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Time Trends in Primary HIV-1 Drug Resistance Among Recently Infected Persons
Robert M. Grant, MD, MPH;
Frederick M. Hecht, MD;
Maria Warmerdam, BS;
Lea Liu, MD, MSc;
Teri Liegler, PhD;
Christos J. Petropoulos, PhD;
Nicholas S. Hellmann, MD;
Margaret Chesney, PhD;
Michael P. Busch, MD;
James O. Kahn, MD
JAMA. 2002;288:181-188.
ABSTRACT
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Context Transmission of multiclass drug-resistant human immunodeficiency virus
type 1 (HIV-1) may increase with wider use of antiretroviral therapy.
Objective To determine trends in prevalence of HIV-1 drug resistance among recently
infected individuals in a geographic area with a high penetration of antiviral
treatment.
Design, Setting, and Patients Consecutive case series of 225 patients referred to a San Francisco,
Calif, hospital with recent HIV-1 infection from June 1996 through June 2001.
Main Outcome Measure Time trends in the prevalence of genotypic and phenotypic primary drug
resistance.
Results Mutations associated with resistance to nonnucleoside reverse transcriptase
inhibitors (NNRTIs) steadily increased from 0% in 1996-1997 to 12 (13.2%)
in 2000-2001 (P = .01). There was 1 mutation associated
with protease inhibitor resistance in 1996-1997 (2.5%) and there were 7 (7.7%)
in 2000-2001 (P = .25). Genotypic resistance to nucleoside
reverse transcriptase inhibitors (NRTIs) initially decreased and then returned
to prior levels (P = .007 for test of homogeneity).
Genotypic resistance to 2 or more classes of drugs increased from 1 (2.5%)
to 12 (13.2%) (P = .004), but only 1 infection (1.2%)
in the latter period was resistant to all 3 classes of agents (P = .58). Primary phenotypic resistance decreased for NRTIs from 21%
to 6.2% (P = .03) and increased for NNRTIs from 0
to 8 (9.9%) (P = .02). Phenotypic resistance increased
for protease inhibitors from 2.6% to 6.2% (P = .32).
Median time to virologic suppression (<500 copies/mL) during therapy was
12 weeks for patients with genotypic evidence of resistance compared with
5 weeks for patients with drug-sensitive infections (P
= .02).
Conclusions The frequency of primary resistance to NNRTIs is increasing, although
resistance to all available classes of antiretroviral therapy remains rare.
Genotypic resistance testing in recently infected persons predicts time to
viral suppression during therapy.
INTRODUCTION
Primary HIV-1 (human immunodeficiency virus type 1) resistance to antiretroviral
drugs has been reported.1-10
The proportion of recently infected individuals who acquire HIV-1 that is
resistant to 2 or more classes of antiretroviral drugs is 2.7% (1/37) in San
Francisco,4 2.9% (2/70) in Geneva,10 3.8% (3/80) in New York City,8
and 1.4% (2/141) in Los Angeles, San Diego, Boston, and Denver.9
The potential for epidemic spread of resistant HIV-1 is difficult to assess
because surveillance is limited to small numbers of participants at each geographic
location and short duration of observation. In this study, we monitored recently
infected and drug-naive individuals in San Francisco from June 1996 through
June 2001 to assess time trends in primary drug resistance in a community
with widespread use of anti-HIV therapies and where virologic drug failure
is common.11-12
The clinical significance of primary drug resistance is determined by
its prevalence and its implications for virologic and immunologic outcomes.
Observations of drug-treated patients indicate that drug-resistant infection
is associated with virologic failure during combination therapy, but CD4 cell
counts are often relatively preserved,13 and
clinical disease progression may be substantially delayed.14
Individuals recently infected with drug-resistant HIV-1 offer unique opportunities
to study the effects of drug resistance on CD4 T-cell counts and treatment
responses in participants without prior exposure to antiretroviral therapy.
METHODS
Study Population
Consecutive participants with evidence of acute or recent HIV-1 infection
in the San Francisco Bay area were enrolled in the Options Project at San
Francisco General Hospital. Participants were recruited through referrals
from physicians, HIV-1 testing and counseling sites, community-based organizations,
community health centers, and self-referral. Individuals at risk for HIV-1
infection and complaining of 2 or more symptoms of acute infection and asymptomatic
individuals with recent receptive anal sex with a known HIV-1–infected
partner were eligible to receive laboratory screening for acute HIV-1 infection.
Participants were eligible for this study if they met 1 of the following
criteria for recent HIV infection at specimen collection for resistance testing:
(1) detectable HIV-1 RNA in blood plasma and a negative or indeterminate Western
blot assay for anti–HIV-1 antibodies, with subsequent antibody seroconversion
on follow-up; (2) a positive enzyme immunoassay (EIA) with Western blot confirmation
within 12 months of a documented negative HIV-1 antibody result; or (3) an
optical density signal-to-cutoff ratio of less than 0.75 according to a less
sensitive and standard dual EIA testing system,15
provided there was a history compatible with recent HIV infection and a CD4
cell count higher than 200/µL.
Participants were excluded from the analysis of primary resistance if
they had received antiretroviral therapy for more than 7 days before blood
collection for resistance testing. The study was approved by the University
of California, San Francisco, institutional review board, and written informed
consent was obtained from all study participants.
Genotypic Assessment
Genotypic resistance is defined as the presence of viral mutations associated
with impaired drug susceptibility or virologic response as specified by the
International AIDS Society-USA mutations panel, with alterations as noted.16 The presence of at least 1 primary mutation (PR D30N,
M46I, G48V, V82A, I84V, or L90M) was required for genotypic protease inhibitor
(PI) resistance, while any mutation was used to define genotypic resistance
to nucleoside reverse transcriptase inhibitors (NRTIs) (RT M41L, E44D, K65R,
D67N, any insertion at T69, K70R, L74V, V75T, V118I, Q151M, M184I/V, L210W,
T215Y/F, and K219Q) and nonnucleoside reverse transcriptase inhibitors (NNRTIs)
(RT A98G, L100I, K103N, V106A, V108I, Y181C/I, Y188C/L/H, and G190A). In addition,
the RT T215C/D/S/N mutations were included because they indicate previous
resistance involving the RT T215Y mutation.17
For 213 participants, the presence of mutations was assessed by population
sequencing of codons 3 to 99 of the protease gene and codons 38 to 247 of
the reverse transcriptase reading frame by using the TRUGENE HIV-1 Genotyping
Kit (Visible Genetics, Inc, Atlanta, Ga). For 12 individuals with limited
specimen, a noncommercial method of automated cycle sequencing of the protease
and reverse transcriptase reading frames was used.18
Information from sequencing reactions was assembled with OpenGene software
(Visible Genetics, Inc) or Seqman (DNAstar, Madison, Wis) and proofread manually.
Mixtures of sequences were reported if 2 or more bases had more than 20% relative
peak height in the forward and reverse sequencing reactions. Consensus sequences
from different individuals were aligned and manually edited, and neighbor-joining
phylogenetic trees were used to seek evidence of laboratory contamination.
Phenotypic Assessment
Phenotypic drug-susceptibility testing was performed with the PhenoSense
Assay (ViroLogic, Inc, South San Francisco, Calif).19
Viruses were defined as resistant if the fold change in IC50 (inhibitory
concentration, or the concentration of a drug that inhibits viral replication
by 50%) was at least 1.7 for stavudine, didanosine, and zalcitabine; at least
4.5 for lamivudine, zidovudine, and abacavir; at least 10 for delavirdine,
efavirenz, nevirapine, and lopinavir; and at least 4 for nelfinavir, amprenavir,
saquinavir, indinavir, and ritonavir (N.S.H., written communication, January
2002). For abacavir, stavudine, didanosine, and lopinavir, the phenotypic
cutoffs were levels of drug susceptibility above which there is detectable
impairment in virologic response.20-22
For NNRTIs, the 10-fold cutoff represents the upper limit of the normal range
of biological variation,23 below which virologic
responses were normal in small clinical series.24-25
For other drugs, the phenotypic cutoffs were based on assay precision,19 biological variability,23
and limited clinical experience. Phenotypic resistance defined by using cutoffs
of 2.5 and 10 are also reported to allow comparison with prior reports.8-9
Other Laboratory Assays
Plasma viral RNA load was measured with the Roche HIV-1 Amplicor Monitor
assay (Roche Diagnostics, Branchburg, NJ), and CD4 cell counts were measured
by using flow cytometry.
Statistical Analysis
Before analysis, the data were categorized by year of enrollment for
convenience and to allow correlation with other epidemiologic information.
For statistical analysis and reporting of resistant proportions, the calendar-year
periods were collapsed into 3 intervals, 1996 and 1997, 1998 and 1999, and
2000 and 2001, which allowed primary resistance proportions to be estimated
with greater precision in 3 periods. Comparisons with categorical variables
throughout the study were evaluated with the Fisher exact test. Differences
in continuous variables were evaluated with Kruskal-Wallis tests. Time trends
in the prevalence of drug resistance were assessed with the Cochran-Armitage
exact trend test. To ensure that dividing observations into time periods did
not bias the results, the proportion resistant was also evaluated with logistic
regression by using study enrollment date to predict the probability of resistance.
Multiple logistic regression was used to determine whether any genotypic evidence
of drug resistance was associated with the duration of HIV infection and CD4
cell count and whether primary resistance changed over time after these baseline
factors were controlled. Viral load data were available from weekly time points
for the first 4 weeks and then monthly time points thereafter. Time to viral
load suppression was evaluated with Kaplan-Meier survival analysis. All statistical
tests were 2-tailed (P<.05). Data analyses were
performed with SAS version 8.2 (SAS Institute, Cary, NC).
RESULTS
Cohort Characteristics
From June 10, 1996, through June 30, 2001, 243 participants were found
to have evidence of recent HIV-1 infection (Figure 1). All of these participants were included in the study
of primary drug resistance. Eighteen (7.4%) were excluded from the analysis
because a drug-resistance genotype was unavailable from a point within 7 days
of initiation of antiretroviral therapy. The reasons for an unavailable genotype
included no specimen available (n = 9) or a failed genotyping assay (n = 9).
The remaining 225 participants were divided according to the year they were
identified. There were no significant differences over time in age, sex, risk
group, CD4 cell count, CD4 percentage, or viral load (Table 1). The mean optical density to cutoff ratio in the less-sensitive
EIA test15 fluctuated significantly in the
first 2 years of the study but did not change significantly after 1997. Resistance
determinations were obtained before any treatment in 215 (95.6%) participants
and during the first 7 days of treatment in 10 (4.4%) persons. Genotypic analysis
was based on the TRUGENE HIV-1 Genotyping Kit (Visible Genetics, Inc) in 213
persons (94.7%) and a noncommercial cycle sequencing assay in the remaining
12 (5.3%). The demographic characteristics of the overall sample were comparable
to those of seroincident cases of HIV-1 in San Francisco as defined by an
expert consensus panel in 1997.26
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Figure 1. Genotypic and Phenotypic Resistance
by Class of Antiretroviral Drugs by Calendar Year
All treated individuals received 3 or more antiretroviral agents.
PI indicates protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor;
NNRTI, nonnucleoside reverse transcriptase inhibitor.
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Table 1. Participant Characteristics by Time
Interval*
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Genotypic Analysis
Genotypic evidence of resistance was detected in 52 (23.1%) individuals
(Table 2). The proportion with
genotypic resistance to NRTIs varied significantly over time, decreasing from
25.0% (10/40) in 1996-1997 to 7.4% (7/94) in 1998-1999 and then increasing
to 20.9% (19/91) in 2000-2001 (test for homogeneity, P
= .007). The prevalence of genotypic resistance to PIs was 2.5% in 1996-1997
and 7.7% in 2000-2001 (trend test, P = .25). Genotypic
resistance to NNRTIs increased steadily from 0% in 1996-1997 to 13.2% in 2000-2001
(trend test, P = .01). Genotypic resistance to 2
or more classes of antiretroviral drugs increased from 2.5% (1/40) in 1996-1997
to 13.2% (12/91) in 2000-2001 (trend test, P = .004).
Only 1 (0.4%) of 225 recently infected individuals had genotypic resistance
to all 3 classes of antiretroviral therapy. Plots of time trends by calendar
year suggest rapid and recent increases in primary resistance to NNRTIs, while
resistance to PIs appeared earlier and has remained more stable (Figure 2).
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Table 2. Summary of Mutations Over Time
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Figure 2. Flow Diagram of the Analysis of
Time to Virologic Suppression (Viral Load Less Than 500 Copies/mL)
Genotypic resistance was defined as any mutation associated with
decreased susceptibility or poor virologic response to nucleoside reverse
transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors
(NNRTIs) or any primary mutation associated with protease inhibitor (PI) resistance.
Phenotypic drug resistance was defined by using susceptibility cutoff thresholds
that have been associated with poor virologic response, when such information
is available. These cutoffs ranged from 1.7 to 10.0, depending on the drug.
Categories in the upper panels are not mutually exclusive, since viruses may
be resistant to more than 1 drug class. Categories of number of drug classes
affected in the lower panels are mutually exclusive.
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Phenotypic Analysis
Phenotypic drug susceptibility testing was attempted in all 225 participants
with completed genotypic analysis and was successful in 210 (93.3%) (Table 3). The proportion of new infections
with NNRTI resistance increased over time from 0 in 1996-1997 to 9.9% in 2000-2001
(Figure 2) (trend test, P = .02). The prevalence of primary phenotypic resistance to PIs was
2.6% in 1996-1997 and 6.2% in 2000-2001 (trend test, P
= .32). Primary phenotypic resistance to NRTIs decreased throughout the study
from 21.0% in 1996-1997 to 6.2% in 2000-2001 (trend test, P = .03). The proportion of individuals with decreased susceptibility
to 2 or more classes of antiretroviral agents was 2.6% in 1996-1997 and 4.9%
in 2000-2001 (trend test, P = .35). Phenotypic resistance
to all 3 classes of antiretroviral agents occurred in only 1 person, who enrolled
in 2000.
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Table 3. Summary of Phenotypic Susceptibility
Over Time*
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Virologic Responses to PI-Containing Therapy
To determine whether primary resistance was associated with delayed
virologic response, we analyzed the time to virologic suppression, defined
as the first plasma viral RNA concentration less than 500 copies/mL. This
analysis included only the subset of 141 (62.7%) participants who initiated
antiretroviral therapy, which consisted of NRTIs and a PI in 139 participants,
NRTIs and an NNRTI in 1 individual, and 3 NRTIs in 1 individual (Figure 2). Participants were classified according
to whether there was genotypic resistance to any antiretroviral drug class
used. If therapy was stopped for any reason, observations were excluded from
the analysis after the last treatment date. Resistance testing was not used
to select the initial drug regimen in any participant. Median time to viral
load suppression was longer in 30 individuals with genotypic resistance compared
with 111 without resistance (Figure 3,
12 weeks vs 5 weeks; log-rank test, P = .02). One
of these individuals was infected with HIV-1 resistant to NRTIs and PIs and
had persistent plasma viral load after 6 months of combination therapy, as
reported earlier.4
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Figure 3. Time to Viral Load Suppression Below
500 Copies/mL During Treatment
Participants were categorized into resistance groups (Figure 2).
Viral load in all treated groups was assessed weekly and censored from the
analysis for any report of stopping therapy. Time to viral suppression was
longer among participants with any evidence of resistance to the regimen used
(P = .02).
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Baseline Correlates of Genotypic Drug Resistance
The detection of primary genotypic resistance was more frequent among
individuals who were infected for shorter periods, as estimated by the less-sensitive
EIA optical density to cutoff ratio (Spearman rank correlation, P = .02). The detection of genotypic resistance was 28.8% among those
in the first quartile of duration of infection, 27.4% among the second quartile,
19.2% among the third quartile, and 11.5% among the quartile infected for
the longest period (trend test, P = .01). These indexes
of the duration of infection were not associated with year of enrollment (Spearman
rank correlation, P = .64). The initial plasma viral
RNA load was highly variable, most likely because of rapid changes in viremia
that occur during recent HIV-1 infection (Figure 4). There was no difference in initial plasma viral load
between the individuals with resistant virus and those with sensitive virus
(P = .71). In contrast, baseline CD4 cell counts
and CD4 cell percentages were significantly higher among individuals infected
with resistant HIV-1 (P = .02 and P = .04, respectively). Multivariate logistic regression indicated
that a higher CD4 cell count was independently associated with resistant HIV-1
(P = .03) after duration of infection was controlled.
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Figure 4. Viral Load, CD4 Cell Count, and
Genotypic Drug Resistance in Drug-Naive Recently Infected Individuals
The whiskers represent the entire range, the boxes represent the
interquartile range (25% to 75%), and the black horizontal lines within the
boxes represent the median values. The median viral load in individuals with
genotypic drug resistance was not significantly lower than that of individuals
with wild-type HIV-1 (P = .71). The CD4 cell counts
were higher in individuals with drug-selected variants (P = .03), even after duration of infection, as indicated by the less-sensitive
enzyme immunoassay optical density, was controlled.
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COMMENT
The proportion of recent infections that involve NNRTI resistance increased
rapidly in this serial cross-sectional survey. Treatment with NNRTIs became
more common in late 1998, when clinical trial results indicated that virologic
outcomes during treatment with an NNRTI were comparable with those of PI-based
treatment.27 Increases in primary NNRTI resistance
observed after 1999 in this study likely reflect more prevalent use of NNRTIs
in the previous year. A study of primary drug resistance in the United Kingdom
also reported trends toward increasing primary genotypic resistance, which
included NNRTI resistance in 3 of 26 (11.5%) individuals in 2000 and none
of 22 individuals in 1997 through 1999.28 Similarly,
cases of primary PI resistance appeared in San Francisco4
and Geneva10 after approximately 1 year of
widespread PI exposure.
In contrast to primary NNRTI resistance, primary PI resistance remained
relatively stable from 1997 through 2001 (Figure 2). The transmission of HIV-1 resistance to all 3 available
classes of antiretroviral therapy continues to be rare, occurring in only
1 of 225 (0.4%) individuals in this series. In contrast, the prevalence of
3-class drug resistance among 268 drug-experienced participants presenting
for clinical resistance testing in our laboratory in San Francisco was 14.3%
during 2000-2001 (data not shown). The infrequent transmission of 3-class
multidrug resistance in our series from San Francisco and elsewhere2, 8-10 may
reflect the poor replication capacity of these extensively mutated viruses.29 Just as lower viral load in untreated individuals
was associated with decreased sexual transmission,30
so too the lower viral load typically observed during multidrug resistant
viremia13, 31 may diminish the
frequency of transmission of these viruses. In contrast, NNRTI-resistant viruses
demonstrate relatively high levels of plasma viral load during drug failure32-33 and may prove to have concordantly
preserved capacity for transmission.
The changing proportions of NRTI-resistant HIV-1 over time may reflect
changing virologic outcomes among persons who transmit HIV-1. Before 1996,
antiretroviral therapy consisted of single or dual NRTIs, which typically
lead to viremia with drug-resistant HIV-1 in the majority of patients. Transmission
of NRTI-resistant viruses in San Francisco may have decreased in 1998-1999
as treated populations changed to more active regimens that contain PIs, NNRTIs,
or both. Trends toward decreasing primary resistance to nucleoside analogues
have been observed in other settings as well.2, 34
Since 1998, genotypic resistance testing has indicated that the proportion
of NRTI-resistant cases is increasing once again, although this trend was
not confirmed by phenotypic analysis. Increases of genotypic NRTI resistance
possibly reflect restored infectiousness of extensively antiretroviral-experienced
individuals. Alternatively, the observed changes in primary resistance prevalence
could reflect changes in risk behavior, which were not assessed in this study.
Further, although demographic characteristics did not change throughout the
course of this study, changes in referral patterns may have occurred and contributed
to the observed trends in resistance prevalence.
Drug-resistance testing is recommended for persons failing antiretroviral
therapy and for HIV-1–infected pregnant women.35-37
For persons with primary HIV infection, the International AIDS Society-USA35 and Department of Health and Human Services36 guidelines indicate that resistance testing should
be considered, and the EuroGuidelines group37
recommends testing. Our data support the use of resistance testing in recently
infected persons in settings where antiretroviral use is widespread. In this
sample of recently infected individuals, primary drug resistance was found
to have high prevalence and was predictive of slower virologic responses.
Although most treated individuals with primary drug resistance eventually
achieved viral loads less than 500 copies/mL, the delay in virologic response
likely reflects decreased drug activity. Whether primary resistance will worsen
long-term virologic and clinical outcomes requires further study. Nevertheless,
the growing prevalence of primary NNRTI resistance and the substantial prevalence
of primary PI and NRTI resistance suggest that resistance testing has a role
in guiding antiretroviral use in recently infected persons.
Overall, the prevalence of primary phenotypic resistance was less than
the prevalence of genotypic resistance, partly because genotypes that indicate
prior drug resistance but do not affect current susceptibility, such as the
RT T215C/D/S/N mutation, were included. In addition, the genotyping assay
detected some mixtures of resistant and sensitive HIV-1 that had normal susceptibility.
Finally, the susceptibility cutoff values used to define phenotypic resistance
have not been defined for all drugs, and conservatively high levels were selected
when there was uncertainty.
The higher average CD4 cell count among individuals infected with drug-resistant
HIV-1 suggests that resistant isolates may cause less initial injury to the
immune system, possibly because of decreased viral replication capacity38 or decreased tropism for tissues involved in T-cell
production, such as the thymus.39 Relatively
preserved CD4 cell counts and slower T-cell turnover have been observed in
individuals during multidrug-resistant viremia.11, 40
These partial CD4 cell-count responses require continued use of antiretroviral
therapy,29 which maintains partial viral load
suppression41 and selection for drug-resistant
HIV-1 that has diminished replication capacity.29
Our observations indicate that drug-resistant HIV-1 infection is associated
with higher CD4 cell counts in drug-naive persons as well, providing additional
evidence that CD4 cell-count sparing may be due to viral factors such as diminished
replication capacity.
Primary HIV-1 drug resistance indicates that the risks of antiretroviral
therapy extend beyond the treated individual to uninfected populations.2, 4, 9-10,42
Indeed, primary resistance indicates triple failure of the health care system,
including failure of drug treatment to control viral replication in the source
partner, failure of behavioral prevention in the source partner receiving
treatment, and failure of behavioral prevention in the recently infected person.
Intervention to minimize transmission of drug-resistant HIV-1 will require
physician education to improve prescribing, more tolerable drug regimens,
counseling to promote adherence, and more effective prevention programs targeted
to infected and uninfected persons. Prevention programs specifically linked
to treatment may serve to ensure that the clinical and epidemiological benefits
of widespread antiretroviral therapy are not offset by increases in risk behavior
and the transmission of drug-resistant HIV-1.43-44
AUTHOR INFORMATION
Financial Disclosures: Drs Hellmann and Petropoulos
are employees of ViroLogic Inc, commercial provider of PhenoSense HIV, the
assay used to measure HIV-1 drug susceptibility in this study. Dr Kahn is
a paid consultant of ViroLogic Inc. Dr Grant is a paid consultant of Visible
Genetics Inc, and has received honoraria and research support from ViroLogic
and Visible Genetics. He also has received honoraria for speaking at educational
programs supported by ViroLogic, Visible Genetics, GlaxoSmithKline, Bristol-Myers
Squibb, Roche Pharmaceuticals, and Agouron and he directs a nonprofit academic
laboratory that has provided services for clinical research supported by grants
to the University of California from Merck, GlaxoSmithKline, Bristol-Myers
Squibb, Boehringer Ingelheim, Roche, Abbott, Agouron, Gilead, Visible Genetics,
Oxo-Chemie, and Chiron. Dr Chesney has received honoraria for speaking at
educational programs supported by Bristol-Myers Squibb, Merck, GlaxoSmithKline,
and Agouron. Dr Kahn has received honoraria for speaking at educational programs
supported by Merck, Bristol-Myers Squibb, Agouron, ViroLogic, GlaxoSmithKline,
Abbott, Oxo-Chemie, and Chiron. These companies and Gilead Sciences, Immune
Response Corporation, DuPont Pharmaceuticals, and GeneLabs have previously
provided funds to the University of California to support Dr Kahn's research
activities.
Author Contributions: Study
concept and design: Grant, Hecht, Kahn.
Acquisition of data: Grant, Hecht, Warmerdam,
Liegler, Petropoulos, Chesney, Busch, Kahn.
Analysis and interpretation of data: Grant,
Hecht, Warmerdam, Liu, Hellmann, Kahn.
Drafting of the manuscript: Grant, Hecht, Petropoulos,
Kahn.
Critical revision of the manuscript for important
intellectual content: Grant, Hecht, Warmerdam, Liu, Liegler, Hellmann,
Chesney, Busch, Kahn.
Statistical expertise: Grant, Hecht, Liu.
Obtained funding: Grant, Hecht, Chesney, Busch,
Kahn.
Administrative, technical, or material support:
Grant, Hecht, Warmerdam, Liegler, Hellmann, Chesney, Busch.
Study supervision: Grant, Hecht, Liegler, Petropoulos.
Funding/Support: This work was supported by
the Gladstone Institute of Virology and Immunology and grants from the Centers
for Disease Control and Prevention (U64/CCU913941), the UCSF Center for AIDS
Research (P30 MH59037), the University of California Universitywide AIDS Research
Program (CC97-0962 and CC99-SF-001), and the National Institutes of Health
(AIEDRP AI 41531 and MH64384-01).
Acknowledgment: We thank Jacqueline Javier,
MS, MT, Birgit Drews, BS, Timothy Schmidt, BS, MT, and Kenneth Plamenco, MD,
for outstanding technical support. We are indebted to the ViroLogic Clinical
Reference Laboratory for performing the phenotypic analysis and Visible Genetics,
Inc, for provision of TRUGENE HIV-1 Resistance Kits.
Corresponding Author and Reprints: Robert
M. Grant, MD, MPH, Gladstone Institute of Virology and Immunology, PO Box
914100, San Francisco, CA 94141 (e-mail: rgrant{at}itsa.ucsf.edu).
Author Affiliations: Gladstone Institute of
Virology and Immunology (Drs Grant and Liegler and Ms Warmerdam), Positive
Health Program, San Francisco General Hospital (Drs Grant, Hecht, Liu, and
Kahn), Center for AIDS Prevention Studies (Dr Chesney), Department of Medicine,
University of California, San Francisco (Drs Grant, Hecht, Liu, Busch, and
Kahn), Blood Centers of the Pacific (Dr Busch), San Francisco; and ViroLogic,
South San Francisco, Calif (Drs Petropoulos and Hellmann).
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