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HIV-treatment bulletin
ISSN 1472-4863
VOLUME 3 NO.4
MAY 2002
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TREATMENT
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Volume 3 No.4 - MAY 2002
ANTIRETROVIRALS
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METABOLIC TOXICITIES AND SIDE EFFECTS
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Incorporating resistance testing into clinical practice
Management of co-infection with HIV and TB
The March 2002 issue of The PRN Notebook
Entry and fusion inhibitors: an update
Nucleoside reverse transcriptase inhibitors: resistance, cross-resistance and resistance testing
Polypharmacy problems: drug interactions in the multidrug therapy of HIV infection
The plot thickens: KSHV and molecular piracy
PUBLICATIONS AND SERVICES FROM i-BASE
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Gilead made misleading and illegal statements about Viread, says FDA
Barcelona conference organisers issue nine-point plan of action on global emergency
ON THE WEB
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HIV infection is a risk factor for external genital warts, study suggests
American study finds KS-associated herpesvirus is highly prevalent among gay men
OTHER NEWS
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Altered adipocyte differentiation associated with protease inhibitors and lipoatrophy
High mortality rate in patients with severe NRTI-associated lactic acidosis
Tenofovir adversely affects development in foetal monkeys
Tenofovir not toxic to mitochondria in human cell culture
OPPORTUNISTIC EVENTS
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Hydroxyurea: in vitro evidence of potency against HIV viral reservoirs
Reduction of mother to child HIV-1 transmission: Breastfeeding negates benefits of short course regimens
Nevirapine at the centre of MTCT controversy
Mothers, orphans, and prevention of paediatric AIDS
Transient increases in viral load are common among people on HAART, finds a study of UK patients
Meta-analysis supports triple therapy for HIV infection
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New issue of Positive Treatment News (PTN)
Changing treatment: an updated guide to second-line and salvage therapy
French and Chinese translations of our booklet on avoiding and managing side effects
Treatment information request service
Order i-Base publications via the internet, post or fax
Editor: Paul Blanchard Associate Editor: Graham McKerrow Medical Consultants: Dr Graeme Moyle, Chelsea & Westminster Hospital, London. Dr Stefan
Mauss, Düsseldorf. Prof. Clive Loveday, Royal Free Hospital, London. Dr Gareth Tudor-Williams, Imperial College, London. Dr Karen Beckerman, UCSF, USA.
HIV Treatment Bulletin
Vol 3 No 4 May 2002
ANTIRETROVIRALS
Hydroxyurea: in vitro evidence of potency against HIV viral reservoirs
Dendritic cells (DCs), which take up antigen and display it to the immune system, are found in the skin, joints and circulating
blood as well as in lymphoid tissue. HIV is able to infect a number of different types of immune system cells, and there is
mounting evidence that DCs play an important role in the disease.
Along with macrophages, DCs are now thought to be responsible for spreading the initial HIV infection, despite HIV replication
occurring at only very low levels in these cells. DCs are also thought to act as a long-term reservoir of the virus. Failure to
eradicate sequestered virus can result in a rebound of infection, and archiving of resistant mutant viruses in such reservoirs
negates re-use of a drug that has previously failed, even after a prolonged treatment holiday.
The treatment options for HIV-infected individuals include a range of different drugs, and previous work has established that
cells of the immune system are differentially susceptible to these agents. In vitro analysis carried out by Giampiero Piccinini,
and published in the Journal of Virology this month, was designed to compare the antiretroviral activity of different agents in
dendritic cells and T lymphocytes.
Cells were cultured in the presence of either hydroxyurea, a chemical that reduces the availability of dNTPs that are required
for viral DNA replication, or one of two inhibitors of the HIV protease enzyme, ritonavir and indinavir. The drugs were
administered at therapeutic concentrations. The study found evidence that HIV was released at a low level by DC cultures,
measured by recording the level of a viral protein, p24. However, when incubated with hydroxyurea or indinavir viral release
from DCs was potently inhibited.
The antiretroviral activity of these agents, and that of ritonavir, was then compared in parallel experiments, in DCs and
lymphocytes. The protease inhibitors were found to completely inhibit HIV release in lymphocytes, but not in DCs, at the
maximum drug concentration used. In contrast, clinically relevant concentrations of hydroxyurea were found to significantly
inhibit release of the virus in DC but not T lymphocyte cells.
Control experiments accounted for any effects of drug toxicity on the cells, and found that the agents did not induce maturation
of the DCs, a phenomenon known to affect virus release.
Finally, the ability of the agents to prevent the spread of HIV from DCs to lymphocytes was gauged. In the absence of drugs,
the amount of viral antigen released into mixed cultures of HIV-infected DCs and uninfected lymphocytes increased as a result
of lymphocyte infection and consequent viral replication. In the presence of hydroxyurea, release of HIV was strongly inhibited.
Since the previous experiments had shown no effect of hydroxyurea on T lymphocytes, the authors conclude that the agent
potently suppressed the transmission of HIV from DCs.
These results suggest that a drug that selectively targets HIV in viral reservoirs may be an important addition to a successful
antiretroviral regimen. Clinical trials to determine the toxicity profile of new combinations are needed before studies can be
carried out to assess the clinical relevance of these findings.
Ref: Piccinini G, Foli A, Comolli G et al. Complementary antiviral efficacy of hydroxyurea and protease inhibitors in human immunodeficiency virusinfected dendritic cells and lymphocytes. J Virol 2002 Mar;76(5):2274-8
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11836405&dopt=Abstract
Source: Mediscover Infectious Diseases
http://www.mediscover.net/menu2.cfm
Reduction of mother to child HIV-1 transmission:
Breastfeeding negates benefits of short course regimens
‘Short course regimens to prevent mother-to-child transmission of HIV-1 in less-developed countries should be accompanied
by interventions to minimise the risk of subsequent transmission via breastfeeding’
Antiretrovirals and elective caesarean sections have successfully reduced mother-to-child HIV-1 transmission rates in the
more-developed world. With limited resources in the less-developed world, short-course anti-retroviral regimens are the most
feasible option to reduce transmission to a minimum. The Petra study team did a randomised controlled trial to assess the
efficacy of different regimens with zidovudine and lamivudine in 1797 women. They report two regimens that were effective
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in reducing HIV-1 transmission up to week 6 after birth; however, the benefits had diminished considerably after 18 months
of follow-up. These results emphasise the importance of including interventions to reduce the risk of vertical transmission via
breastfeeding. In a Commentary (see below), Karen Beckerman adds that instead of inducing resistance to AIDS therapies,
prophylaxis against mother-to-child transmission must be linked to preventing the creation of orphans.
Source: The Lancet
Nevirapine at the centre of MTCT controversy
Polly Clayden, HIV i-Base
In recent weeks the spotlight has been on the drug nevirapine and its role in the reduction of mother to child transmission
(MTCT). The results of the HIVNet 012 study — in which a single dose of nevirapine given to a mother in labour followed by
a single dose to her baby was shown to significantly reduce the incidence of mother to child transmission — and data from
other studies supporting these findings, was followed by an application submitted to the US Food and Drug Administration
(FDA) by the drug’s manufacturer Boehringer Ingelheim to market the drug for this purpose.
On examination, the HIVNet 012 results were found to have paperwork irregularities and therefore may not conform to the
FDA regulatory requirements, and owing to the timeline for the review, Boehringer then withdrew the application. The company
will however continue to support the use of nevirapine and to donate the drug to developing countries for the prevention of
mother to child transmission.
This news of the FDA’s concerns was greeted with alarm by some, provoking statements from the WHO/UNAIDS, the National
Institute of Allergy and Infectious Diseases (NIAID), the Elizabeth Glaser Foundation and several activist groups, defending
the drug’s safety and its use within this setting.
None of these statements, however, addressed the ease with which nevirapine resistance can occur — from even a single
dose — or the importance of treating the mother’s own disease and risking her future treatment options.
Meanwhile, in her commentary, reproduced below, following the publication of the results from the PETRA trial which used
a two-drug combination of AZT and 3TC to reduce mother to child transmission, Dr Karen Beckerman, writing in The Lancet,
criticises these interventions which ignore treatment for maternal disease and the inevitable creation of orphans.
She asks: “Is it justifiable to visit the antiretroviral mistakes of the industrialised world on regions that have been devastated
by the HIV epidemic but are at least antiretrovirally naïve?”
Beckerman argues for strategies that save the lives of mothers, and continues that the “lack is particularly disturbing in view
of the developed world’s experience that treatment of maternal HIV disease results in transmission rates far lower than
transmission prophylaxis alone.”
Mothers, orphans, and prevention of paediatric AIDS
Karen Palmore Beckerman, MD
In the Lancet (6 April 2002), investigators from the Petra trial of the prevention of transmission of HIV from mother to child report
that short-term prophylaxis with a two-drug antiretroviral combination significantly reduces vertical transmission rates more
than two-fold in early infancy. At 6 weeks of age, 15% of infants in the placebo group were infected, compared with 6% in the
group that received antepartum, intrapartum, and neonatal prophylaxis with zidovudine plus lamivudine. However, when
measured as HIV-free survival at 18 months of age, this benefit was not sustained.
This study was planned many years ago and used a two-drug combination that, in developed countries at least, is no longer
administered without a third antiretroviral agent. While the risks and benefits of such an intervention were acceptable when
this study was planned, progress in HIV treatment and geometric expansion of the HIV pandemic have altered such
considerations significantly.
Benefits of prophylaxis for perinatal transmission include protection of babies from HIV infection and an opportunity to
introduce communities to AIDS education, testing, and drugs. Considerable infrastructure is required for the distribution of
even the simplest antiretroviral prophylactic regimens—a good start when looking forward to expansion of AIDS therapies in
the developing world. Indeed declines in cost of AIDS therapies, availability of generic and proprietary formulations of double
and triple antiretroviral combinations, and changing global commitment against the pandemic have made arguments
discounting the feasibility of treatment access in poorer nations largely irrelevant. Successful AIDS treatment protocols among
the marginally housed, the urban poor in Brazil, and the displaced rural poor in Haiti have been published.
The risks of Petra and other perinatal prophylaxis interventions, such as HIVNET 012, which use single-dose nevirapine
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intrapartum and neonatally as prophylaxis, have increased in proportion to the increasing probability of access to AIDS
treatment in resource-poor settings. Treatment success in such regions will hinge on the use of low-pill-burden non-proteaseinhibitor combinations, relying on the very classes of drugs used in such studies. Nevirapine prophylaxis used in HIVNET 012
resulted in selection of single-point mutations strongly associated with high resistance to non-nucleoside reverse transcriptase
inhibitors that were detectable in 19% of mothers and 46% of the 16% of infants infected despite nevirapine prophylaxis. Given
the 6-week absence of nevirapine exposure (and therefore of selective pressure favouring replication of resistant virus), the
reported resistance underestimates the true rates. That these mutations may fade from detection after a year provides little
comfort. The K103N and Y181C mutations produce virus that is resistant and fit (ie, will continue to replicate and compete
with wild-type virus, even in the absence of nevirapine to produce selective pressure against wild-type virus), and current
assays fail to detect minority populations and mutations archived in lymphocytes. By contrast with HIVNET 012, where
intrapartum and neonatal exposure to nevirapine or zidovudine was limited, the Petra interventions led to ongoing maternal
exposure to zidovudine plus lamivudine from 36 weeks’ gestation (arm A) or from delivery (arm B) to 7 days’ postpartum.
Induction of significant single-mutation (M184V ) lamivudine resistance in one or both of these arms is certain.
Is it justifiable to visit the antiretroviral mistakes of the industrialised world on regions that have been devastated by the HIV
epidemic but are at least antiretrovirally naive? Active deployment of Petra A or B or the HIVNET 012 protocols for millions
of pregnancies (as both teams and many others advocate) may prevent hundreds of thousands of paediatric infections per
year. However, these same women and their infected children exposed to short-course zidovudine plus lamivudine or singledose nevirapine will be at substantial risk of treatment failure when antiretroviral therapy becomes available.
Instead of inducing resistance to AIDS therapies, prophylaxis against mother-to-child transmission must be linked to
preventing the creation of orphans. We know that 3-4% of HIV-infected sub-Saharan mothers die within a year of delivery.
Within 2 years, 11% of HIV-infected breast-feeding mothers die. Their babies are unlikely to survive infancy. An older child
who survives the death of mother will join the rapidly growing global ranks of orphans less than 15 years of age predicted to
reach 44 million by 2010. With or without antiretroviral prophylaxis, most of these children will be HIV-uninfected. They will
face extraordinary risk of inadequate nutrition, housing, and health care, in addition to servitude, harshness, abuse, and
acquisition of HIV infection themselves. Sub-Saharan teenagers will outnumber adults by 2020, rendering already politically
unstable regions potentially explosive. However, although support for home care, community programmes, and government
services are routinely mentioned as effective responses to the global orphan tragedy, strategies to prevent the creation of
orphans - that is, saving the lives of parents - are rarely discussed. This lack is particularly disturbing in view of the developed
world’s experience that treatment of maternal HIV disease results in transmission rates far lower than transmission prophylaxis
alone.
The silence surrounding HIV disease and maternal health has been long-standing. Typical of perinatal prophylaxis trials, the
Petra report mentions no maternal-health endpoints and no maternal mortality data later than 6 weeks after birth. 10-15 years
into the pandemic when these trials were conceived, treatment access and success had not been widely demonstrated or
acknowledged anywhere in the world. Now, in the third decade of AIDS, HIV prevention and AIDS treatment can and must
be integral parts of the global response to the AIDS catastrophe. What better place to start than with mothers and children?
Ref: Beckerman KP. Mothers, orphans, and prevention of paediatric AIDS. Lancet 2002 Apr 6;359(9313):1168-9.
Fully referenced text at:
http://www.thelancet.com/journal/vol359/iss9313/full/llan.359.9313.editorial_and_review.20702.1
Correspondence: Karen Palmore Beckerman, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San
Francisco/San Francisco General Hospital, San Francisco, CA 94110, USA (e-mail:[email protected]).
Full Petra study paper text at:
http://www.thelancet.com/journal/vol359/iss9313/full/llan.359.9313.original_research.20661.1
An alternative view on the usefulness of nevirapine in the reduction of MTCT has been articulated by Bob Huff of Gay Mens
Health Crisis (New York). He starts his article by stating:
“A single-dose of the AIDS drug nevirapine when taken at the onset of labor is a proven method for dramatically reducing
rates of mother to child transmission (MTCT) of HIV. So why does Dr. Joep Lange, President of the International AIDS
Society and vocal advocate for expanding the worldwide access to antiretroviral (ARV) drugs, take every opportunity to
warn that resistance to nevirapine (NVP) can arise after single-dose use? His purpose is to raise this question: if singledose NVP brings resistance, then should the drug be reserved exclusively for chronic treatment regimens and never used
as a single-dose for preventing MTCT? Such talk causes shivers of alarm to dance through the networks of doctors and
advocates working to extend ARV medicines to all corners of the world. But what is the basis for his nervousness?”
Full text available at:
http://www.gmhc.org/living/treatment/ti1603/ti1603.html#5
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Transient increases in viral load are common among
people on HAART, finds a study of UK patients
Graham McKerrow, HIV i-Base
Transient increases in viral load are common among patients for whom highly active antiretroviral therapy (HAART) has
previously reduced their viral loads to fewer than 50 copies/mL, according to a study at the Royal Free Hospital in London.
Researchers found that 35% of the patients they studied had transient increases in their viral loads, most of them in the 50
to 400 copies/mL range.
For the majority of people studied, subsequent viral load estimations showed a return to fewer than 50 copies/mL. The
researchers, led by Dr Antonia Moore, advise in the journal AIDS of 8 March 2002 that: “A single raised viral load should lead
to adherence support and intensified monitoring. Subsequent treatment decisions can then be based on evidence of true
virological rebound or failure.”
Dr Moore’s team at the Royal Free Centre for HIV Medicine followed a cohort of 553 patients on HAART with viral loads of
fewer than 50 copies/mL from their first viral load of fewer than 50 copies/mL (in some cases this was when the ultrasensitive
viral load assay first became available in the clinic) until their last viral load measurement or until they had experienced
virological failure (two consecutive viral loads > 400 copies/mL).
Of the 553 patients studied, 207 (37%) had a viral load of fewer than 50 copies/mL measured within 48 weeks of starting their
first HAART regimen, 79 (14%) between 48 and 72 weeks, 97 (18%) between 72 and 96 weeks, 86 (16%) between 96 and
120 weeks, and 84 (15%) after more than 120 weeks of treatment.
The majority of patients, 326 (66%), were taking three-drug combinations, although 45 (8%) were on more than five drugs.
The median follow-up time was 56 weeks (range 4-174 weeks). A total of 192 patients (35%) experienced at least one viral
load measurement over 50 copies/mL during the period of study, whereas 42 (8%) experienced virological failure as defined
above. Of the 192 patients with a value of more than 50 copies/mL recorded, 40% had values of more than 200 copies/mL.
The researchers report that those who had ever used more than four drugs were significantly more likely to experience both
a transient increase in viral load and virological failure than those who had used four or fewer antiretroviral agents (P < 0.0001
and P = 0.004, respectively).
In their conclusion, Dr Moore and colleagues write: “In our cohort it appears that those with an initial raised value of over 400
copies/mL are more likely to have a sustained increase and become virological failures, whereas those with a first raised value
of between 50 and 400 copies/mL have a follow-up of less than 50 copies/mL in the majority of cases and over 400 copies/
mL in under 10% of cases. Both ‘blips’ and virological failure were found to be more common in those patients with greater
drug experience.”
The explanation behind the increase in viral load is often established only in retrospect, they report, but a single raised value
may be the result of intercurrent infection or vaccination, which may be associated with a transient increase in viral load [2,
3].
Other transient increases may be the result of the emergence of drug resistance, but as shown in the study of Cohen Stuart
et al [4], in the short term, this does not necessarily translate into virological failure. Many such apparent increases could be
caused by assay variability.
In common with others [5], Dr Moore and colleagues found that two consecutive values of 50-400 copies/mL are likely to be
followed by a value of less than 50 copies/mL in approximately half the cases, and by a value of over 400 copies/mL in less
than 10% of cases.
The authors write: “In the context of any apparent increase in viral load, the importance of adherence must be reiterated [6],
and the patient’s drug combination must be assessed to evaluate the possibility of drug interactions, leading to subtherapeutic
levels of antiretroviral drugs and the possible emergence of resistant virus.
“As our results have shown, the majority of first viral load values over 50 copies/mL do not signal treatment failure, and are
more likely to turn out to be ‘transient’ increases. This finding may not be the result of a spontaneous reduction to less than
50 copies/mL, and is possibly the result of improved patient adherence when faced with the potential threat of treatment failure.
“A single increased viral load measurement should lead to adherence support and intensified monitoring of the patient in order
that subsequent treatment decisions can be based on evidence of true virological rebound or failure,” the authors advise.
References:
1. Moore AL, Youle M, Lipman M et al. Raised viral load in patients with viral suppression on highly active antiretroviral therapy: transient increase
or treatment failure? AIDS 2002 Mar 8;16(4):615-8
2. Gunthard HF, Wong JK, Spina CA et al. Effects of influenza vaccination on viral replication and immune response in persons infected with human
immunodeficiency virus receiving potent antiretroviral therapy. J Infect Dis 2000, 181:522-531
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3.
4.
5.
6.
King Jr JC, Treanor J, Fast PE et al. Comparison of the safety, vaccine virus shedding and immunogenicity of influenza virus vaccine, trivalent,
types A and B, live cold-adapted, administered to human immunodeficiency virus (HIV)-infected and non-HIV-infected adults. J Inf Dis 2000,
81:725-728.
Cohen Stuart JWT, Wensing AMJ, Kovacs C et al. Transient relapses (‘blips’) of plasma HIV RNA levels during HAART are associated with drug
resistance. J Acquir Immune Defic Syndr 2001, 28:105-113.
Greub C, Cozzi-Lepri A, Staszewski S et al. Swiss and Frankfurt cohorts. Low level HIV viral rebound and blips in patients receiving potent
antiretroviral therapy. In: 8th Annual Conference on Retroviruses. Chicago, 4-8 February 2000 [Abstract 522].
Paterson DL, Swindells S, Mohr J et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med
2000, 133:21-20.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11873005&dopt=Abstract
C O M M E N T
Although patients in this cohort study were receiving HAART it is unclear if this included both protease inhibitor
and NNRTI based combinations (or indeed triple nucleoside analogue combination). The significance of a
single increased viral load measurement may be expected to be of greater significance in NNRTI based
combinations due to the low genetic barrier to resistance that these agents present.
Further analysis in terms of class of combination would appear warranted.
Meta-analysis supports triple therapy for HIV infection
Analysis by British researchers of 54 randomised control trials involving more than 20,000 patients strongly supports the use
of triple therapy as the initial treatment for HIV-infected patients.
The University of Birmingham collaborators searched six electronic databases and citation lists and consulted pharmaceutical
companies for trials of HIV-seropositive patients at least 12 years old. The research reports included trials lasting 12 weeks
to nearly five years. Dr Rachel Jordan and associates report their findings in the British Medical Journal for March 30.
Triple therapy with two reverse transcriptase inhibitors (RTIs) and a protease inhibitor or a non-nucleoside reverse
transcriptase inhibitor reduced the risk of progression or death to 0.6 times that of patients receiving therapy with two RTIs.
Dropout rates were similar between triple and double therapy if no protease inhibitor was involved. However, trial arms that
included a protease inhibitor had significantly higher withdrawals.
Dr Jordan’s team notes that “no fully published evidence on the effectiveness of quadruple or higher combination” has been
presented as of February 2001.
Dr Charles Carpenter, of Brown Medical School in Providence, Rhode Island, comments in an associated editorial that patients
who adhere to triple therapy do so well that it is difficult to show a significant benefit to a four-drug regimen.
“However, a sound scientific rationale exists for using an initial four drug regimen that includes two protease inhibitors,” he
adds. Dr Carpenter recommends including a low dose of ritonavir, in addition to a second protease inhibitor, to provide a
booster effect while lowering the risk of viral resistance.
Source: Reuters
References:
1. Jordan R, Gold L, Cummins C et al. Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral
combination therapy, BMJ 2002; 324:757-760
http://bmj.com/cgi/content/full/324/7340/757
2. Carpenter C. Editorial; Initial antiretroviral regimens: In general three drugs are better than two are better than one, BMJ 2002;324:747-748
http://bmj.com/cgi/content/full/324/7340/747
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METABOLIC TOXICITIES AND SIDE EFFECTS
Altered adipocyte differentiation associated with protease inhibitors and lipoatrophy
Simon Collins, HIV i-Base
The underlying mechanisms for lipoatrophy have not yet been explained although in vitro and animal studies reported at the
annual lipodystrophy workshops have pointed to several possible theories. These include the class action of either protease
inhibitors through impaired adipocyte differentiation or reverse transcription inhibitors due to mitochondrial damage or indeed
a cumulative effect of these two classes together. Importantly, a new French study helps confirm that lipodystrophy is not
simply a matter of redistributed fat, or even absence or accumulation of fat at local sites, but involves structural changes to
fat cells resulting from interference with normal cell differentiation.
The French national INSERM laboratories have produced important research into impaired adipocyte differentiation
associated with protease inhibitors and Jean-Philippe Bastard and colleagues published their latest results in the Lancet of
23 March. [1] Previous studies from the group have shown in vitro effects of protease inhibitors on cell differentiation and insulin
sensitivity, and preventative effect in vitro of rosiglitazone against cell differentiation, apoptosis and insulin resistance. [2]
The new study looked at the internal structure of fat cells together with chemical markers of differentiation of these cells from
HIV-positive people with lipoatrophy and found significant differences to cells from a control group of HIV-negative individuals.
Adipocyte differentiation involves sequential activation of transcription factors that regulate the expression of adipocyte
specific markers – many of which have already been shown to be directly inhibited by protease inhibitor in vitro. This network
involves three major factors: CCAAT-Enhancer binding protein beta (C/EBP-b), peroxisome proliferator activated receptor
gamma (PPAR–g) and C/EBP-alpha that are activated in cascade. Differentiation is enhanced by sterol-regulatory-elementbinding-protein-1 (SREBP-1).
Twenty-six HIV-positive subjects (21 men, 5 women) with peripheral lipoatrophy (treated with both PIs and RTIs) were
consecutively selected from a sample of patients undergoing autologous fat transfer at a single hospital. The control group
contained eight women undergoing abdominal level plastic surgery and 10 men in a nutritional study that involved
subcutaneous biopsies.
Subcutaneous abdominal fat was sampled in all cases, immediately fixed in 10% zinc formol, embedded in paraffin, cut into
5mm slices and stained with haemalun-phloxine-safron. The size of 100 adipocytes were measured on to separate slices for
each sample. The concentration in fat-tissue RNA of transcription factors involved in adipocyte differentiation was measured
by reverse transcription followed by competitive PCR amplification.
Results
Fat cells from the control group were relatively homogenous in size and distribution whereas fat from HIV patients contained
clusters of small cells together with normal cells. The percentage of cells < 50um and <70um was 6% vs 13% and 18% vs
32% in the control and HIV group respectively. Mean size of adipocytes (including > 90% cells) was 117um (SD 24) in the
control and 94um (SD15) in the HIV-positive group (p=0.03).
Concentration of transcription factors and adipose markers was also consistently higher in the control group:
C/EBP-a
C/EBP-b
PPAR-g
SREBP-1c
GLUT-4
Leptin
TNF-a
Median total mRNA concentration (amol/ug)
Control
HIV-positive lipoatrophic
114
23
29.1
12.9
13.5
3.3
25.2
1.6
24.7
4.7
4.82
0.18
0.043
0.126
Concentrations of transcription factors and adipocyte markers correlated in most cases and often strongly (C/EBP-a and
GLUT-4, and C/EBP-a and Leptin, both p <0.0001). Concentrations of TNF-a, a cytokine secreted by adipose tissue that has
been reported to inhibit expression of adipogenic factors and induce adipocyte apoptosis was 2.9-fold higher in patients, and
this correlated negatively with levels of SREBP-1, C/EBP-a and PPAR-g.
The researchers suggest that the larger proportion of smaller cells and clusters of small cells in the HIV-positive patients could
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be young regenerative cells replacing previous cells lost by apoptosis – rather than representing a general thinning of cells
caused by triglyceride depletion – and that this would be supported by increased levels of TNF-a.
The alteration of adipocyte function at the level of SREBP-1, which has been shown in murine models to directly link to
dyslipideamia, diabetes and insulin resistance, could enhance adipose tissue dysfunction, possibly through increased
adipocyte expression and result in lipoatrophy through both loss of adipocytes and reduction in adipocyte size.
As SREBP-1 has already been shown to be targeted by protease inhibitors in vitro the study concludes that lipoatrophy may
therefore be a protease effect. The researchers acknowledge that the role of RTIs, which fail to alter adipocyte differentiation
in vitro, but which may work in synergy with protease inhibitors at the onset of lipoatrophy, remains to be determined.
References:
1.
2.
Bastard J-P, Caron M, Capeau J – Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from
HV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet March 23 Vol359 1026-1031.
Caron M, Auclair M, Capeau J et al – Differential in vitro effects of indinavir, nelfinavir and amprenavir on cell differentiation, insulin sensitivity
and apoptosis in an adapted adipose cell model: preventative impact of rosiglitazone. Antiviral Therapy 2001; 6 (Supplement4):17.
C O M M E N T
It is disappointing that, while early results of thiazolidinediones, particularly the PPAP-g modulators rosiglitazone
and piaglitazone have shown improvement in congenital and acquired lipoatrophy, they have shown
disappointing results in early HIV studies. Notably, rosiglitazone failed to show benefit after 24 weeks dosed
at 8mg/day at the recent Retrovirus conference. Perhaps these metabolic effects are particularly resistant to
reversal in the setting of HIV-infection.
In relation to the above study researchers from Switzerland reported last year (Miserez AR. AIDS 2001 Oct
19;15(15):2045-9) that a single-nucleotide polymorphism in the sterol-regulatory element-binding protein 1c
gene is predictive of HIV-related hyperlipoproteinaemia. SREBP-1c-3’322C/G was predictive of highly active
antiretroviral therapy-related hyperlipoproteinaemia. Additionally Increases in cholesterol were less frequently
associated with homozygous SREBP-1c-3’322G (genotype 22) than with heterozygous/homozygous SREBP1c-3’322C (genotypes 11/12) and correlated with leptin and insulin increases, particularly in genotype 11/12
carriers.
Controlled trials initiating agents such as rosiglitazone at the same time as initiation of antiretrovirals may be
useful to determine if any preventative action may be possible. Perhaps patient selection for such prophylactic
use may also be guided by genotyping of the SREBP-1c gene.
High mortality rate in patients with severe NRTI-associated lactic acidosis
Graham McKerrow, HIV i-Base
Lactic acidosis, a rare side effect of treatment with nucleoside-analogue reverse transcriptase inhibitors (NRTIs), is often fatal,
according to a study by doctors at Barcelona.
They studied 5,400 HIV-positive patients attending four Spanish hospitals and being treated with NRTIs over a four-year
period, and found that 12 developed otherwise unexplained metabolic lactic acidosis.
The researchers, led by Dr Vicente Falco of the Infectious Diseases Division of the Hospital Vall d’Hebron in Barcelona, also
reviewed 60 additional published cases in order to describe the clinical picture, prognostic factors and final outcome for
nucleoside-associated lactic acidosis.
They report that the mortality rate is high: 33% for their own patients, and 57% for the patients described in the literature.
Multivariate analysis revealed that a range of factors including CD4+ T cells and age were not associated with mortality, but
that there was one “strongly positive” correlation. A lactate serum level of > 10mM (odds ratio [OR], 13.23, 95% confidence
interval [CI], 2.96-59.25) was the only factor associated with higher mortality.
The administration of essential cofactors like thiamin and riboflavin could play an important role in the treatment of patients,
report the authors. Seven of the group of 12 patients were treated with riboflavin, some also with thiamin, and only one of these
patients died. Eleven of the patients reported in the literature received essential cofactors and of them three died, which
represents a lower mortality rate than that for patients who were not given the cofactors.
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The efficacy of this type of treatment has yet to be established, but the authors say that there appears to be no risk of toxicity
with the cofactors so they recommend their use in patients with this rare and severe complication.
They conclude: “The administration of specific therapy with cofactors against acidosis was associated with a lower mortality
(OR, 0.17, 95% CI, 0.04-0.73). We conclude that specific therapy with cofactors may improve the outcome for patients with
this syndrome.”
Ref: Falco V, Rodriguez D, Ribera E et al. Severe nucleoside-associated lactic acidosis in human immunodeficiency virusinfected patients: report of 12 cases and review of the literature. Clin Infect Dis 2002 Mar 15;34(6):838-46
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850865&dopt=Abstract
Tenofovir adversely affects development in foetal monkeys
Brian Boyle MD, for HIVandHepatitis.com
Studies have shown that the newest antiretroviral to be approved by the US Food and Drug Administration (FDA), tenofovir
(Viread), crosses the placenta in sufficient quantities to result in sustained reductions in viral load in simian immunodeficiency
virus (SIV)-infected foetal monkeys. In some studies, however, chronic exposure to tenofovir has been shown to cause
significant bone-related toxicity in 25% of the monkey infants studied.
In order to better clarify the potential risk of toxicity in foetal monkeys exposed to tenofovir, investigations were conducted using
four gravid rhesus monkeys that were given 30mg/kg subcutaneously of tenofovir once daily from days 20 to 150 of gestation.
The study results were recently published in the Journal of Acquired Immune Deficiency Syndromes.
The investigators found that although the infants did not develop any gross structural abnormalities and had relatively normal
foetal development, they had lower overall body weights and crown-rump lengths than those for age-matched controls, a
significant reduction in circulating IGF-I (insulin-like growth factor), a small reduction in foetal bone porosity, and transient
alterations in maternal body weights and bone-related biomarkers during the treatment period.
The authors conclude: “Although tenofovir is highly efficacious, when considering the treatment of gravid individuals, several
factors should be considered. First, we have shown that exposure to tenofovir at 30mg/kg can have an impact on select foetal
parameters, including body weight, circulating IGFs (insulin-like growth factors), and bone porosity… Nevertheless, the
benefits of tenofovir, including efficacy when administered once daily to HIV- and SIV-infected individuals and efficiency in
crossing the placenta in quantities sufficient to suppress viral load, must also be considered.
“Although the efficient placental transport and significant reduction of viral loads in SIV-infected foetuses were shown to result
in healthy newborns in our prior studies, the potential long-term ramifications of exposure may warrant more restricted use
in pregnancy and at significantly lower doses than the one investigated in these studies.”
Ref: Tarantal AF, Castillo A, Ekert JE et al. Fetal and Maternal Outcome After Administration of Tenofovir to Gravid Rhesus Monkeys (Macaca
mulatta). JAIDS 2002; 29:207-220.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11873070&dopt=Abstract
Copyright 2002 by HIV and Hepatitis.com. All Rights Reserved.
C O M M E N T
It should be noted that the daily dose of tenofovir administered to the monkeys in this study (30mg/kg)
corresponds to a daily dose in humans of about 2100mg per day. The approved dosage of tenofovir as a
component of HIV treatment is 300 mg per day.
The tenofovir in this study was also administered subcutaneously to these monkeys which should provide
close to 100% bioavailability. In humans, however, tenofovir is dosed orally with an oral bioavailability of 25
– 40% depending on fasting state.
A rough calculation would suggest, therefore that the doses of tenofovir used in this study were 17 to 28 times
higher than the therapeutic levels achieved during HIV treatment.
Caution would seem to be warranted in the interpretation of these findings and further studies are needed to
determine the correct role (if any) of tenofovir in pregnant women. Given the delayed development of resistance
and the long half-life of this agent it may represent a useful candidate for inclusion in MTCT regimens.
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Tenofovir not toxic to mitochondria in human cell culture
Unlike nucleoside reverse transcriptase inhibitors (NRTIs) used to treat HIV infection, the nucleotide analogue tenofovir
(Viread) is not associated with mitochondrial toxicity at concentrations well above those seen clinically, according to a report
in the March issue of Antimicrobial Agents and Chemotherapy.
Many of the clinical toxicities associated with NRTIs have been attributed to their mitochondrial toxicity, the authors explain.
Dr Tomas Cihlar and colleagues, from Gilead Sciences (the manufacturers of tenofovir) in Foster City, California,
characterized the potential of tenofovir and currently used NRTIs to cause mitochondrial toxicity in various types of cells of
human origin.
In concentrations ranging from 3 to 300 micromolar, tenofovir caused no significant changes in mitochondrial DNA levels in
human hepatoblastoma cells, skeletal muscle cells, or renal proximal tubule epithelial cells, the authors report.
Along with abacavir (Ziagen) and lamivudine (Epivir), tenofovir was the least potent drug in inhibiting mitochondrial DNA
synthesis, the report indicates, followed (in increasing order) by zidovudine (Retrovir), stavudine (Zerit), didanosine (Videx),
and zalcitabine (Hivid).
Moreover, tenofovir increased extracellular lactate production by less than 20%, the results indicate, compared with two- to
threefold increases by zidovudine and 30% to 50% increases by ddC.
“In summary, this study demonstrates that the potential of the anti-HIV nucleotide analogue tenofovir to induce mitochondrial
toxicity in different human cell types is low,” the authors conclude. “These data are consistent with the favorable tolerability
profile of tenofovir observed in HIV-infected patients.”
Ref: Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside
reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002 Mar;46(3):716-23
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11850253&dopt=Abstract
Source: Reuters Health
OPPORTUNISTIC EVENTS
HIV infection is a risk factor for external genital warts, study suggests
Graham McKerrow, HIV i-Base
The development and recurrence of cervical lesions associated with the human papillomavirus (HPV) are more common in
HIV-infected women than in HIV negative women, according to an Italian study of 1,336 patients.
Relapses after treatment for external genital warts were more common in women with HIV than in those without, report Dr
Giuseppe De Panfilis and colleagues at the Department of Dermatology at Brescia Hospital, Brescia, Italy, in the March issue
of the journal Sexually Transmitted Diseases. They advise clinicians to encourage patients with recurring genital warts to be
tested for HIV.
Dr De Panfilis and colleagues compared relapses after treatment for external genital warts in 241 HIV-positive and 1,095 HIVnegative patients examined between 1990 and 1999 at the STD centre at Brescia. Various local treatments were used.
Treatment generally triggered recovery from the lesions, report the researchers, but the relapses observed up to one year after
response, examined by survival analysis, were significantly (P < 0.001) more frequent in the HIV-positive (160 cases, 66.4%)
than in the HIV-negative (294 cases, 26.8%) subjects. Multiple relapses observed up to one year after treatment occurred in
69 of 241 HIV-positive patients, as compared with 14 of 1,095 HIV-negative subjects (P < 0.001).
A comparable pattern of recurrences of cervical intraepithelial neoplasia (CIN), which like genital warts are also associated
with HPV, was also observed by Dr De Panfilis and colleagues. In 127 HIV-positive women referred for CIN evolution,
recurrences continued to develop after treatment, reaching 62% by three years. However, CIN recurred in only 18% of 193
HIV-negative patients over a similar time period.
The authors write: “Thus, as with CIN, we can assume that the natural histories of external genital warts after treatment in HIVpositive and HIV-negative subjects are distinct.” And they conclude: “According to the study findings, HIV infection can be
considered a risk factor for the development and recurrence of external genital warts. Multiple relapses should drive patients
to HIV testing.”
Ref : De Panfilis G, Melzani G, Mori G et al. Relapses after treatment of external genital warts are more frequent in HIV-positive patients than in HIVnegative controls. Sex Transm Dis 2002 Mar;29(3):121-5
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11875372&dopt=Abstract
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American study finds KS-associated herpesvirus is highly prevalent among gay men
Graham McKerrow, HIV i-Base
Infection with Kaposi’s sarcoma-associated herpesvirus (KSHV) is common among men who have sex with men (MSM),
according to a study by researchers in Seattle, USA.
The incidence of KSHV among the gay and bisexual men studied is even higher than the incidence of genital herpes, the
researchers report in the 1 April issue of the Journal of Infectious Diseases.
The study, aimed at determining the correlates of infection, assessed 578 HIV-negative MSM by serologic assays, questionnaires,
and physical examinations. Of those, 474 were studied for 12 months. At baseline 76 (16%) were KSHV seropositive.
The researchers from the University of Washington Department of Medicine did not find any sexual behaviour particularly
associated with having antibodies to KSHV, but multivariate analysis revealed that a history of hepatitis A, serology suggesting
hepatitis B or HSV-2 infection, and a history of more than four sex partners in the previous six months were all independent
predictors.
The researchers, led by Dr Corey Casper, report that prevalent KSHV infection was significantly associated with hepatitis A
(odds ratio [OR], 3.3; 95% confidence interval [CI], 1.5-7.5), hepatitis B seropositivity (OR, 2.6; 95% CI, 1.4-4.8), herpes
simplex virus (HSV)-2 (OR, 2.4; 95% CI, 1.3-4.4), and more than four male partners in the previous six months (OR, 1.9; 95%
CI, 1.1-3.2).
Fifteen KSHV seroconversions (4%) were observed for an incidence of 3.8/100 person-years, similar to HSV-1 incidence in
this cohort and more frequent than incidence of HIV and HSV-2.
Reporting >/=1 HIV-positive partner (OR, 5.9; 95% CI, 1.8-19.3), amyl nitrite use (OR, 7.0; 95% CI, 2.1-23.0), and
lymphadenopathy in the past six months (OR, 7.7; 95% CI, 1.9-31.0) correlated with KSHV seroconversion.
Dr Casper says the study is the largest prospective study looking at incident infection but still there were only 15 men who
had new infections. He said the fact that there wasn’t statistical significance did not mean there wasn’t an association.
The researchers believe the virus may be transmitted through saliva and in a large study of almost 1,000 participants they
are starting to ask questions not only relating to whether or not the participants have anal, oral, protected and unprotected
sex but also questions about the exchange of saliva.
Ref: Casper C, Wald A, Pauk J et al. Correlates of Prevalent and Incident Kaposi’s Sarcoma-Associated Herpesvirus Infection in Men Who Have
Sex with Men. J Infect Dis 2002 Apr 1;185(7):990-3
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11920325&dopt=Abstract
OTHER NEWS
Gilead made misleading and illegal statements about Viread, says FDA
Graham McKerrow, HIV i-Base
Gilead Sciences Inc has been instructed by the US Food and Drug Administration (FDA) to stop making what it says are
misleading and illegal statements to promote the drug tenofovir, sold as Viread. Representatives of the company claimed it
was a “miracle drug” and they minimised important risk information, says the FDA.
The FDA has written to the company ordering it to stop making the “violative statements”, not to distribute promotional material
containing the statements, and to reply to the FDA in writing.
The company says it has never made the statements in promotional material. However, the FDA “identified promotional
activities that are in violation of the Federal Food, Drug and Cosmetic Act and its implementing regulations,” writes Laura
Pincock, Regulatory Review Officer of the FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC) in
a letter sent to Gilead in March.
Gilead representatives made the suspect statements to DDMAC representatives at the ICAAC (Interscience Conference on
Antimicrobial Agents and Chemotherapy) in Chicago in December last year, writes Pincock. Her letter says one company
representative said the drug had “no toxicities”, was “extremely safe” and “extremely well tolerated” – statements the FDA
describes as “false or misleading”.
The boxed warning on Viread’s approved product labeling says that lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other
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antiretrovirals. Pincock says two Gilead representatives claimed this was “a product class warning, and there are no problems
but it was put into the product labelling as a ‘wait and see’ warning.”
The representatives also said, according to Pincock, that Viread “does not affect mitochondria; therefore you would not expect
to see lactic acidosis.”
Further, the letter says the company representatives told the DDMAC reviewers that the warning “is a class effect” and “our
product labelling is the only one that does not name the drug because Viread is a nucleotide, not a nucleoside.”
Pincock writes: “These statements are in violation of the Act because they minimise the boxed warning for Viread and
misleadingly suggest that the drug is safer than has been demonstrated by substantial evidence. In fact, there have been case
reports of lactic acidosis in patients receiving Viread in clinical trials and the expanded access programme.”
Pincock adds in her letter: “Furthermore, Viread functions as a nucleoside analogue and, therefore, carries the same class
warnings as other nucleoside reverse transcriptase inhibitors.”
A fourth Gilead representative is criticised by Pincock for overstating Viread’s efficacy by saying the drug “is approved for a
broad indication” and characterising it as a “miracle drug”. Pincock tells the company: “In fact, Viread was approved by the
Food and Drug Administration under accelerated approval status, and the clinical benefit of Viread in HIV patients has not yet
been determined.” Pincock underlined the last part of that sentence.
A press officer for Gilead, based at Foster City, California, said the company took Pincock’s letter very seriously and was trying
to identify the company representatives concerned. It has never published promotional material containing the statements
Pincock complains about, she said, adding that the company has sent a reply to the FDA.
Viread is a once a day drug approved by the FDA in October for use in combination anti-HIV therapy. It is the first nucleotide
drug – a group of drugs similar to nucleosides - to be approved for antiretroviral therapy.
Full text of FDA warning letter to Gilead available as a PDF file at:
http://www.fda.gov/cder/warn/2002/10666.pdf
C O M M E N T
The Gilead marketing department and publicity machine are understandably in full swing following the
approval of tenofovir. It is sad, however, that the provision of accurate and cautious information on this drug
appears to have taken second place to marketing spin and overdrive.
There has been relatively little use of tenofovir so far in clinic, with small numbers of patients exposed to this
novel agent. Approval under accelerated procedures is also notorious in failing to identify longer term toxicity
concerns with antiretrovirals. Such inflated claims and the downplaying of concerns over toxicity highlighted
by the FDA do little to enhance the standing of this pharmaceutical company with treatment advocates,
prescribers and patients.
A further example of this seemingly inappropriate behaviour by Gilead was evident after the recent Retrovirus
Conference when the company circulated a press release with the grand title “Viread Demonstrates Anti-HIV
Potency Similar to the Protease Inhibitor Ritonavir in Short-Term Study of Treatment-Naive Patients”. This
presentation of a short-term monotherapy study did indeed demonstrate that tenofovir produced comparable
viral load drops and decay rates to ritonavir when dosed as a monotherapy agent for 21 days in antiretroviral
naïve subjects - 80% of whom were non-Caucasian (we’ll leave aside the ethical implications of such a
monotherapy study for the moment as well as the fact that the ritonavir “potency” was not a direct comparison
but was determined from historical data).
Perhaps “Anti-HIV Potency”, however, might for most critical readers encompass somewhat more than a 21
day fall in plasma viral load. Ritonavir is one of the few antiretrovirals which has demonstrated improved
survival in patients with advanced HIV-disease and impressive durability of response as part of triple
combination regimens despite considerable tolerability difficulties when dosed as the sole protease inhibitor.
It would seem to us that Gilead, in the wording of this press release, may be attempting to suggest that tenofovir
might be suitable to replace protease inhibitors as a component of triple combination therapy.
Of course such interpretations are themselves subjective and perhaps we are being oversensitive. Why not
judge for yourself?
Gilead press release on the “impressive” potency of tenofovir available at:
http://www.aegis.com/news/bw/2002/BW020207.html
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Barcelona conference organisers issue nine-point plan of action on global emergency
HIV/AIDS remains a global emergency with far reaching effects, and immediate action is necessary to prevent further
catastrophe. This is according to the organisers of the XIV International AIDS Conference, which will be held in Barcelona,
Spain in July this year (7-12 July 2002).
In recognition of this global emergency, the conference has prepared a list of nine key elements for immediate action.
“These nine elements form the guiding principles upon which the conference programme is being developed. They reflect the
reason we are holding this conference, as well as the reason why people should attend,” said co-chair, Dr Jordi Casabona.
“This is the world’s largest and most important HIV/AIDS conference, bringing together more than 15,000 leading scientists,
community leaders, people living with HIV/AIDS, media representatives and policy experts from around the world. It will help
to translate the latest scientific advances into action. It will address all aspects of the global HIV/AIDS epidemic, from science
to community responses, and human rights to economics. It will present a renewed opportunity for action.”
The conference’s key guiding principles are as follows:
1. HIV/AIDS is a global emergency with far-reaching effects: There is no country that has been left unscathed by the epidemic.
It affects all countries socially, economically and culturally. It threatens development and human security.
2. Immediate action is necessary to prevent further catastrophe: Violence, poverty, insecurity and war contribute to the spread
of HIV/AIDS. In today’s uncertain climate, HIV/AIDS demands increased focus, commitment and effort. HIV/AIDS is a
worsening crisis, which will increase further in times of war and instability.
3. Commitments of the United Nations Special Session on HIV/AIDS (UNGASS) urgently require implementation: In June
2001, world leaders met at UNGASS in New York City. The UNGASS Declaration sets out priorities and targets for fighting
the epidemic on a global and a national level.
4. With political commitment given at UNGASS, there is now renewed opportunity for action: This action must be directed
toward the creation of global, regional and national responses to HIV/AIDS that are sustainable and based on sound
knowledge.
5. Knowledge must be used to translate commitment into action: The world has gained a vast amount of knowledge about
effective strategies against HIV/AIDS from scientific inquiry and community mobilisation. This knowledge must now be used
to increase the scale and effectiveness of our response to this epidemic.
6. A unified effort is needed: All aspects of HIV/AIDS must be addressed by a unified body of scientists, politicians, people
living with HIV/AIDS, community groups, religious leaders, business and the media. All groups have valuable experience and
lessons to share, and these can accelerate this shared response.
7. Decreasing the impact of HIV/AIDS depends on effective prevention: Prevention and care are complementary, not
competing priorities. Effective prevention efforts that combine education, information, services and structural change to the
social environment are needed on a massive scale around the world.
8. Access to care and treatment must be available to all people living with HIV/AIDS: Maximising access to comprehensive
care and effective treatment requires more support to communities, better health infrastructures, cheaper drugs and more
resources. Resources for new Global Fund to fight AIDS, TB and Malaria (GFATM) need to be increased along with boosts
to direct national and private sector spending on AIDS.
9. Social exclusion is at the root of HIV-vulnerability: Exclusion of people from social support and networks because of their
religion, social standing, sexual orientation, HIV status, race or gender contributes to vulnerability to HIV and worsens the
impact of HIV. Extending dignity and respect to all people is therefore key to responding to HIV.
The theme of the conference is KNOWLEDGE AND COMMITMENT FOR ACTION. This theme was selected to reinforce the
need that all involved sectors at all levels - including scientists, the community, people working in the field, and the public and
private sectors - work together to review the knowledge gained through science and experience, and use this knowledge to
commit to action. This action must be focused across all aspects of HIV and include all infected and affected groups.
The conference is organised by the International AIDS Society (IAS) and the Fundació Barcelona SIDA 2002. It is co-organized
by the Joint United Nations Project for HIV/AIDS (UNAIDS), the International Community of Women Living with HIV/AIDS
(ICW), the Global Network of People Living with HIV/AIDS (GNP+), the International Council of AIDS Service Organizations
(ICASO) and Red 2002 (a Spanish-based network of NGOs).
Source: Media release issued by XIV International AIDS Conference.
Further information:
http://www.aids2002.com/IE_Home.asp
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ON THE WEB
Incorporating antiretroviral resistance testing into clinical practice
Medscape CME Circle, 2002
Richard T. D’Aquila
An explanation of why knowing when and how to use resistance testing in clinical practice will lead to better clinical
management of HIV-1-infected patients.
Antiretroviral resistance due to viral gene mutations accounts for a large portion of treatment failures. The emergence of these
genetic changes in the human immunodeficiency virus type 1 (HIV-1) is fostered by ongoing viral replication in the presence
of subinhibitory concentrations of antiretrovirals. Poor penetration of drugs into certain bodily compartments (sanctuary sites),
inadequate adherence, and variable pharmacokinetic factors may contribute to subtherapeutic drug levels in vivo. This, in turn,
may allow for selection of either preexisting (archived) or newly generated drug-resistant mutants. The critical problem in the
clinical setting is that a mutant selected for by a failing regimen may have some degree of cross-resistance to other drugs in
the same class that have not yet been prescribed to that patient. The development of cross-resistance may lead to a reduced
virologic or immunologic response to subsequent regimens. As scientists develop new agents active against resistant virus,
clinical medicine is also implementing diagnostic strategies designed to detect antiretroviral resistance and individualise
subsequent regimens.
Identification of the presence of drug resistance by means of genotypic or phenotypic resistance assays can help a healthcare
provider select a combination of antiretrovirals that is likely to suppress HIV-1 replication (ie, “active drugs” to which that
patient’s virus population is not cross-resistant). To maximise the therapeutic benefit and minimise toxicity, information
collected from the viral genotype or phenotype must be used in conjunction with the patient’s antiretroviral treatment history,
response to past regimens, immunologic status, pharmacologic data, and the clinician’s own knowledge of antiretroviral drugs.
Knowing when and how to use resistance testing in a clinical practice will lead to better clinical management of HIV-1-infected
patients.
http://www.medscape.com/viewprogram/1697
Management of co-infection with HIV & TB
BMJ 2002;324:802-803
Improving tuberculosis control programmes and access to highly active antiretroviral treatment is crucial. About a third of the
36 million people living with HIV worldwide are co-infected with mycobacterium tuberculosis; 70% of those co-infected live
in sub-Saharan Africa. In developing countries half of people with HIV infection will develop active tuberculosis; in some
countries in sub-Saharan Africa more than 70% of patients with active tuberculosis are also HIV seropositive.
Tuberculosis is the leading cause of death among people with HIV infection, accounting for a third of deaths due to AIDS world
wide. The introduction of highly active antiretroviral therapy has decreased death and opportunistic infections by 60% to 90%
among people living with HIV in affluent countries.
But in developing countries highly active antiretroviral therapy is available to a tiny minority of those who need it. Today there
is a shocking inequality worldwide in the prognosis of HIV and tuberculosis co-infection, and it depends on whether patients
or their country have access to highly active antiretroviral therapy.
Full text at
http://bmj.com/cgi/content/full/324/7341/802
The March 2002 issue of The PRN Notebook is available online at
http://www.prn.org/
Articles in this issue include the following, which are accessible in both HTML and PDF formats:
Nucleoside reverse transcriptase inhibitors: resistance, crossresistance and resistance testing
Daniel R Kuritzkes MD, Associate Professor of Medicine, University of Colorado Health Sciences Centre, Denver
http://www.prn.org/prn_nb_cntnt/vol7/num1/kuritzkes_frm.htm
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Polypharmacy problems: drug interactions in the multidrug therapy of HIV infection
Alice K Pau, PharmD
Patients with HIV receive an abundance of daily medications, often including a triple-drug antiretroviral regimen, primary and/
or secondary prophylactic drugs, and other compounds as needed (eg lipid-lowering drugs). Clinicians will be the first to admit
that the proper use of these drugs has yielded highly desirable effects including prolonged survival and fewer opportunistic
infections but will also attest to the burgeoning task of monitoring possible drug interactions.
Of course, the risk of harmful interactions does not stop with the pharmacokinetic profiles of individual drugs. Clinicians must
also remain aware of possible interactions between the drugs they prescribe and such things as foods, other diseases, and
nontraditional agents such as vitamins, herbal remedies, and an often unacknowledged factor: recreational drugs.
http://www.prn.org/prn_nb_cntnt/vol7/num1/pau_frm.htm
The plot thickens: KSHV and molecular piracy
Yuan Chang MD
Perhaps the greatest advance in the area of AIDS-related malignancies has been the identification of human herpesvirus-8
(HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV). Since its discovery by Drs Yuan Chang and
Patrick Moore and their colleagues almost eight years ago, KSHV has been identified in virtually all AIDS- and non-AIDSrelated KS lesions. At the same time, several research teams have identified the virus in a subset of other less common
pathologic conditions, including primary effusion lymphomas (PEL) and multicentric Castlemans disease (MCD). But while
a definitive link exists between KSHV and these specific malignancies, the precise role that it plays in their development is
just now coming into focus.
This article is based on a PRN lecture delivered by Dr Chang in November 2001. In essence, it is a more focused update of
an extensive review that originally appeared in the December 1999 issue of The PRN Notebook discussing KSHV, KS, and
MCD. Information related to the approved and experimental treatments for KS, as highlighted by Drs Susan Krown of Memorial
Sloan-Kettering Cancer Centre and Patrick Hennessey of New York University Medical Centre, while not discussed in this
article, can be found in the previously published summary.
http://www.prn.org/prn_nb_cntnt/vol7/num1/chang_frm.htm
Entry and fusion inhibitors: an update
Joseph J Eron MD and Christine M Hogan MD
Eradication of HIV has not been possible with currently available reverse transcriptase inhibitors and protease inhibitors; and
multiclass drug-resistant mutants of HIV along with a multitude of disabling and sometimes life-threatening side effects are
a growing threat. Thus, there is a great need for compounds that target non-protease and reverse transcriptase elements of
the HIV lifecycle. Not only might such novel therapies increase the potency of initial HIV treatment, but they may also provide
hope for patients who have exhausted current treatment options.
This article, based on PRN lectures delivered by Drs Joseph Eron and Christine Hogan in January 2002, reviews one of the
most promising areas of HIV drug development: inhibitors of HIV fusion and entry. As reviewed by both investigators, two
fusion inhibitors targeting HIVs gp41 envelope protein (T-20 and T-1249) continue to advance through clinical trials and have
both received fast-track designations by the US Food and Drug Administration. As for other entry inhibitors targeting cellular
proteins in the earlier stages of development (eg inhibitors of CD4, CCR5, and CXCR4), Drs Eron and Hogan noted some
of the advances and setbacks that have occurred over the past few years.
http://www.prn.org/prn_nb_cntnt/vol7/num1/eron_frm.htm
PUBLICATIONS AND SERVICES FROM i-BASE
New issue of Positive Treatment News (PTN)
The latest issue of Positive Treatment News, our magazine for positive people, looks at adherence (missed any pills recently
- need any advice?), the latest information about side effects and treatments, and the benefits and risks of joining a drug trial
or study.
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There is also a detailed look at facial lipoatrophy and what can be done about it, a review of the BHIVA treatment guidelines,
salvage therapy and treatment information provision for the African community.
To order copies, see below.
Changing treatment: an updated guide to second-line and salvage therapy
A is a16-page non-technical guide to resistance testing, intensifying treatment, treatment interruptions, switching drugs to
avoid side-effects, experimental drugs and drugs available through expanded access programmes.
HIV i-Base treatment guides are reviewed every six months to keep them up-to-date.
Since the previous edition several new treatments have become available to use in salvage therapy:
• The nucleotide tenofovir (Viread) has been approved for use in second-line therapy. This drug can work against virus that
has low level resistance to AZT, 3TC and other nucleosides.
• T-20 has started trials in the UK for people resistant to current drugs - with a limited expanded access programme expected
to follow later in the year. T-20 will have activity against any resistant virus.
Other changes to this edition are to the sections on phenotypic resistance testing, treatment interruptions and Mega-HAART
(and the Optima Study) and changing treatment because of side effects.
The sections on expanded access and experimental treatments have also been updated.
This booklet is included with the postal and pdf distribution of this issue of HTB.
To order further copies, see below.
French and Chinese translations of a booklet on avoiding and managing side effects
This comprehensive 36-page guide is aimed at helping anyone using HIV drugs to get the most out of their treatment, the most
out of their relationships with their doctor and other health professionals, to get better medical care to improve their health and,
most importantly, to enjoy a better quality of life.
It was written by people who are HIV-positive, who have been on most of the treatments, who have had many of the side effects
and who have learnt to negotiate their own healthcare.
The original English edition has now been produced in French and Chinese language editions.
To order copies, see below.
Treatment information request service
i-Base offer a specialised treatment information for individuals, based on the latest research.
We can provide information and advice over the phone, and we can also mail or email copies of the latest research studies
relevant to the caller.
For details call the i-Base treatment information free phone line on 0808 800 6013. The line is usually staffed by positive people
and is open Mondays, Tuesdays and Wednesday from 12 noon to 4pm.
All calls are in confidence and are free within the UK.
Order i-Base publications via the internet, post or fax
People with internet access can use our site to order and receive publications. You can access our publications online or
subscribe to receive our publications by email or by post; and you can order single copies or bulk deliveries by using the forms
at:
http://www.i-base.org.uk/
Copies of publications can also be ordered by post or fax using the form on the back page of this journal. These methods of
ordering are suitable for all our publications: HIV Treatment Bulletin (HTB), Positive Treatment News (PTN) and all our
treatment guides and new reports.
All publications are available free of charge — including bulk orders for the UK or single copies for other countries.
16
HIV i-Base publication
HIV Treatment Bulletin
Vol.3
No.4
3 No
4 - May
May2002
2002
Vol
HIV i-Base
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DECEMBER 2001
A P R I L
introduction to
combination
therapy
introduction
adherence
resistance
drugs
ptn
2 0 0 2
introduzione
changing
Paediatric HIV
Care
alla
terapia
combinata
treatment
what...
when...
why
Introduzione
Aderenza
Resistenze
Combinazioni
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i-Base
Adherence
Planners
&
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HIV Treatment Bulletin (HTB)
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Guide To Avoiding and Managing Side Effects (August 2001)
IN ENGLISH
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Introduction to Combination Therapy (December 2001)
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Also available in several other languages - please state how many of each of the translations you require
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Changing Treatment - Guide to Second-line and Salvage Therapy (April 2002)
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Positive Treatment News (PTN) from Spring 2002
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