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Little SJ, Daar ES, D'Aquila RT, et al. Reduced Antiretroviral Drug Susceptibility Among Patients With Primary HIV Infection. JAMA. 1999;282(12):1142–1149. doi:10.1001/jama.282.12.1142
Author Affiliations: Departments of Medicine (Drs Little and Richman) and Pathology (Dr Richman), University of California, San Diego, and the Department of Veterans Affairs Medical Center, San Diego (Dr Richman); Department of Medicine, Cedars-Sinai Burns and Allen Research Institute, and the University of California, Los Angeles (Dr Daar and Ms Pitt); Department of Medicine, University of Texas Southwestern Medical Center, Dallas (Drs Keiser and Koup); Department of Medicine, Massachusetts General Hospital, Boston (Drs D'Aquila, Rosenberg, and Walker and Ms Sutton); Department of Medicine, University of Colorado Health Sciences Center, and the Department of Veterans Affairs Medical Center, Denver (Dr Connick); and ViroLogic Inc, South San Francisco, Calif (Drs Whitcomb, Hellmann, and Petropoulos).
Context The transmission of drug-resistant human immunodeficiency virus (HIV)
has been documented, but the prevalence of such transmission is unknown.
Objective To assess the spectrum and frequency of antiretroviral susceptibility
among subjects with primary HIV infection.
Design, Setting, and Patients Retrospective analysis of 141 subjects identified from clinical research
centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV
seroconversion within the preceding 12 months and no more than 7 days' prior
antiretroviral (ARV) therapy.
Main Outcome Measures Phenotypic and genotypic ARV susceptibility of HIV from plasma samples.
Results The transmission of drug-resistant HIV as assessed by a greater than
10-fold reduction in ARV susceptibility to 1 or more drugs was observed in
3 (2%) of 141 subjects, including to a nonnucleoside reverse transcriptase
inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor
and a protease inhibitor in 2 patients. Population-based sequence analysis
of these 3 samples identified multidrug-resistance mutations in reverse transcriptase
(M184V, T215Y, K219K/R) and protease (L10I/V, K20R, M36I, M46I, G48V, L63P,
A71T, V77I, V82T, I84V, L90M) in the 2 latter patient samples, along with
numerous polymorphisms. A reduction in susceptibility of greater than 2.5-
to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients
(26%). Sequence analysis of these 36 samples identified well-characterized
drug resistance mutation in reverse transcriptase and protease in only 1 of
Conclusions Reductions in drug susceptibility of more than 10-fold were rare among
this cohort of recently HIV-infected subjects and were distributed among each
of the 3 major classes of ARV drugs tested. Reductions in susceptibility of
more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance
were highly prevalent among newly infected patients. Resistance testing may
be warranted to monitor the frequency of drug resistance over time and to
assess the potential for geographic variability.
Antiretroviral (ARV) drug resistance is associated with diminished responses
and increased mortality3,4 in
patients with established human immunodeficiency virus (HIV) infection. The
transmission of single drug–resistant5,6
and multidrug-resistant7,8 virus
has been documented, although the overall frequency of these events in the
United States is unknown. Persistent viral replication (plasma HIV RNA >500
copies/mL) is observed in 10% to 40% of therapy-naive subjects with established
infection treated for 24 weeks with potent ARV therapy.9-11
More widespread use of these potent regimens among infected patients at both
early and later stages of infection12 may increase
the number of individuals in whom drug resistance is selected during therapy
and perhaps increase the population-based risk for transmission of resistant
HIV. Furthermore, the use of a suboptimal initial treatment regimen in a person
infected with drug-resistant virus is expected to limit the magnitude and
durability of an antiviral response and may preclude the preservation of HIV-specific
immune responses associated with early, effective ARV therapy.13
Prospective studies are needed to evaluate the clinical significance of primary
HIV infection with drug-resistant virus and the subsequent virological response
to ARV therapy.
The evaluation of drug resistance in HIV-infected persons may include
an assessment of viral sequence (genotype) or viral drug susceptibility (phenotype).
Consensus guidelines are available to facilitate interpretation of the often
complex results of such assays and summarize their potential role in clinical
management.14 In vitro techniques to assess
viral susceptibility provide a quantitative assessment of viral growth characteristics
in the presence of ARV drugs, which may correlate more directly than genotype
results with virological responses.2,15,16
Clinical validation of genotypic and phenotypic assays is ongoing for each
of these methods. Sequence analyses have identified amino acid substitutions
in reverse transcriptase and protease, which confer varying levels of resistance
to specific ARV drugs.
Many well-characterized drug resistance mutations (also called primary
mutations) have been identified that are selected in virus exposed to antiviral
therapy and are often associated with treatment failure.14
Less well-characterized amino acid substitutions that emerge with treatment
have been described; these are often identified as viral polymorphisms in
therapy-naive subjects and are less clearly associated with drug resistance
as assessed by in vitro drug susceptibility results. These genetic variants
may exist as predominant or minority populations in the patient before the
introduction of drug therapy17 but are selected
during ARV therapy.
The clinical and virological consequences of primary HIV infection with
drug-resistant virus may include suboptimal treatment responses,8
reduced viral fitness,18-20
and the potential for transmission of drug-resistant virus following defined
We report an analysis of the spectrum and frequency of ARV susceptibility
among subjects with acute and early HIV infection.
We evaluated subjects from a widespread referral network within each
of 5 metropolitan cities across the United States (San Diego, Calif; Los Angeles,
Calif; Dallas, Tex; Denver, Colo; and Boston, Mass) who had a history of HIV
seroconversion during the preceding 12 months or documented evolution of an
HIV antibody or Western blot response during study screening. All study participants
signed an informed consent approved by the local institutional human subjects
committee. Demographic information and an HIV risk assessment for each subject
were obtained. Subjects with more than 7 days of prior ARV therapy or plasma
viral RNA levels of less than 400 copies/mL were excluded from the study.
Subjects from 5 clinical research centers were identified over a 10-year
period from 1989 to 1998 and were retrospectively enrolled in our cohort.
Clinical and laboratory features of acute or early HIV infection22,24,25
were documented in all subjects. All subjects who were HIV seropositive at
study entry reported a negative HIV test result during the preceding 12 months.
Documentation of prior negative HIV test results was generally available if
these test results were collected confidentially (ie, not anonymously). For
subjects who reported a high-risk exposure followed by the onset of symptoms
consistent with an acute retroviral syndrome, we estimated the date of HIV
infection as either (1) the date of the HIV risk exposure, if the exposure
was reported during the preceding 30 days, or (2) the date of symptom onset,
if the exposure date was unknown. For asymptomatic seroconverters, the date
of HIV infection was reported as the date of the first documented virological
or serologic test result for HIV infection within 12 months of a negative
A baseline plasma sample was collected from each subject and stored
at −70°C. Human immunodeficiency virus antibody status was determined
by enzyme immunoassay (Abbott Laboratories, North Chicago, Ill) with confirmation
by Western blot (Cambridge Biotech Corp, Rockville, Md). Quantification of
plasma HIV RNA (Amplicor, Roche Molecular Systems, Branchburg, NJ) and analysis
of CD4 lymphocyte subsets by dual-color fluorescent-activated cell sorter
analysis (FACScan, Becton Dickinson Cytometry Systems, San Jose, Calif) were
performed within 30 days of study entry (baseline). Patients identified in
the Los Angeles area had plasma HIV RNA detected using the Chiron (Emeryville,
Calif) branched-chain DNA assay (Version 2.0).
The baseline plasma sample was analyzed for phenotypic drug susceptibility
by PhenoSense HIV (ViroLogic Inc, South San Francisco, Calif). Reference sensitivity
testing for this assay has demonstrated that among 154 patient plasma samples
with viral loads of more than 500 copies/mL, 148 samples (96%) were successfully
amplified and yielded acceptable phenotypic drug susceptibility results.26 Recombinant resistance test vectors were constructed
by inserting amplified protease and reverse transcriptase gene segments from
the plasma virus population into a replication-defective retroviral vector
derived from a molecular clone of HIV-1 (pNL4-3) containing a luciferase indicator
gene (luciferase). The assay was performed by cotransfecting 293 human embryonic
kidney cells with resistance test vector DNA and an expression vector that
produces amphotropic murine leukemia virus envelope protein. Pseudotyped virus
particles were collected after transfection and used to infect fresh 293 cells.
Protease inhibitors were added to virus producer cells during transfection
and reverse transcriptase inhibitors were added to target cells during infection.
Infected cells were lysed and luciferase activity was measured.
Production of luciferase activity in the target cells is dependent on
1 round of virus replication. Drugs that inhibit reverse transcriptase or
protease reduce the amount of luciferase activity in the target cell. Inhibition
of luciferase activity was plotted vs drug concentration (log10).
Differences in drug susceptibility were measured by comparing the IC50 (50% inhibitory concentration) values of the patient virus with the
IC50 values of a drug-sensitive reference virus (NL4-3). Assay
validation studies have demonstrated that IC50 values 2.5-fold
greater than the drug-sensitive reference virus (NL4-3) are indicative of
reduced drug susceptibility.26 Assay variability
(based on 95% confidence intervals) around repeated evaluations of the same
sample was less than 3.2-fold for IC50 values and less than 2.3-fold
for fold-change values, and was similar for all tested drugs in the validation
Although small retrospective studies have demonstrated a correlation
between reduced assay susceptibility results and virological outcomes,27-31
insufficient clinical data are available to determine what level of reduced
susceptibility is reproducibly associated with virological failure for each
ARV drug. As a result, arbitrary classifications of reduced susceptibility
were proposed for this analysis. Antiretroviral susceptibility results were
reported as samples with wild type susceptibility (within 2.5-fold of the
NL4-3 reference virus), samples with reductions in susceptibility of more
than 2.5- to 10-fold less than reference virus, and samples with reductions
in susceptibility of more than 10- to 1000-fold less than reference virus.
These categories are provided to distinguish viral isolates with susceptibility
differences within an order of magnitude. When a patient sample was noted
to have a greater than 10-fold reduction in susceptibility to one drug and
a greater than 2.5- to 10-fold reduction in susceptibility to another drug,
summary results for that subject were reported among those with a more than
10-fold reduction in susceptibility.
Validation studies of the phenotype assay demonstrate that highly resistant
viruses are generally detected at resistant virus concentrations ranging from
10% to 40%, depending on the virus and the drug.26
Population-based sequence analysis (PE Biosystems, Foster City, Calif)
of the polymerase chain reaction amplicon generated in the phenotype assay
was used to evaluate the reverse transcriptase and protease coding regions
(HIV-1 pol) from samples with more than a 2.5-fold
reduction in susceptibility to any of the drugs tested (n=39). All amino acid
substitutions based on the pNL4-3 consensus sequence were reported. The consensus
guidelines for ARV drug resistance testing were used to identify the most
common amino acid substitutions selected by ARV therapy and associated with
Categorical variables are reported as frequency measures. Continuous
variables are reported as arithmetic and geometric mean values with ranges.
Two sample McNemar binomial exact tests were used to compare the frequency
of reduced susceptibility among patient samples among each of the drug classes
tested. A 2-tailed P<.05 was considered significant.
A total of 141 subjects infected with HIV-1 between 1989 and 1998 were
evaluated; 120 (85%) of these since 1996. Eighteen subjects infected during
this period were not included in the analysis, including 4 for having HIV
RNA of less than 400 copies/mL, which precluded susceptibility testing; 7
for failed amplification reactions despite having an HIV RNA of at least 400
copies/mL; and 7 for prior ARV therapy of more than 7 days' duration.
Study volunteers were referred to participating study centers from local
urgent care clinics, medical care providers, inpatient hospital services,
community-based organizations, and by self-referral. Eighty percent of subjects
reported symptoms consistent with an acute retroviral syndrome (fever, fatigue,
sore throat, myalgias, headache) within 30 days of recognized high-risk HIV
exposure(s). Documentation of primary HIV infection was available in 71% of
the study cohort, including 62 subjects (44%) who presented with an evolving
HIV antibody response (ie, acute HIV infection) and 38 subjects (27%) who
had documented seroconversion within 12 months of presentation (ie, early
HIV infection). Primary HIV infection was presumed in the remaining 41 subjects
(29%) who reported symptoms consistent with an acute retroviral syndrome following
a high-risk exposure within 12 months of a negative anonymous (undocumented)
HIV antibody test. The patients were predominantly men with an average age
of 32 years whose HIV risk factor was having sex with men (Table 1). Because initial plasma HIV RNA results were greater than
the upper assay limit (750,000 copies/mL) in 13 patients (9%), the calculated
mean baseline RNA represents a minimum estimate.
A plasma sample for ARV susceptibility testing was collected an average
of 64 days (range, 0-279 days) after the estimated date of HIV infection.
The mean interval between the first documented positive HIV test result (serologic
or virological) and the collection of a drug susceptibility plasma sample
was 40 days. At the time of baseline specimen collection, 6 subjects had received
prior ARV therapy for a mean of 6 days (range, 4-7 days). Forty-eight (34%)
of the 141 study subjects were from San Diego, 48 (34%) from Los Angeles,
19 (14%) from Dallas), 13 (9%) from Boston, and 13 (9%) from Denver.
Virus with reduced susceptibility to 1 or more nucleoside reverse transcriptase
inhibitor (NRTI) was present in 5 samples (3%) (Figure 1). Two of these samples (1%) exhibited a greater than 10-fold
reduction in susceptibility and 3 (2%) showed a greater than 2.5- to 10-fold
reduction. The percentage of samples with reduced susceptibility to each NRTI
was, for zidovudine, 2%; lamivudine, 2%; stavudine, 1%; didanosine, 0%; and
zalcitabine, 1% (P>.05). Virus from 1 subject had
reduced susceptibility to more than 1 NRTI tested.
Twenty-four patient samples (17%) had virus with reduced susceptibility
to a nonnucleoside reverse transcriptase inhibitor (NNRTI), although only
1 sample (1%) exhibited a greater than 10-fold reduction in drug susceptibility
(Figure 1). The observed reductions
in susceptibility to this class were generally less than the reductions previously
reported from nevirapine-treated patients.32
Reduced susceptibility to either nevirapine (10%) or delavirdine (14%) was
observed in a significantly greater percentage of samples compared with efavirenz
(1%; P<.001). Among the 24 samples with reduced
susceptibility to NNRTIs, 9 (38%) had reduced susceptibility to both nevirapine
and delavirdine, while 2 (8%) had reduced susceptibility to all 3 NNRTIs.
The observed reductions in protease inhibitor susceptibility were generally
between 2.5- and 10-fold that of the reference virus (Figure 1). Greater than 10-fold reductions in protease inhibitor
susceptibility were observed in only 2 subjects (1%). Virus from both subjects
had reduced susceptibility to all 4 tested protease inhibitors (Figure 2). In contrast, more than 2.5- to 10-fold reductions in
susceptibility to a protease inhibitor were observed in 10% of patients, including
1% to saquinavir, 2% to indinavir, 5% to ritonavir, and 9% to nelfinavir (Figure 1). The number of subjects with reduced
susceptibility to nelfinavir was significantly greater than observed for saquinavir
or indinavir (P=.002). Comparisons among other drugs
were not statistically significant.
Reductions in drug susceptibility of more than 10-fold to 1 or more
ARV drugs were observed in 3 (2%) of 141 patient samples (Figure 2). Patient 97-546 from San Diego had 4- to 20-fold reductions
in susceptibility to each of the NNRTIs tested and responded well to a protease
inhibitor–NRTI–based treatment regimen (without use of an NNRTI).
Patient 98-1093 from Los Angeles had a 12-fold reduction in susceptibility
to zidovudine and 4- to 121-fold reductions in susceptibility to the protease
inhibitors. The patient was initially treated with nelfinavir-stavudine-lamivudine
and hydroxyurea but showed incomplete virological suppression (HIV RNA >400
copies/mL) at 24 weeks of therapy. After assessing the drug susceptibility
of the patient's virus, his treatment regimen was changed to nevirapine-didanosine-stavudine-hydroxyurea
and amprenavir, which resulted in complete viral suppression (<50 copies/mL)
after 12 weeks of the new regimen. Patient 98-1186 from Boston had reduced
susceptibility to multiple drugs, including zidovudine (9-fold), lamivudine
(>300-fold), zalcitabine (4-fold), nevirapine (6-fold), and multiple protease
inhibitors (5- to 45-fold) (Figure 2).
He was given a regimen of indinavir-lamivudine-zidovudine and exhibited a
slow decline in viral load compared with a typical patient (97-513) with drug-sensitive
virus initiating the same regimen (Figure
3). As a result of the slow decline in viral load, population-based
and clonal sequence analyses were performed on day 53. Mutations associated
with resistance to zidovudine (M41L, T215Y), lamivudine (M184V), and multiple
protease inhibitors (L10V, K20R, M36I, L63P, A71T, V77I, L90M) were identified
in a background of numerous polymorphisms. The treatment regimen was changed
to an NNRTI-NRTI–based regimen (efavirenz-didanosine-stavudine-abacavir
with hydroxyurea added 54 days later) with subsequent sustained suppression
of viral load to less than 50 copies/mL.
Population-based sequence analysis was used to evaluate the reverse
transcriptase and protease sequence of all recombinant virus pools with reduced
drug susceptibility (n=39). In 2 of 3 subjects with more than 10-fold reduction
in drug susceptibility, drug resistance mutations in reverse transcriptase
(M41L, M184V, T215Y) and protease (L10I/V, K20R, M36I, M46I, G48V, L63P, A71T,
V77I, V82T, I84V, L90M) were observed in a background of numerous polymorphisms
not characteristically associated with drug resistance. In patient 97-546,
who had up to 20-fold reduced susceptibility to the NNRTIs (Figure 2), amino acid substitutions in reverse transcriptase were
identified (ie, I135M, E138A), which may have accounted for the observed reduction
in susceptibility to the NNRTIs. However, none of the well-characterized mutations
in the binding pocket of reverse transcriptase were identified. A single resistance
mutation to zidovudine (K219K/R) was identified in this subject, associated
with a 2.2-fold reduction in susceptibility to zidovudine (below the threshold
of a more than 2.5-fold reduction in susceptibility). Among the 36 patient
samples (26%) with more than 2.5- to 10-fold reductions in susceptibility,
numerous polymorphisms were detected, but only 1 well-defined drug resistance
mutation (T215Y) was found, which corresponded to an 8.4-fold reduction in
susceptibility to zidovudine.
No geographic clustering was observed among patients with reduced susceptibility
to the antiretroviral drugs tested (data not shown); however, this study did
not have power to detect significant geographic variability. Although 70%
of these patients were identified after the release of the first potent protease
inhibitors (1997), the proportion of patients with moderately reduced susceptibility
to the protease inhibitors and NNRTIs did not significantly increase between
1989 and 1998 (data not shown). However, both subjects with more than 10-fold
reductions in protease inhibitor susceptibility were identified in 1998. Similarly,
samples with more than 10-fold reductions in susceptibility to either NRTIs
or NNRTIs were collected during 1997 (n=1) or 1998 (n=2). Virus with more
than 10-fold reductions in susceptibility to 2 classes of ARVdrugs (multidrug-resistant
virus) were present in 2 subjects (1%). No subject had a more than 10-fold
reduction in susceptibility to all 3 classes of drugs.
The observation of preserved HIV-specific CD4+ T-cell proliferative
responses in subjects who initiated potent ARV therapy during acute HIV seroconversion13 has resulted in modification of the consensus guidelines
for ARV therapy to include a recommendation for prompt therapy in the setting
of primary HIV infection.12 Studies from Europe33,34 and the United States35
have reported the transmission of drug-resistant variants in up to 10.5% to
15% of subjects with primary HIV infection and 13% of ARV therapy–naive
subjects. We identified a smaller proportion of subjects (2%) from 5 metropolitan
US cities infected with drug-resistant virus. These differences do not appear
to be related to selection bias or delay between HIV infection and testing
in our study cohort. Although we cannot exclude the possible reversion of
transmitted drug-resistant mutants prior to performance of study sequence
analyses, persistence of transmitted or acquired drug resistance mutations
for zidovudine36 and nevirapine32
in the absence of selective drug pressure has been demonstrated for 12 months
and 3.5 months, respectively. Rather, regional differences in ARV treatment
practices or risk behaviors among treatment-experienced patients from previously
published cohorts (San Francisco, Switzerland, and Spain), which were not
observed within our cohort, may account for this difference.
We believe it is important to monitor the prevalence of drug resistance
for epidemiological reasons and to assess the need for routine drug resistance
testing to guide clinical management of subjects with primary HIV infection.
Multiple studies have demonstrated an increased frequency of treatment failure
in subjects with established infection and drug-resistant virus.3,4,32,37
Similar studies of virological outcomes among subjects infected with drug-resistant
virus may require the screening of very large numbers of patients with primary
Reductions in susceptibility of more than 10-fold to ARV drugs were
confirmed in 2 of 3 subjects by the identification of well-characterized drug
resistance mutations in reverse transcriptase and protease. The initial response
to a protease inhibitor–NRTI–based treatment regimen was suboptimal
in these 2 subjects. Complete viral suppression was observed in the third
subject with greater than 10-fold reduced susceptibility to delavirdine, although
his treatment regimen did not include an NNRTI. In contrast, among a subset
of 13 patients from this Los Angeles cohort with wild-type drug susceptibility,
all had viral suppression (plasma HIV RNA <500 copies/mL) by week 12 of
Because the first therapeutic regimen is the most important in terms
of producing a maximal and durable virological response, suboptimal initial
therapy in subjects infected with drug-resistant virus may be associated with
the outgrowth of increasingly drug-resistant mutants and more rapid disease
progression. Poor adherence related to drug toxicities may further confound
our ability to identify subjects in whom suboptimal treatment responses may
be related to infection with drug-resistant virus. The cost of frequent viral
load testing to identify subjects with slow treatment-induced declines in
plasma viral load should be compared with that of routine drug resistance
testing in patients with primary HIV infection. Drug resistance testing in
newly infected subjects might be expected to limit the stepwise accumulation
of drug resistance mutations associated with incomplete viral suppression
in patients who receive an initial therapeutic regimen that contains only
1 or 2 active drugs.
The high prevalence of reduced drug susceptibility of more than 2.5-
to 10-fold to certain ARV drugs in this population (26%) was not associated
with the presence of recognized drug resistance mutations. The absence of
a significant delay between HIV seroconversion and drug susceptibility testing
in this population does not suggest selective outgrowth of a more fit virus.
However, we cannot exclude the possibility that minor subpopulations of more
highly resistant virus were present and not detected by population-based sequencing.
Greater natural variability in the susceptibility of wild-type virus to NNRTIs
and some protease inhibitors compared with NRTIs may represent another explanation
for the higher proportion of samples in this cohort with moderately reduced
susceptibility to these drugs. Assay validation studies support the highly
reproducible low-level reductions in NNRTI susceptibility (more than 2.5-
to 10-fold) among clinical isolates that lack well-characterized resistance
mutations,39 such as were observed in this
cohort, and suggest that additional mutations that confer reduced NNRTI susceptibility
have not yet been defined.40 The high prevalence
of more than 2.5- to 10-fold reductions in drug susceptibility also may be
related to the use of new, more precise recombinant assays. Lower levels of
reduced drug susceptibility may be detected with these assays compared with
conventional peripheral blood mononuclear cell assays used in the past. The
prevalence of NRTI drug resistance in our population was lower than previously
reported.35 The higher prevalence of NRTI drug
resistance previously reported may be attributed to inclusion of mutations
that represent polymorphisms and do not confer reduced drug susceptibility
or more widespread use of these drugs among unique study cohorts. Reductions
in drug susceptibility of more than 2.5- to 10-fold to certain ARV drugs may
have treatment implications in newly infected patients; however, further studies
are needed to determine the clinical significance of such reductions in susceptibility
and to determine whether the presence of more resistant subpopulations account
for some of these observations.
These data demonstrate that the transmission of multidrug-resistant
HIV has occurred in multiple cities across the United States. We were unable
to identify the source partner to ascertain ARV treatment histories among
most subjects or a particular exposure history in patients infected with drug-resistant
virus. The cost-effectiveness of resistance testing should be evaluated in
the context of efforts to rapidly identify and optimally treat those patients
infected with drug-resistant virus.
Extrapolation of these findings to include screening of drug-naive patients
with established infection will require demonstration that resistance mutations
persist in the absence of drug selection pressure. Transmitted resistant virus
may be outcompeted over time by subpopulations of more fit wild-type virus.
Available resistance assays do not readily detect minor populations of resistant
virus, which might subsequently be selected with initiation of ARV therapy.
Longitudinal studies are needed to monitor changes in the frequency of primary
drug resistance, the utility and limitations of phenotypic and genotypic testing
in this setting, the extent to which each ARV drug class is affected, and
the clinical consequences of primary infection with drug-resistant virus.
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