Download Prevalence of Primary HIV-1 Drug Resistance among Recently

BRIEF REPORT
Prevalence of Primary HIV-1 Drug
Resistance among Recently Infected
Adolescents: A Multicenter
Adolescent Medicine Trials Network
for HIV/AIDS Interventions Study
1
University of California, San Diego School of Medicine, San Diego,
and 2University of Southern California, Los Angeles; 3University of Maryland,
Baltimore; 4National Institute of Child Health and Human Development,
National Institutes of Health; 5Westat; 6Monogram Biosciences, Inc.;
7
University of Alabama at Birmingham, Birmingham
This study examined the prevalence of primary human immunodeficiency type 1 (HIV-1) drug resistance among recently infected youth in the United States. Of the 55 subjects
studied, major mutations conferring HIV drug resistance
were present in 10 (18%). Eight (15%) had nonnucleoside
reverse-transcriptase inhibitor (NNRTI) mutations, with the
majority (6) having the K103N mutation; 2 (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations; and
2 (4%) had protease inhibitor (PI) mutations. Phenotypic
drug resistance was present in 12 (22%) subjects: 10 (18%)
for NNRTIs, 2 (4%) for NRTIs, and 3 (5.5%) for PIs. The
prevalence of primary HIV-1 drug resistance, particularly to
NNRTIs, in this group of recently infected youth was high.
Combination antiretroviral therapy leading to virologic control
and immune system recovery has had a major impact on the
care of persons infected with HIV-1, with declining morbidity
and mortality associated with HIV-1 infection [1]. Drug resistance often develops in patients with incomplete viral suppression and limits the magnitude and durability of the response to antiretroviral treatment [2]. HIV-1 drug resistance
has been reported in cases of sexual, parenteral, and vertical
HIV-1 transmission.
Received 2 March 2006; accepted 10 July 2006; electronically published 20 October 2006.
Reprints or correspondence: Dr. Rolando M. Viani, University of California, San Diego School
of Medicine, 9500 Gilman Dr., MC 0672, La Jolla, CA 92093-0672 ([email protected]).
The Journal of Infectious Diseases 2006; 194:1505–9
2006 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2006/19411-0006$15.00
Presented in part: 13th Conference on Retroviruses and Opportunistic Infections, February
2006, Denver (abstract 21).
Potential conflicts of interest: Y.S.L., J.M.W., and M.P.B. are employees of Monogram
Biosciences, Inc., the company that performed the HIV resistance testing (phenotypes and
genotypes) for this project. All other authors report no conflicts of interest.
Financial support: National Institute of Child Health and Human Development, National
Institutes of Health (NIH; grants U01 HD40506-01 and HD U01 40533 to Adolescent Medicine
Trials Network for HIV/AIDS Interventions [ATN]); National Institute on Drug Abuse; National
Institute on Mental Health; National Institute on Alcohol Abuse and Alcoholism. Four of the
ATN sites were supported by grants from the General Clinical Research Center Program of
the National Center for Research Resources, NIH, Department of Health and Human Services:
Children’s National Medical Center (grant M01-RR13297), University of Pennsylvania/Children’s
Hospital of Philadelphia (grant M01 RR00240), Tulane Medical Center (grant M01 RR 0509610), and the University of California, San Diego (grant M01 RR00827).
The views expressed in this article are those of the authors and do not necessarily represent
the views of the National Institute of Child Health and Human Development, the National
Institutes of Health, or the Department of Health and Human Services.
a
Network sites participating in this study are listed after the text.
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Rolando M. Viani,1 Ligia Peralta,3 Grace Aldrovandi,2
Bill G. Kapogiannis,4 Rick Mitchell,5 Stephen A. Spector,1
Yolanda S. Lie,6 Jodi M. Weidler,6 Michael P. Bates,6 Nancy Liu,5
Craig M. Wilson,7 and the Adolescent Medicine Trials Network
for HIV/AIDS Interventionsa
An increase in the prevalence of primary HIV-1 genotypic
resistance among recently infected individuals, from 8% to
22.7%, was documented in North America between 1995 and
2000 [3]. This study used convenience samples predominately
composed of high risk men who have sex with men. The presence of baseline resistance markers, not available on initiation
of therapy, was predictive of poorer response to subsequent
antiretroviral therapy [3]. However, resistance testing was unavailable on therapy initiation. Studies of the prevalence of HIV1 drug-resistance markers conducted in Europe have documented similar phenomena, although to a lesser degree [4, 5].
These studies have been conducted predominantly with middleaged white males, and data on the prevalence of HIV-1 drug
resistance in recently infected youth are lacking.
Herein are reported the results of Adolescent Medicine Trials
Network for HIV/AIDS Interventions (ATN) study 022, substudy 029, a multicenter study that enrolled recently HIV-1–
infected youth who were identified by means of a serologic
“detuned” assay, the Organon Technika Dilutional Vironostika
sensitive/less sensitive (DV S/LS) test [6]. We present the prevalence of primary genotypic as well as phenotypic HIV-1 drugresistance patterns among these youth.
Subjects, materials, and methods. Antiretroviral naive
HIV-1–seropositive youth who were 12–24 years old, were referred to any of the 15 sites (table 1) of the ATN, and were
identified as having been recently infected were eligible to participate in ATN 029. Study participants signed an informed
consent form that had been approved by the local human subject protection board, and the human experimentation guidelines of the US Department of Health and Human Services
were followed.
Recent HIV-1 infection was ascertained by means of a se-
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tailed) to compare categorical variables and the Mann-Whitney
U test to compare continuous variables. The 25th–75th percentile was calculated for continuous variables. Statistical significance was designated at P ! .05.
Results. Eighty-eight subjects were identified as having
been recently infected with HIV-1 by the detuned assay. Sixteen
subjects had no samples collected for drug-resistance testing.
Fifteen subjects (17%) had an HIV-1 RNA VL !400 copies/
mL; therefore, drug-resistance testing was not performed. Two
additional samples could not be analyzed for drug resistance.
Fifty-five subjects from 15 different cities had HIV-1 genotypic
and phenotypic testing performed. Nineteen (35%) were female, 36 (65%) were male, and both sexes had a diverse ethnic
distribution (table 1). The mean SD age was 19.7 1.9 years
for males and 18.6 1.9 years for females (P p .06). The following nonexclusive risk factors for HIV-1 acquisition were
present in male subjects: sex with multiple partners (78%), men
who have sex with men (81%), recent sexually transmitted
diseases (31%), having sex under the influence of drugs or
alcohol (36%), exchanging sex for money or drugs (14%), having been a victim of sexual assault (8%), and having an HIVinfected partner (47%). Risk factors for HIV-1 acquisition in
female subjects were sex with multiple partners (63%), recent
sexually transmitted diseases (53%), having sex under the influence of drugs or alcohol (21%), exchanging sex for money
or drugs (5%), having been a victim of sexual assault (16%),
Table 1. Demographic characteristics of the 55 recently HIV-1–
infected adolescents and young adults, 2004.
Characteristic
Age, mean SD, years
Sex
Male
Female
Race/ethnicity
Non-Hispanic black
Hispanic
Non-Hispanic white
Other/mixed race
Location
Northeast
Value
19.3 1.9
36 (65)
19 (35)
26 (47)
13 (24)
12 (22)
4 (7)
21 (38)
West
Southeast
19 (35)
6 (11)
Midwest
South
4 (7)
4 (7)
Puerto Rico
CD4+ T cell count, mean (25th–75th
percentile), cells/mL
Plasma HIV-1 RNA VL, mean (25th–75th
percentile), copies/mL
1 (2)
535 (352–707)
153,407 (4393–209,765)
NOTE. Data are no. (%) of subjects, unless otherwise indicated. VL, viral
load.
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rologic detuned assay, the DV S/LS test (bioMérieux) that identifies HIV infection within 180 days of exposure [6]. Briefly,
serum samples from all HIV-1–infected subjects, as determined
by a positive HIV-1 EIA and Western blot result at individual
ATN clinical sites, were tested at the University of Maryland
by the DV S/LS test. For the DV S/LS EIA testing, each sample
was first tested by DV in the S mode to ensure reactivity, followed by DV testing in the LS mode. Samples giving a reactive
result in the S mode but a nonreactive result in the LS mode
were considered to represent recent HIV-1 infection [6]. Information on demographics and risk factors for HIV-1 acquisition were recorded. CD4+ T cell count and plasma HIV-1
RNA viral load (VL) were determined at study entry. Plasma
was stored centrally at ⫺70C for batched phenotypic and genotypic analysis of resistance to standard antiretroviral drugs.
Population-based nucleotide-sequence analysis of the HIV1 protease and reverse-transcriptase gene sequences (55 specimens [GenBank accession numbers DQ832114–DQ832168])
was done centrally, by use of the GeneSeq HIV Assay Protocol
(Monogram Biosciences). Final interpretation of the sequence
variation data provided by Monogram was done using the International AIDS Society–USA Drug Resistance Mutations interpretation guidelines [7]. Multidrug resistance was defined
by the identification of major mutations conferring resistance
to drugs in 3 classes.
Phenotypic analysis was performed with a rapid recombinant
virus assay (PhenoSense HIV; Monogram Biosciences), which
uses test vectors derived from the amplified products of HIV1 protease and reverse-transcriptase gene sequences from
patient viral isolates [8]. Individual drug susceptibility was measured by determining the ratio of the drug concentration required to inhibit 50% (IC50) of the patient’s virus to the IC50
of the drug-sensitive reference virus (IC50 fold change). An IC50
fold change for a subject’s virus that was higher than that for
the drug-sensitive reference virus by more than the drug-specific reduced-susceptibility factor indicated decreased susceptibility to that drug. The reduced-susceptibility factors for the
relevant medications were either clinical (C)– or biological assay
(BA)–defined fold-change cutoffs and were as follows: abacavir
(4.5 [C]), didanosine (1.3 [C]), lamivudine (3.5 [C]), emtricitabine (3.5 [BA]), stavudine (1.7 [C]), zidovudine (1.9 [BA]),
tenofovir (1.4 [C]), delavirdine (2.5 [BA]), efavirenz (2.5 [BA]),
nevirapine (2.5 [BA]), atazanavir (2.2 [C]), ritonavir-boosted
atazanavir (5.2 [C]), amprenavir (2 [BA]), indinavir (2.1 [BA]),
ritonavir-boosted indinavir (10 [C]), ritonavir-boosted lopinavir (10 [C]), nelfinavir (2.5 [BA]), ritonavir (2.5 [BA]), saquinavir (1.7 [BA]), and ritonavir-boosted tipranavir (4 [C]).
Multidrug resistance was defined as an IC50 fold change of more
than the reduced-susceptibility cutoff for 3 classes of drugs.
Statistical analyses were performed with SAS (version 9.1;
SAS Institute). We used the x2 test or the Fisher exact test (2-
and having an HIV-infected partner (26%). Mean CD4+ T cell
counts and plasma HIV-1 RNA VLs of study participants are
shown in table 1.
Evidence of phenotypic and/or genotypic resistance was
identified in 13 subjects (24%): 9 (16%) had genotypic and
phenotypic resistance, 1 had genotypic resistance alone, and 3
had phenotypic resistance alone. Major mutations conferring
drug resistance were present in 10 subjects (18%) (figure 1).
Eight (15%) had nonnucleoside reverse-transcriptase inhibitor
(NNRTI) mutations: K103N alone (5), K103N and Y181C (1),
Y181C alone (1), and V108I alone (1). Two (4%) had nucleoside reverse-transcriptase inhibitor (NRTI) mutations: M41L,
L74V, and T215F (1); and M184V (1). Two (4%) had protease
inhibitor (PI) mutations: L90M (1); and M36I and M46L (1).
Evidence of phenotypic drug resistance was present in 12 subjects (22%) (figure 1): 10 (18%) for NNRTI; 2 (4%) for NRTI;
and 3 (5.5%) for PI. Two subjects had NNRTI phenotypic
resistance alone, and 1 had PI phenotypic resistance alone. One
subject had phenotypic and genotypic resistance to NNRTIs
and only phenotypic resistance to PIs. One (2%) subject had
genotypic and phenotypic resistance to antiretrovirals in all 3
classes (table 2).
Discussion. The rates of NNRTI-resistant HIV-1 that we
report in these recently infected adolescents and young adults
are among the highest ever reported in the United States, and
the overall rates of drug resistance are concerning. Given the
correlation between convenient regimens that lead to improved
adherence and superior virologic control, particularly among
this age group, simplified regimens are now highly sought after
by many clinicians. These data raise public health concerns
over the use of NNRTI-based regimens as empiric first-line
therapy in HIV-1–infected adolescents without initial screening
for resistance.
It is estimated that, of the 40,000 new HIV infections in the
United States each year, 25% occur in adolescents 13–19 years
of age, and ∼50% of all new infections occur in persons !24
years of age [9]. The mean age among the subjects in this study
was 19 years, compared with 35 years and 37 years in other
studies characterizing the prevalence of HIV-1 drug resistance
among recently infected adults [3, 5, 10]. Most of these studies
have been conducted among middle-aged white men, whose risk
factor for HIV-1 acquisition was having sex with men [3, 5, 10].
In contrast, the present study is more representative of the sex
demographics and risk factors for HIV-1 acquisition among the
recently infected youth in the United States [11]. Women composed 35% of this population, 47% of the subjects were African
Americans, and 24% were Hispanics. In contrast, the demographic characteristics of other reported US studies have reflected
Table 2. Primary HIV-1 genotypic and phenotypic drug-resistance among recently infected US adolescents and young adults.
The table is available in its entirety in the online
edition of the Journal of Infectious Diseases.
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Figure 1. Prevalence of primary HIV-1 drug resistance in 55 recently infected adolescents and young adults. NNRTI, nonnucleoside reversetranscriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor.
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drug resistance in recently infected youth places them at risk
of poor response to future NNRTI-based regimens. These observations support the current guidelines for resistance testing
in adults and adolescents recently infected with HIV-1 before
initiating antiretroviral therapy [15].
Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) sites and support. The present study was scientifically reviewed by the ATN Therapeutic Leadership Group.
Network scientific and logistical support was provided by the
ATN Coordinating Center at the University of Alabama at Birmingham. Network operations and analytic support was provided by the ATN Data and Operations Center at Westat (Jim
Korelitz and Barbara Driver).
The following ATN sites participated in this study: University
of South Florida (Patricia Emmanuel, Jorge Lujan-Zilberman,
and Silvia Callejas); Childrens Hospital of Los Angeles (Marvin
Belzer, Cathy Salata, and Diane Tucker); Children’s Hospital
National Medical Center (Lawrence D’Angelo); The Children’s
Hospital of Philadelphia (Brett Rudy, Mary Tanney, Adrienne
DiBenedetto, and John H. Stroger, Jr.); Hospital and the CORE
Center (Lisa Henry-Reid and Jaime Martinez); University of
Puerto Rico (Irma Febo, Ileana Blasini, and Evelyn Rivera);
Montefiore Medical Center (Donna Futterman, Marina Catallozzi, and Elizabeth Enriquez-Bruce); Mount Sinai Medical
Center (Linda Levin-Carmine, Mary Geiger, and Angela Lee);
University of California, San Francisco (Barbara Moscicki and
Coco Auerswald); Tulane University Health Sciences Center
(Sue Ellen Abdalian, Leslie Kozina, and Trina Jeanjacques); University of Maryland (Ligia Peralta, Edwin Colocho, and Leonel
Flores); University of Miami School of Medicine (Lawrence
Friedman, Donna Maturo, and Hanna Major-Wilson); Children’s Diagnostic and Treatment Center (Ana Puga, Esmine
Leonard, and Amy Inman); Children’s Hospital Boston (Cathryn Samples, Ellen Cooper, and Helen Mahoney-West); and
University of California, San Diego (Stephen Spector, Rolando
Viani, and Lisa Stangl).
Acknowledgments
We are grateful to the study coordinators and to the members of the
Community Advisory Board, for their insight and counsel, and we are
particularly indebted to the youth who participated in this study.
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