infection
with the genetic marker in question.
Examples of Well Studied Genetic Markers
People with a mutant CCR2 receptor gene at position V64I are moderately protected from HIV disease progression but not
susceptibility to HIV infection. The effect is less for heterozygotes (who have 1 mutant allele of the gene) and greater for
homozygotes (who have 2 mutant alleles of the gene). Conversely, the genotype E/E for the CCR5 promoter gene area in
homozygotes is associated with an increased risk of a high viral load set point and therefore increased risk of disease progression. A
variety of HLA class I (A, B, C) protein gene variants have also been identified where homozygosity increases the viral set point and
time to clinical event in disease progression but has not effect on protection from HIV infection.
Donor-recipient sharing of HLA class I alleles was also associated with increased horizontal and vertical transmission in African
American patients. Excess sharing of alleles from 3 to 6 in vertical transmission pairs (mother and child) resulted in an increased risk
of vertical transmission in a step-wise fashion. Examples of this are B*5701/B*5703, which is strongly associated with decreased
progression but no effect on infection or seroconversion, and B*35 (*3502-*3503) and B*53 which are related to increased disease
progression and time to AIDS-defining clinical events. HLA B*5301 also carries the Bw4 marker as discussed above.
Finally, HLA A*205/A*6802 supertype is protective in HIV infection even though there is no effect in disease progression. In
Africans with clade C (a different strain of HIV than is seen in the US), this genetic variation is associated with increased risk of both
disease progression and susceptibility to HIV infection. In the multicenter AIDS cohort study (MACS) high-risk seronegatives with
A*0205/a*6802 is protective by and odds ratio 4.45 fold (p=0.0009) that is statistically significant.
Whether there will be regional differences in vaccine responses based upon HLA differences remains to be seen. Whether genetic
variation information accelerates or delays antiretroviral therapy remains to be determined.
HIV Adaptation to Genetic Polymorphisms of the Host
Dr. Mina John, substituting for Dr. Simon Mallal, described their work involving the study of HIV adaptation to human genetic
variation (abstract 54). During the immune system encounter between HIV and us, HLA proteins bind to HIV. HIV responds by can
evolving escape mutations to these bindings, thus setting up a cycle of constant adjustment.These HLA proteins confer cytotoxic T
lymphocyte (CTL) responses that have been shown to be very important in long-term control of HIV replication.
Their group studied 473 individuals with 2303 person-years of observation in whom both HIV sequencing of the whole HIV
genome and comprehensive HLA genotyping were performed and correlated.They found that variations in the HIV genome tend to
occur in areas that do not have functional importance.They also found that HIV-1 reverse transcriptase (RT) polymorphisms are
HLA allele specific. For example, the HLA B5 subtype-in all 52 patients with it but one-had a I135T mutation in the RT.The one
patient who did not was an acutely infected individual who was treated with highly active antiretroviral therapy (HAART), thus
preventing him from developing the escape mutation.
In 249 patients with pre-treatment viral load measurements, they performed HLA A, B and C typing to identify if adaptive
polymorphisms were present. If there was a mutant, it was considered a positive adaptive association while the usual (consensus)
amino acid was considered a negative association.They looked at large number of sites with escape mutants and developed a score for
adaptation based on percentage of adaptive mutants present.They found that ranges of adaptive mutants of 40-60%, 60-80%, and 80100% percent of sites were associated with viral load set points of 11,000, 67,000 and 107,000 copies respectively. Of course, the
higher the set point, the greater the HIV progression and the better the adaptation of escape mutants.
The overall effect was surprising. High adaptation scores had odds ratio of 2.20 fold (p=0.003) in a multivariate model with a variety
of protective mutations that persisted even though the only protective mutation was the CCR5 delta32 mutation, with an odds ratio
of -0.43 (a reduction of risk by 57%) that was statistically significant (p=.0512). In other words, the adaptive escape mutants in a large
number could overcome the effects of single protective genetic variations found in humans over time.
Similar adaptation mutants occur with respect to drug resistance as well. For example, HLA B7 is associated with indinavir resistance
at position 82 of the HIV-1 protease gene.
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Clinical Relevance of Genetic Variation
This symposium highlighted examples known associations between genetic variation in humans with differential effects on both
susceptibility to HIV infection and HIV disease progression. Once these associations are more completely understood, the result could
be the development of a battery of genetic tests that would identify patients who are at greater risk of disease progression, drug
resistance, or adverse drug reactions (such as abacavir hypersensitivity). Such testing would also identify those who are not likely to
progress and in whom antiretroviral therapy can be more safely delayed.There are also implications for vaccine development, as
known genetic variations in a population could dictate changes needed in various vaccine component targets to maximize the
protective effect.
S Ahuja. Genetic Condoms of HIV-1 Infection: Using Host Genetics to Dissect HIV-1 Pathogenesis. Session 11. Abstract 53 (not available).
S Mallal. HIV Adaptation to the Genetic Polymorphism of the Host. Session 11. Abstract 54 (oral).
M Carrington. Influence of the KIR Genes on HIV-1 Disease. Session 11. Abstract 55 (oral).
RA Kaslow and others. Comparison of Effects on Infection and Disease Progression. Session 11. Abstract 56.
MISCELLANEOUS STUDIES
By Ronald Baker, PhD
Does Pegylated Interferon Have a Role in the Treatment of Early Stage HIV Infection?
There is now overwhelmingly convincing evidence that the pegylated alfa interferons (PEG-Intron and Pegasys) offer a significantly
greater clinical benefit and significant improvement in the quality of life compared to standard interferon alfa (Intron A and Roferon)
for the treatment of patients with chronic hepatitis C.
Early in the AIDS epidemic, researchers experimented with standard interferon alfa for the treatment of HIV infection.This
therapeutic approach has largely been abandoned due to the sometimes severe adverse side effects of interferon alfa, especially among
patients with chronic and/or late stage HIV infection using Retrovir (zidovudine; AZT). However, standard interferon alfa is FDAapproved for the treatment of Kaposi’s sarcoma in AIDS patients with > 200 CD4+ cells/mm3 and for the treatment of genital warts.
Despite its toxicities, interferon alfa is known to have both antiviral and immuno-enhancing effects.To assess the potential for the new
pegylated interferons to contribute to current therapy for HIV, researchers in Bochum, Germany conducted a controlled pilot study
using pegylated interferon alfa-2b (PEG-Intron) in 10 treatment-naïve patients with asymptomatic HIV infection.
The 10 patients were enrolled in 2 study arms (treatment group = 5 pts; control group = 5 pts).Those in the treatment group
received 80 micrograms PEG-Intron subcutaneously once weekly for 24 weeks.This compares to the standard dose of PEG-Intron
1.0 micrograms per kilogram of body weight given weekly in the treatment of chronic hepatitis C, and which is almost always given
in combination with ribavirin 800-1200mg daily)
After 24 weeks, no study participants experienced severe side effects, according to the investigators.The mean number of CD4 cells in
the treatment group rose from 462 cells/mm3 to 611 cells/mm3 versus a decline of 535 to 450 cells/mm3 in the control group.
Furthermore, the plasma HIV-RNA in the treatment group declined 0.9 log10 versus a plasma HIV-RNA increase of 0.8 log10 in
the control group, according to the researchers.
Based on the viral load decrease and the CD4 increase in the low dose treatment group, the German investigators conclude,
“pegylated interferon alfa –[2b] allows early control of HIV replication and a rapid decline of the viral reservoir while CD4-cell levels
improve…..Pegylated interferon alfa monotherapy might be a new therapeutic option in the treatment of early-stage HIV infection.”
Commentary
While the results of this small pilot study in Germany are intriguing and somewhat encouraging, larger studies will be needed to
validate the results of significantly decreased viral load and significantly increased CD4 cell counts from the use of pegylated
interferon monotherapy in asymptomatic HIV patients. In addition, the adverse side effects of pegylated interferon alfa could limit the
utility of this therapeutic strategy in many patients.
I Schugt and others. Pegylated Interferon Alfa-2b: A New Therapeutic Option in the Treatment of Early-stage HIV Infection.
Abstract 59 (oral).
Older Age Predicts HIV Disease Progression with or without HAART
Older age is a strong predictor of accelerated HIV disease progression, both in the presence and in the absence of HAART.To
identify potential immune correlates of this interaction, the current study compared the viral and immune responses to a uniform
antiretroviral regimen according to age.
10th Conference on Retroviruses and Opportunistic Infections
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HIV and Hepatitis.comTM
This study was a multi-center, prospective treatment trial of older (?45 yrs) and younger (£30 yrs) HIV positive antiretroviral therapynaïve subjects, with HIV-RNA > 2000 copies/ml and CD4 < 600 cells/mm3. All subjects received lopinavir/ritonavir, d4T and FTC.
Forty-five (45) older (median age 50; range 45–79 yrs) and 45 younger (median 26; 18–30 yrs) subjects with similar demographic
characteristics were enrolled.
Baseline median values for older vs younger subjects were log10HIV-RNA: 4.81 vs 4.45 (p = 0.083); CD4 counts 155 vs 287 (p =
0.029); naïve CD4 counts 37 vs 105 (p < 0.001); and naïve CD8counts 125 vs 185 (p = 0.030).
At 48 wks, HIV-RNA < 50 copies/ml was found in 30 of 41 (73%) older subjects compared with 26 of 39 (67%) younger subjects
(p = 0.628). Median changes (and IQR) from baseline to wk 48 in T-cells were:
Older, n = 41
Younger, n = 39
P-values
CD4 counts
155
(92,264)
188
(109,300)
—
CD4%
9
(5,13)
8
(5,12)
—
NaïveCD4 counts
47
(18, 86)
85
(44,139)
0.028
Naive CD4 %
3
(-3, 8)
3
(-3,12)
—
CD8 counts
22
(-198, 296)
-1
(-227, 167)
—
CD8%
-11
(-17, -6)
-10
(-16, -4)
—
NaïveCD8 counts
56
(11, 128)
102
(53, 170)
—
Naïve CD8%
9
(2, 12)
13
(8, 20)
0.019
There were no differences between the groups in changes, from baseline to wk 48, in other T-cell phenotypes.
The authors conclude, “ Despite similar virologic responses, older HIV-infected subjects had reduced naïve T-cell restoration with
antiretroviral therapy. A diminished potential for naïve cell reconstitution may contribute to the heightened, age-related morbidity and
mortality in HIV-disease.” This study was supported by the German Competence Network HIV/AIDS Ministry of sciences (BMBF).
R Kalayjian and others. Older Age is Associated with Reduced Naïve T-cell Responses to Antiretroviral Therapy: 48-week Results of ACTG
Protocol 5015. Abstract 346 (poster).
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G L O S SA R Y O F T E R M S
Adipocytes: fat cells
Adipose: fatty; relating to fat
Adiposity: obesity
Arthralgia: pain in one or more joints
Atherosclerosis: fat accumulation in the medium- and
large-sized arteries
Avascular necrosis: death of bone due to poor blood supply
BIA: bioimpedance analysis
Dorsocervical: relating to area of the back nearest the neck
Dyslipidemia: a disorder in the distribution of fat
Glucose intolerance: abnormal metabolism of sugars
HDL cholesterol: high density lipoprotein (“good”)
cholesterol
Lipodystrophic: characterized by fat loss in the extremities
and/or fat build up in the abdomen, breasts or back
Lipodystrophy: strictly speaking, means “abnormal fat”.
Includes lipoatrophy and/or central obesity (fat accumulation) in
the belly or breasts
Lipolysis: the breakdown of fat
Lipoma: a tumor of fatty tissue
Mitochondria: energy factories within all cells. Many of the
side effects of nucleoside analogue drugs are thought to be
secondary to mitochondrial damage
Mitochondrial Toxicity: damage to mitochondria
Myocardial infarction: a “heart attack” caused by sudden loss
of blood supply in the heart
Myositis: muscular discomfort or pain
Osteopenia: reduced bone mass
Hypercholesterolemia: elevated blood cholesterol
(about 200 mg/dl)
Osteoporosis: severe thinning of bone
Hyperglycemia: an excess of sugar in the blood
Randomized study: study where patients are randomly
assigned to receive different treatments
Hyperinsulinemia: an overabundance of insulin in the blood
Hyperlipidemia: the presence of high levels of fat (lipid) in
the blood
Statin: inhibitors of HMG-CoA reductase, an enzyme needed
for the body’s production of cholesterol
Thermogenesis: the production of heat in the body
Hypertriglyceridemia: elevated blood triglycerides
(about 200 mg/dl)
Vasoconstrictor: an agent that narrows blood vessels
Lactic acidemia: Increased lactic acid levels in the blood
Vasodilator: an agent that widens blood vessels
LDL cholesterol: low density lipoprotein (“bad”) cholesterol
Visceral adiposity: fat accumulation in the large cavity of
the trunk
Lipoatrophy: loss of fat under the skin, generally in the face,
arms, legs, and buttocks
10th Conference on Retroviruses and Opportunistic Infections
51
Figure 5. Virologic Success in Gilead Sciences Study 903
Figure 6. Percent of Patients
Undetectable in HIV-NAT 001.4
Figure 7. Weight Changes and DEXA
Findings in Gilead Sciences Study 903
Figure 9. Median Viral Load Changes in T-1249-102
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