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Author Affiliation: Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY.
A near-uniformly fatal clinical syndrome, acquired immunodeficiency
syndrome (AIDS), has been transformed during the past 5 years into a treatable
infectious disease. The availability of potent antiretroviral agents coincided
with the ability to measure levels of circulating virus in vivo. When used
in tandem, an understanding of human immunodeficiency virus (HIV) replication
dynamics in vivo was made possible, forming the scientific basis for the use
of combination antiretroviral therapy.1 However,
the treatment of HIV infection remains far from perfect, and new issues arise
with regularity. Critical to achieving optimal therapeutic outcomes is an
understanding of treatment failure. Early clinical trials of protease inhibitor
monotherapy suggested that the pathway to treatment failure was exclusively
via drug resistance.2,3 Viral
rebound was thought to reflect failure of all components of a regimen. Furthermore,
it was assumed that the absence of resistance-conferring genotypic changes
reflected patient nonadherence.
In this issue of THE JOURNAL, articles by Descamps and colleagues4 and Havlir and colleagues5
question these assumptions in the context of 2 large clinical trials, Trilège6 and AIDS Clinical Trials Group 343.7
The inferior outcomes observed in patients randomly assigned to receive less
intensive maintenance therapy have been recently published.6,7
In the articles in this issue, the authors seek to understand the findings.
In the Trilège Study, a 3-month induction phase with zidovudine,
lamivudine, and indinavir was followed by randomization to either zidovudine
and lamivudine, zidovudine and indinavir, or continued triple-drug therapy
if the level of HIV RNA in plasma was less than 500 copies/mL. The primary
end point was virologic failure, defined by 2 consecutive plasma measurements
above 500 copies/mL on 2 consecutive visits, 6 weeks apart. Fifty-eight (20.8%)
of the 279 randomly assigned patients met this end point, 29 receiving zidovudine
and lamivudine, 21 receiving zidovudine and indinavir, and 8 receiving triple
therapy. Fifty-eight study patients with durable virologic suppression were
carefully selected by investigators as case-controls. The results of genotypic
studies revealed the presence of the lamivudine resistance-conferring M184V
substitution in reverse transcriptase in nearly all patients treated with
lamivudine. However, primary-resistance mutations associated with reduced
susceptibility to indinavir did not emerge during combination therapy with
zidovudine and indinavir or triple therapy. Similarly, zidovudine-associated
resistance-conferring mutations were rare and when present were confined to
changes at codons 41 and 70 of reverse transcriptase.
Adherence as measured by pill counts revealed a statistically significant
difference in median adherence rates between cases and controls for patients
prescribed either zidovudine or indinavir during maintenance therapy. Furthermore,
patients randomly assigned to receive zidovudine with indinavir only demonstrated
statistically significant differences in adherence rates compared with controls.
Plasma indinavir levels were found to be lower than expected in 2 groups,
those failing triple therapy and those failing zidovudine and indinavir maintenance
in association with a greater loss in antiviral efficacy. Indinavir levels
tended to be in the expected range in those patients in the zidovudine and
indinavir group in whom virologic failure was associated with a modest loss
of antiviral activity. Of note, plasma indinavir levels were clearly higher
in controls compared with cases in both the triple therapy and zidovudine
and indinavir groups.
In the AIDS Clinical Trials Group 343 study, after a 6-month induction
with the same triple combination regimen as used in Trilege, patients with
plasma HIV RNA levels below 200 copies/mL were randomly assigned to receive
zidovudine and lamivudine, indinavir monotherapy, or continued triple therapy.
Patients were followed up monthly and the study end point, virologic failure,
was defined as a subsequent plasma HIV RNA level of 200 copies/mL or greater.
Plasma indinavir levels and resistance testing by both genotypic assay and
a novel recombinant phenotypic assay were performed retrospectively in 9 of
23 patients in the indinavir monotherapy group who reached the study end point,
as well as in 17 of 75 patients who experienced virologic failure during the
induction phase, and 10 controls with sustained suppression throughout the
course of study. In those failing indinavir monotherapy, plasma HIV RNA levels
of 103 to 105 copies/mL were found at the time of viral
rebound. In all 9 patients, resistance testing showed no reduced susceptibility
to indinavir or resistance-conferring genotypic changes. Among patients receiving
triple therapy, the M184V codon substitution in reverse transcriptase was
observed in 14 of 17 patients. In 1 patient, a primary-resistance mutation
in the HIV protease (M41L) was associated with rebound. Otherwise, resistance
testing using both assays was consistent with retained indinavir susceptibility.
Plasma indinavir levels were available for 2 patients who received indinavir
monotherapy, and 7 who received triple therapy during both suppression and
virologic rebound whereas the remainder had drug levels available only during
the period of suppression. No differences in weighted mean indinavir concentrations
were observed among the 3 groups. However, the proportion of patients with
at least 1 extremely low indinavir level was significantly higher in the group
failing triple therapy.
These studies indicate that virologic failure is indeed multifactorial
and not solely the result of multidrug resistance. Undoubtedly, adherence
to a treatment regimen is essential. The time and degree of failure observed
in the Trilege study were associated with the degree of adherence. Less toxic,
simpler, and more patient-friendly regimens are urgently needed, but as these
studies point out, not at the expense of the regimen potency.
Reductions in the potency of antiretroviral regimens during the maintenance
phase allowed for the higher incidence of virologic rebound. In patients receiving
zidovudine and indinavir and indinavir monotherapy, rebound occurred in the
absence of readily demonstrable virus-mediated resistance to the antiviral
agents being used. One explanation is that the rebounding virus population
is a mixture of indinavir-susceptible and indinavir-resistant quasi species
and the more fit population, wild-type, predominates. However, an additional
consideration is drug potency.
Bonhoeffer and colleagues8 and Perno
and colleagues9 have suggested that drugs may
exhibit differential efficacy in different cellular populations. Reduction
of potency of 1 of the maintenance regimens may have allowed ongoing wild-type
virus replication in populations of infected cells in which indinavir, or
perhaps indinavir and zidovudine, do not exert a strong selective pressure
for the emergence of resistant virus. Multiple investigators have reported
ongoing viral replication during therapy without demonstrable resistance.10-12 Potential mechanisms
of cellular resistance recently have been identified and include interactions
between inducible cellular gene products such as p-glycoprotein (MDR-1)13 and multiple drug-resistance proteins14
with substrates known to include protease inhibitors and nucleoside reverse
transcriptase inhibitors, respectively.
Taken together, these studies demonstrate that virologic failure is
complex and not exclusively mediated by viral resistance. Furthermore, these
studies point out the relevance of resistance testing in the setting of virologic
rebound. Nonadherence is clearly a critical factor but cannot be assumed to
be the origin of treatment failure in the presence of rebound with wild-type
virus. Understanding issues surrounding drug potency and cellular resistance
seem critical at this juncture. Perhaps with better understanding of these
issues, the elusive universal response to HIV therapy may be achieved.
Markowitz M. Resistance, Fitness, Adherence, and Potency: Mapping the Paths to Virologic Failure. JAMA. 2000;283(2):250–251. doi:10.1001/jama.283.2.250
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