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Dual vs Single Protease Inhibitor Therapy Following Antiretroviral Treatment Failure
A Randomized Trial
Scott M. Hammer, MD;
Florin Vaida, PhD;
Kara K. Bennett, MS;
Mary K. Holohan, BA;
Lewis Sheiner, MD;
Joseph J. Eron, MD;
Lawrence Joseph Wheat, MD;
Ronald T. Mitsuyasu, MD;
Roy M. Gulick, MD;
Fred T. Valentine, MD;
Judith A. Aberg, MD;
Michael D. Rogers, PhD;
Cheryl N. Karol, PhD;
Alfred J. Saah, MD, MPH;
Ronald H. Lewis, MD;
Laura J. Bessen, MD;
Carol Brosgart, MD;
Victor DeGruttola, PhD;
John W. Mellors, MD;
for the AIDS Clinical Trials Group 398 Study Team
JAMA. 2002;288:169-180.
ABSTRACT
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Context Management of antiretroviral treatment failure in patients receiving
protease inhibitor (PI)–containing regimens is a therapeutic challenge.
Objective To assess whether adding a second PI improves antiviral efficacy of
a 4-drug combination in patients with virologic failure while taking a PI-containing
regimen.
Design Multicenter, randomized, 4-arm trial, double-blind and placebo-controlled
for second PI, conducted between October 1998 and April 2000, for which there
was a 24-week primary analysis with extension to 48 weeks.
Setting Thirty-one participating AIDS (acquired immunodeficiency syndrome) Clinical
Trials Units in the United States.
Participants A total of 481 human immunodeficiency virus (HIV)–infected persons
with prior exposure to a maximum of 3 PIs and viral load above 1000 copies/mL.
Intervention Selectively randomized assignment (per prior PI exposure) to saquinavir
(n = 116); indinavir (n = 69); nelfinavir (n = 139); or placebo twice per
day (n = 157); in combination with amprenavir, abacavir, efavirenz, and adefovir
dipivoxil.
Main Outcome Measures Primary efficacy analysis involved the proportion with viral load below
200 copies/mL at 24 weeks. Other measures were changes in viral load and CD4
cell count from baseline, adverse events, and HIV drug susceptibility.
Results Of 481 patients, 148 (31%) had a viral load below 200 copies/mL at week
24. The proportions of patients with a viral load below 200 copies/mL in the
saquinavir, indinavir, nelfinavir, and placebo arms were 34% (40/116), 36%
(25/69), 34% (47/139), and 23% (36/157), respectively. The proportion in the
combined dual-PI arms was higher than in the amprenavir-plus-placebo arm (35%
[112/324] vs 23% [36/157], respectively; P = .002).
Overall, a higher proportion of nonnucleoside reverse transcriptase inhibitor
(NNRTI)–naive patients had a viral load below 200 copies/mL compared
with NNRTI-experienced patients (43% [115/270] vs 16% [33/211], respectively; P<.001). Baseline HIV-1 hypersusceptibility to efavirenz
( 0.4-fold difference in susceptibility compared with reference virus)
was associated with suppression of viral load at 24 weeks to below 200 copies/mL
(odds ratio [OR], 3.49; 95% confidence interval [CI], 1.62-7.33; P = .001), and more than 10-fold reduction in efavirenz susceptibility,
with less likelihood of suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P = .03).
Conclusions In this study of antiretroviral-experienced patients with advanced immunodeficiency,
viral load suppression to below 200 copies/mL was achieved in 31% of patients
with regimens containing 4 or 5 new drugs. Use of 2 PIs, being naive to NNRTIs,
and baseline hypersusceptibility to efavirenz were associated with a favorable
outcome.
INTRODUCTION
Use of potent combination antiretroviral therapy has been associated
with marked reductions in morbidity and mortality related to human immunodeficiency
virus type 1 (HIV-1) infection in the developed world.1-3
Potent regimens are usually defined as those that contain at least 3 antiretroviral
agents, one of which is either a protease inhibitor (PI) or, more recently,
a nonnucleoside reverse transcriptase inhibitor (NNRTI)4-6
or, in treatment-naive subjects, a triple-nucleoside combination that includes
abacavir.7 The PI-containing combination therapy
quickly became a standard of care after widespread PI availability in 1996.4, 8-9 Despite the improved
outcomes, problems associated with combination antiretroviral therapy such
as failure and toxicity are apparent.10-13
Although virologic failure can be caused by suboptimal drug exposure due to
poor adherence or unfavorable pharmacokinetics, drug resistance is of concern
because of resulting limits on therapeutic options.14-15
Studies have shown that response to alternative or "salvage" antiretroviral
combination regimens in the setting of virologic failure is limited16-20
and suggest that higher response rates are seen when 2 or more active agents
are used in the salvage regimen and when a therapy switch is made at a lower
viral load.17, 19-20
Findings from short-term studies suggest that response rates may be improved
if choice of agent is guided by drug resistance testing.15, 21-25
A currently accepted approach to management of virologic failure in patients
already receiving a PI-containing regimen is to include 2 new PIs as part
of the salvage regimen.4, 6 However,
efficacy of this strategy has not been rigorously tested in a prospective
clinical trial. There are 2 rationales for addition of a second PI: to provide
pharmacokinetic enhancement of the first drug as with use of low-dose ritonavir
to increase drug exposure to other agents26-32;
and to provide additional drug exposure with full dosing of both PIs33 (rationale for the present study). Our goal was to
assess whether addition of a second PI to a new 4-drug class regimen including
amprenavir would improve virologic response in patients failing a PI-containing
regimen. Amprenavir34-35 has a
resistance profile different from the 4 previously approved PIs; viral strains
resistant to the latter agents may stay susceptible to amprenavir.36
METHODS
Study Design and Patients
The AIDS (acquired immunodeficiency syndrome) Clinical Trials Group
(ACTG) 398 study was a randomized, double-blind, placebo-controlled study
of saquinavir, indinavir, or nelfinavir added as a second PI to the 4-drug
class regimen of amprenavir, abacavir (a nucleoside reverse transcriptase
inhibitor [NRTI]), efavirenz (an NNRTI), and adefovir dipivoxil (a nucleotide
reverse transcriptase inhibitor [NtRTI]) in patients with virologic failure
defined by a viral load above 1000 copies/mL while receiving saquinavir, nelfinavir,
indinavir, or ritonavir. Randomization was stratified by prior PI use. The
study was designed to enroll 460 patients with no more than 33% having had
prior NNRTI use. During the trial, the latter was modified to permit a maximum
enrollment of 50% NNRTI-experienced patients to better reflect the antiretroviral
experience profile of patients failing PI therapy in the United States. The
primary objectives were to (1) compare the proportion of patients having a
viral load below 200 copies/mL at week 24 across study arms as determined
by an ultrasensitive reverse transcriptase-polymerase chain reaction HIV-1
RNA assay (Roche Molecular Systems, Branchburg, NJ); and (2) compare safety
and tolerance of the regimens across study arms using the ACTG adverse event
grading scheme.37 The stringent primary virologic
end point of a viral load of 200 copies/mL was chosen because virus suppression
to this level is associated with prevention of emergence of drug resistance,
virologic response durability, and improved clinical outcome.38-41
Secondary objectives were to (1) compare proportion of patients with
virologic failure across study arms (defined as a confirmed increase in viral
load above baseline occurring before week 24, indicative of lack of virologic
response,6 failure to achieve a minimum 0.5
log10 copies/mL decrease in viral load by week 8,6, 40-42
a confirmed 1.0 log10 copies/mL increase in viral load above nadir
value before week 24, a confirmed increase in viral load at or above 200 copies/mL
after a confirmed reduction to below 200 copies/mL before week 24, or viral
load at or above 200 copies/mL at week 24)40, 42;
(2) examine influence of prior NNRTI and PI use on virologic outcome at week
24; (3) compare changes from baseline to weeks 24 and 48 in viral load and
CD4 cell count; (4) compare drug concentration areas under the curve (AUCs)
of amprenavir, efavirenz, adefovir, saquinavir, indinavir, and nelfinavir
(selected for study because of potential for drug interactions43-44
in a subset of patients; and (5) explore the relationship between baseline
HIV-1 drug susceptibility and virologic response, and changes in drug susceptibility
at time of virologic failure.
Patients were recruited from 31 AIDS Clinical Trials Units. Inclusion
criteria were: 13 years of age or older, laboratory documentation of HIV-1
infection, prior exposure to a maximum of 3 PIs from among saquinavir, ritonavir,
indinavir, and/or nelfinavir for a cumulative period of PI therapy of at least
16 weeks, receiving the failing PI-containing regimen at time of screening15 (defined as a viral load >1000 copies/mL; a higher
level than that reported for transient virologic "blips"45),
having a Karnofsky performance status of 70 or more, and having certain laboratory
parameter levels (hemoglobin  9.1 g/dL for men and 8.9 g/dL for women,
absolute neutrophil count 850/µL, platelet count 65 000/µL,
aspartate and alanine aminotransferase levels 5 times upper limit of normal,
serum amylase 1.5 times upper limit of normal, serum creatinine 1.5
times upper limit of normal, normal serum phosphate and bicarbonate, no glycosuria,
and grade 1 proteinuria). Patients were required to be treatment-naive
to amprenavir, abacavir, and adefovir dipivoxil. Institutional review boards
of the participating institutions approved the study and each patient gave
written informed consent.
Study Treatment
Patients received open-label amprenavir 1200 mg twice daily, abacavir
300 mg twice daily, efavirenz 600 mg once daily, and adefovir dipivoxil 60
mg once daily (with L-carnitine supplementation 500 mg once daily) and were
randomized to receive saquinavir (soft-gel capsule formulation) 1600 mg twice
daily (saquinavir arm), indinavir 1200 mg twice daily (indinavir arm), nelfinavir
1250 mg twice daily (nelfinavir arm), or placebo matched for saquinavir, indinavir,
or nelfinavir (placebo arm). Selective randomization was carried out to prevent,
as possible, patients from receiving PIs to which they had been exposed (ie,
randomized to a PI arm containing PI[s] to which they were naive) (Figure 1). Patients with prior use of 3 PIs
were randomized to any of the 4 arms because no arm contained a second PI
to which they had not been exposed. Prior ritonavir and indinavir use was
considered use of a single PI because of overlapping resistance profiles of
these agents.46-48
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Figure 1. Flow Diagram of AIDS Clinical Trials
Group 398 Study Design and Patient Disposition
*Primary analysis time point was week 24. Follow-up continued through
week 48.
 Reasons for off study include patient not able to get
to clinic, withdrew consent, or site unable to contact patient.
 Reasons
for discontinuing treatment of any drug include virologic failure, toxicity
(both protocol and nonprotocol defined), and compliance.
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Monitoring and Enrollment
Patients were scheduled for follow-up visits at weeks 2, 4, 8, 16, and
every 8 weeks until the last patient completed 48 weeks on study. Follow-up
consisted of clinical assessments, routine laboratory monitoring, and viral
load measurement, the latter being measured twice at baseline. The CD4 cell
counts were measured twice at baseline and at weeks 4, 8, 16, and every 8
weeks until the study end. An interim review committee examined study results
on April 26, 1999, after 40 virologic failure end points had occurred and
again on August 24, 1999, at study team request. The recommendation after
each review was to continue the study unchanged. The primary analysis of the
study was prespecified in the protocol document and conducted when the last
patient reached 24 weeks on study.
A pharmacokinetics substudy was completed at day 14 in 46 patients accrued
when the first 187 patients were enrolled into the main study from 14 sites.
The 46 patients differed from the overall population (n = 481) with a higher
median CD4 cell count (303/µL vs 202/µL) and a higher proportion
of white, non-Hispanic enrollees (76% vs 58%). Patients were admitted to the
general clinical research centers of the participating institutions. Regular
scheduled doses of study medications were given under direct observation and
blood samples for assay of PIs, efavirenz, and adefovir dipivoxil levels were
drawn prior to dosing and at 1, 2, 4, 6, 8, and 12 hours after dosing. Amprenavir
levels were assayed at GlaxoSmithKline; saquinavir, indinavir, and nelfinavir
levels at Stanford University School of Medicine; efavirenz levels at State
University of New York at Buffalo; and adefovir dipivoxil levels at Harris
Laboratories (Lincoln, Neb). Levels of the nelfinavir M8 metabolite, which
contributes to its overall activity, were not assayed, but omission of these
data does not affect interpretation of the pharmacokinetic or main studies.
The AUCs were calculated using the trapezoidal rule assuming steady-state
and without infinity extrapolation.
To determine phenotypic HIV-1 drug susceptibilities retrospectively
using baseline plasma samples, 200 patients were randomly selected from the
entire study population using a random number generator. The 200 patients
did not differ from the overall study population in baseline demographic criteria.
Baseline phenotypic drug susceptibilities were assessed for all Food and Drug
Administration (FDA)–approved antiretroviral agents but only data from
drugs received in the study are presented herein. Of the 200 patients, 139
were chosen for study because of receiving study treatment for at least 8
weeks and having an available sample. The 139 patients did not differ from
the overall study group demographically. Of the 139, 59 had virologic failure
and phenotypic susceptibility testing was done on plasma samples at time of
failure. Plasma samples from baseline and at time of virologic failure were
tested using a recombinant virus assay (PhenoSense, ViroLogic Inc, South San
Francisco, Calif). For this study, virus having a 50% inhibitory concentration
(IC50) for an individual drug that was more than 2.5-fold higher
than the IC50 for the reference virus (HIV-1NL4-3) was
considered to have reduced drug susceptibility; virus that showed an IC50 that was 2.5-fold or less higher than the reference strain was considered
sensitive.49 Virus having an IC50
0.4-fold or less than that of the reference virus for a drug was considered
to be hypersusceptible to that drug, based on assay ability to differentiate
this level of susceptibility as different from that of the reference virus
and because it has been used in prior studies.50-51
In an additional analysis, an IC50 that was more than 10-fold higher
than that of the reference virus was used to define drug resistance. Use of
the 10-fold cutoff is arbitrary; it accounts for the known variability (as
much as 10-fold in clinical isolates52)of wild-type
virus in susceptibility to NNRTIs due to natural polymorphisms in reverse
transcriptase. The 10-fold cutoff was used to explore the utility of the phenotypic
susceptibility score in predicting virologic outcome with various cutoffs.
Ten-fold is a level for which it is known that reduced susceptibility exists.49
Statistical Analysis
The intent-to-treat subject allocation was used for the primary analysis.
If patients discontinued a component of the original study treatment, they
were allowed to continue the rest of the regimen (in combination with FDA-approved
agents), with study team approval. Patients stopping any component of the
study regimen were characterized as discontinuing study treatment for purposes
of the primary analysis but study follow-up continued. The nonstudy, FDA-approved
drugs used by patients within 40 days of discontinuing study treatment included
zidovudine, stavudine, lamivudine, didanosine, nevirapine, delavirdine, ritonavir,
and hydroxyurea. Data from patients who dropped out of the study were censored
at the last recorded clinic visit. Data from the first 24 weeks of follow-up
were used in the primary analysis. The 48-week analysis also included adefovir-related
nephrotoxicity and AIDS-defining events or deaths. All viral load assays were
done at The Johns Hopkins University Laboratory (Baltimore, Md). Lower and
upper limits of quantification were 200 and 75 000 copies/mL, respectively;
samples with more than 75 000 copies/mL were retested after dilution.
Viral load values were log10 transformed for analysis. In analyzing
the proportion below 200 copies/mL at week 24, missing viral load data at
week 24 were considered to be 200 copies/mL or more. Missing data due to death
or study discontinuation were counted as virologic failures.
Baseline characteristics were compared for differences among treatment
arms using the Mantel-Haenszel exact test for categorical data and F test
of analysis of variance for continuous scale data. Primary analysis of proportion
below 200 copies/mL at week 24 included pairwise comparisons of each saquinavir,
indinavir, and nelfinavir arm with placebo arm and comparison of dual PI treatment
(combined saquinavir, indinavir, and nelfinavir arms) with single PI treatment
(placebo arm), using the Mantel-Haenszel exact test, stratified as protocol-prespecified
for prior PI and prior NNRTI use, without adjustment for multiple comparisons.
The study was designed to detect a 40% vs 20% success rate difference in each
PI arm vs the placebo arm, with more than 80% power. With study sample sizes,
there was 89%, 70%, and 93% power to detect a difference of 40% vs 20% in
the saquinavir, indinavir, and nelfinavir vs placebo comparisons, respectively.
The study was not designed to compare dual PI arms with each other.
Analysis of time to viral load below 200 copies/mL used a Cox proportional
hazards model with NNRTI use, baseline viral load, and treatment arm as covariates,
stratified by prior PI use. Analysis of proportion of virologic failures occurring
through week 24 and of proportion of patients with viral load below 200 copies/mL
at week 24 among those continuing assigned treatment included the 3 pairwise
comparisons described above plus a comparison of combined dual PI arms vs
the single PI arm (placebo), with stratification, as described for the primary
analysis. Assumptions for Cox models used in analyses presented herein were
tested and met with the exception of time to virologic suppression for the
nelfinavir arm vs the placebo arm comparison, in which nelfinavir effect on
suppression was time-dependent. Preliminary comparisons of virologic failure
at week 48 (viral load of 200 copies/mL) used the stratified Mantel-Haenszel
exact test. Analysis of change in log10 viral load from baseline
to week 24 used the Buckley-James distribution-free model, which accounts
for censored data.53 Change in mean CD4 cell
count from baseline to week 24 was analyzed using the Wilcoxon rank test,
stratified by prior PI and NNRTI use. Safety and tolerability of regimens
(time to first grade 3 or 4 sign or symptom, or first grade 3 or 4 laboratory
abnormality) were analyzed using the log-rank test, stratified by prior PI
and NNRTI use. Analysis of variance was used to assess effect of treatment
arm on drug level AUCs for amprenavir, efavirenz, adefovir, saquinavir, indinavir,
and nelfinavir.
Influence of baseline viral load on time to virologic response (viral
load <200 copies/mL) and virologic failure used a Cox model and binary
regression with log-log link, respectively. Influence of prior NNRTI and PI
use on virologic failure was assessed using the likelihood ratio test for
logistic regression to calculate risk ratios, adjusted for baseline covariates.
For patients having virologic failure and with phenotypic results available,
change in susceptibility to study medications was calculated as ratio of IC50 (fold IC50) at failure divided by IC50 (fold
IC50) at baseline. Geometric means of the fold-resistance ratios
were tested to assess if these significantly differed from 1 using the 1-sample t test. For drug susceptibility analyses, baseline phenotypic
sensitivity scores54 were calculated for drug
combinations (for 2.5-fold and 10-fold cutoff analyses, a score of 1 was given
for each drug in the regimen to which the virus showed an IC50 2.5-fold
or 10-fold above the reference virus IC50; a score of 0 was
given for a drug with an IC50 >2.5-fold or >10-fold above). Relationship
between baseline resistance and virologic failure was examined using odds
ratios (ORs) generated by logistic regression. The ORs should not be interpreted
as risk ratios when analyzed events involve common outcomes.55
SAS version 6.12 (SAS Institute Inc, Cary, NC) and Splus version 3.4 (Splus,
Insightful Corporation, Seattle, Wash) were used and level of significance
was P.05.
RESULTS
Patient Characteristics
The 481 patients were randomized between October 13, 1998, and April
14, 1999, with the study ending in April 2000. Randomization by prior PI use
is given in Table 1 and baseline
characteristics (well-balanced across study arms) of the study group in Table 2. Patient median age was 40 years;
87% were men; and 58% were white, 23%, black, and 15%, Hispanic. The proportions
of patients exposed to 1, 2, or 3 prior PIs were 21%, 53%, and 26%, respectively;
and 44% were NNRTI-experienced. Median baseline CD4 cell count and viral load
were 202/µL and 51 601 copies/mL, respectively.
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Table 1. Accrual by Protease Inhibitor Experience*
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Table 2. Baseline Characteristics by Treatment
Arm*
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Duration of Follow-up and Study Treatment
For the primary analysis, follow-up for virologic outcome and routine
toxicities was 24 weeks (Figure 1).
Secondary analyses for efficacy and toxicity extended through 48 weeks. At
24 weeks, 29 (6%) of 481 patients were off-study and 201 (42%) had discontinued
study treatment (discontinuation of any drug in assigned regimen). Of the
201, 58 (29%) discontinued treatment for virologic failure and 143 (71%) for
other reasons. Most of the latter were for protocol-defined or nonprotocol-defined
toxicities (47 [33%] and 63 [44%], respectively). Most common reasons recorded
by study sites for discontinuing treatment included gastrointestinal symptoms,
drug reaction, and patient preference (eg, for low-grade toxicities). Abacavir
was discontinued in 55 patients, amprenavir in 40, efavirenz in 39, adefovir
dipivoxil in 25, and the second PI in 31 (saquinavir in 13, indinavir in 7,
and nelfinavir in 11). Of the 201 patients, 131 (65%) continued at least 1
original drug in the assigned regimen after permanently discontinuing 1 or
more regimen drugs. The combined proportion of patients off study and discontinuing
treatment was lower in the nelfinavir (but not saquinavir or indinavir) vs
placebo arm (P = .02). Pill burdens in the placebo
arm were comparable with those in the dual PI arms.
Virologic Outcome at 24 Weeks
At 24 weeks, 148 (31%) of the 481 patients had a viral load below 200
copies/mL. Proportions below 200 copies/mL were 34%, 36%, 34%, and 23% in
the saquinavir, indinavir, nelfinavir, and placebo arms, respectively (Table 3). In the Cox model of time to virologic
suppression, the time-dependent effect of nelfinavir vs placebo was significant
(P = .003). At week 12, the risk ratio of suppression
was 2.37 (95% confidence interval [CI], 1.40-4.02; P
= .003) in favor of nelfinavir. As suppression is an early event, week 12
was a relevant time point to assess. The week 24 risk ratio was 3.58 (95%
CI, 1.60-8.01). The proportion below 200 copies/mL at 24 weeks in dual PI
arms combined (35%, Table 3) was
higher than with placebo (23%; P = .002). In 2-way
comparisons of proportions below 200 copies/mL between individual dual PI
arms and placebo, only the nelfinavir vs placebo comparison was significant
(P = .004). The significance of these comparisons
is influenced by variable patient numbers in the strata of prior PI use within
each arm (Table 1). The performance
of the dual PI arms was similar as shown by the proportions with less than
200 copies/mL at week 24. The study was not designed to compare dual PI arms
with each other; thus, these comparisons are not reported.
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Table 3. Proportions of Patients With Viral
Load Below 200 Copies/mL at Week 24*
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In pairwise comparisons of the time to viral load below 200 copies/mL
between each dual PI arm and placebo, the nelfinavir arm had a shorter time
to suppression than placebo (this was time-dependent [see above]), whereas
the saquinavir and indinavir arms did not (risk ratio, 1.35; 95% CI, 0.91-2.01; P = .13; and 1.13; 95% CI, 0.68-1.87; P = .64, respectively).
The study design had a primary end point of 24 weeks with an extension
to 48 weeks. In preliminary analyses, results at 48 weeks were concordant
with the week 24 responses. Overall, 28% (133/481) of patients had a viral
load below 200 copies/mL at 48 weeks. The proportions below 200 copies/mL
in the saquinavir, indinavir, nelfinavir, and placebo arms were 34%, 33%,
26%, and 22%, respectively. A higher proportion in the combined dual PI arms
had a viral load below 200 copies/mL than with placebo (30% vs 22%; P = .04).
Viral Load and CD4 Cell Count Changes From Baseline
Mean (SD) changes from baseline in viral load are shown in Figure 2A. At week 2, mean reduction in viral
load was comparable across treatment arms (-1.37 to -1.43 log10 copies/mL). At week 24, changes from baseline in viral load in saquinavir,
indinavir, nelfinavir, and placebo arms were -1.88, -1.83, -1.64,
and -1.02 log10 copies/mL, respectively. The combined dual
PI arms had greater viral load reduction vs placebo at week 24, controlling
for prior NNRTI use (-2.29 vs -1.59 log10 copies/mL
for naive group, respectively, and -1.14 vs -0.44 log10
copies/mL for experienced group, respectively; P<.001).
At 48 weeks, mean viral load reduction from baseline in combined dual PI arms
was also higher than with placebo, controlling for prior NNRTI use (-1.99
vs -1.51 log10 copies/mL for naive group, respectively, and -1.31
vs -0.82 log10 copies/mL for experienced group, respectively; P<.001).
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Figure 2. Viral Load and CD4 Cell Count Change
From Baseline in Dual Protease Inhibitor and Placebo Arms
Dual protease inhibitor arms received saquinavir, indinavir, and
nelfinavir. All patients also received amprenavir, abacavir, efavirenz, and
adefovir dipivoxil.
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Figure 2B shows mean changes
from baseline in CD4 cell count. At week 24, changes from baseline in saquinavir,
indinavir, nelfinavir, and placebo arms were + 53, + 9, + 33, and + 13 cells/µL,
respectively. Combined dual PI arms had a greater increase in CD4 cells (+34/µL)
vs placebo (+13/µL) at week 24 (P = .048).
At 48 weeks, the increase in CD4 cells (+38/µL) in combined dual PI
arms was not significantly higher than with placebo (+25/µL; P = .63).
On-Treatment Analysis
An on-treatment analysis was performed because of the substantial proportion
of patients discontinuing treatment and to assist with interpretation of intent-to-treat
results. Through week 24, 249 patients (52%) stayed on study treatment. Of
these, 129 (52%) had a viral load below 200 copies/mL at week 24. Proportions
having a viral load below 200 copies/mL in the saquinavir, indinavir, nelfinavir,
and placebo arms were 63%, 68%, 50%, and 40%, respectively (Table 3). Comparison of combined dual PI arms vs placebo showed
that 57% vs 40% had a viral load below 200 copies/mL at 24 weeks. A higher
proportion of the NNRTI-naive patients had virologic suppression at week 24
vs NNRTI-experienced patients (65% vs 31%, respectively). These on-treatment
analyses are concordant with the primary, intent-to-treat analysis but should
be interpreted cautiously because randomized groups are not being compared.
Clinical Disease Progression
At the 48-week analysis timepoint, there were 11 patients with a total
of 13 AIDS-defining illnesses, and 9 patients had died. The AIDS-defining
illnesses were Pneumocystis carinii pneumonia (3),
Kaposi sarcoma (3), cytomegalovirus retinitis (2) and esophagitis (1), Mycobacterium avium intracellulare bacteremia (1), cryptococcal
meningitis (1), esophageal candidiasis (1), and progressive multifocal leukoencephalopathy
(1). Of the 9 deaths, 6 were HIV-1–related. Of the 16 total patients
with HIV-1–related clinical events, numbers and proportions occurring
in the saquinavir, indinavir, nelfinavir, and placebo arms were 5 of 116 (4%),
2 of 69 (3%), 5 of 139 (4%), and 4 of 157 (3%), respectively (no significant
difference).
Adverse Events
Through 24 weeks, 19% (89/481) of patients had grade 3 or 4 signs or
symptoms with gastrointestinal symptoms predominating. Proportion with grade
3 or 4 laboratory abnormalities was 28%, with hypertriglyceridemia and hypophosphatemia
predominating. In saquinavir, indinavir, nelfinavir, and placebo arms, grade
3 or 4 signs/symptoms occurred in 23 (20%), 15 (22%), 27 (19%), and 24 (15%),
respectively; for grade 3 or 4 laboratory abnormalities, 29 (25%), 16 (23%),
41 (29%), and 47 (30%), respectively. There were no significant differences
across study arms regarding grade 3 or 4 adverse events. Analysis of specific
toxicities at lower grades showed a 17% incidence of grade 2 or more rash,
a 17% incidence of grade 2 or more central nervous system abnormalities, and
a 5% incidence of abacavir-related hypersensitivity. No significant differences
across study arms were seen for these toxicities. Through 48 weeks of follow-up,
overall rates of grade 3 or 4 or signs/symptoms and laboratory abnormalities
were 21% (102/481) and 35% (166/481), respectively, with no significant differences
across study arms and with a profile similar to that of week 24. Adefovir-related
nephrotoxicity occurred in 146 (30%) patients.
Pharmacokinetic Analysis
Mean AUCs for study drugs seen in the 46 patients at day 14 are shown
in Table 4. The 12-hour AUCs for
amprenavir were 8913, 19 055, 18 621, and 10 000 ng·h
per milliliter in saquinavir (n = 12), indinavir (n = 10), nelfinavir (n =
12), and placebo (n = 12) arms, respectively. The difference across study
arms was significant (P = .009) with AUCs for amprenavir
in saquinavir and placebo arms being about 50% lower than those in indinavir
and nelfinavir arms. In 2-way comparisons, amprenavir AUCs in saquinavir and
indinavir arms were not different from that in placebo arm (P = .92 and P = .33, respectively), whereas
in the nelfinavir arm it was higher than in placebo arm (P = .01). The AUCs for efavirenz and adefovir dipivoxil were comparable
across study arms and consistent with prior data.56-57
The AUCs for saquinavir, indinavir, and nelfinavir were within the ranges
reported when given alone or with nucleoside analogs only.58-60
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Table 4. Areas Under the Curve for Study Drug
by Treatment Arm*
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Influence of Baseline Viral Load and Prior NNRTI and PI Use on Virologic
Outcome
In all analyses, baseline viral load was significantly related to virologic
outcome. A 10-fold higher baseline viral load and a baseline level above the
median (vs below) were each associated with virologic failure (risk ratio,
1.45; 95% CI, 1.24-1.69; P<.001; risk ratio, 1.64;
95% CI, 1.30-2.05; P<.001, respectively). Prior
NNRTI use was also correlated with virologic outcome. Of 270 NNRTI-naive patients,
115 (43%) had a viral load below 200 copies/mL at 24 weeks vs 33 (16%) of
211 NNRTI-experienced patients (P<.001 [stratified
by prior PI use and treatment arm, and adjusted for baseline log10
viral load]). In contrast, proportions of patients with single vs 2 or more
prior PI use with viral load below 200 copies/mL at 24 weeks were not significantly
different (37% vs 29%, respectively; P = .13 [adjusted
for prior NNRTI use, treatment arm, and baseline viral load]).
Phenotypic Drug Susceptibility
Baseline phenotypic drug susceptibilities were determined on samples
from 139 randomly selected patients at baseline (Figure 3). Of these 139 patients, 59 had virologic failure and susceptibilities
were also assessed at time of virologic failure for them. At baseline, 50
of 139 (36%), 91 of 139 (66%), 37 of 139 (27%), and 26 of 139 (19%) patients
had virus with IC50 values of more than 2.5-fold higher than reference
virus for amprenavir, abacavir, efavirenz, and adefovir dipivoxil, respectively
(drugs common to all study arms). Thus, a substantial proportion had reduced
susceptibility to 1 or more study regimen components at baseline. For efavirenz
and other NNRTIs, the level of reduced drug susceptibility that may affect
treatment response is likely more than 10-fold; lower levels of reduced susceptibility
(2.5-fold to 10-fold) are caused by natural polymorphisms in reverse transcriptase
that may not affect treatment response.52, 61
The level of reduced susceptibility was more than 10-fold for amprenavir,
abacavir, efavirenz, and adefovir dipivoxil in 3 (2%), 5 (4%), 23 (17%), and
1 (1%) of 139 patients studied, respectively.
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Figure 3. Phenotypic Susceptibility of Virus
Strains
NRTI indicates nucleoside reverse transcriptase inhibitor; NtRTI,
nucleotide reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase
inhibitor; B, baseline; and VF, virologic failure. The samples were derived
from 139 patients randomly selected at baseline continuing study treatment
for at least 8 weeks and 59 patients developing virologic failure. Data are
represented as fold-change in susceptibility in relation to a laboratory reference
strain as assessed via a recombinant virus assay (PhenoSense, ViroLogic Inc).
Dots represent individual data points for assigned drugs. A 50% inhibitory
concentration more than 2.5-fold higher (dotted line) than reference virus
was considered to have reduced drug susceptibility (see Methods).
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To assess overall treatment susceptibility, a baseline phenotypic sensitivity
score was calculated.54 Using a 2.5-fold or
less cutoff for sensitivity, the median score for the 139 patients was 3.0,
meaning they received 3 drugs on average potentially active against baseline
virus. The median score was 4.0 when a 10-fold or less cutoff was used. Only
in the latter instance (cutoff 10-fold or less) was the score associated with
outcome (ie, a higher phenotypic sensitivity was associated with a higher
likelihood of virologic suppression) at 24 weeks (OR, 2.03; 95% CI, 1.17-3.54; P = .01) but was not significantly associated with virologic
suppression at 48 weeks (OR, 1.34; 95% CI, 0.78-2.30; P = .29).
Baseline efavirenz susceptibility was also examined regarding virologic
outcome because of the importance of prior NNRTI use on virologic response.
Reduced baseline efavirenz susceptibility (>10-fold) was associated with lesser
likelihood of virologic suppression at 24 weeks (OR, 0.28; 95% CI, 0.09-0.87; P = .03) and 48 weeks (OR, 0.16; 95% CI, 0.04-0.72; P = .02). In contrast, baseline efavirenz hypersusceptibility
(an IC50 of 0.4-fold or less compared with reference virus) was
detected in 42 of 139 patients and associated with greater likelihood of virologic
suppression at 24 weeks (OR, 3.49; 95% CI, 1.62-7.33; P = .001) and 48 weeks (OR, 5.66; 95% CI, 2.57-12.46; P<.001). This association was significant at 48 weeks even after
controlling for prior NNRTI use (OR, 3.21; 95% CI, 1.36-7.59; P = .008).
Susceptibility change from baseline to time of virologic failure was
also assessed for 59 (of the 139) patients with virologic failure by week
24; this showed that virologic failure by week 24 was mostly associated with
decreasing susceptibility to efavirenz but not other study drugs (Table 5 and Figure 3). Overall, there was a 35.4-fold median decrease in susceptibility
to efavirenz comparing baseline with time-of-failure IC50 values
(P<.001). For NNRTI-naive patients, median fold
decrease in susceptibility was 65.1; for NNRTI-experienced patients, it was
26.5. Subset numbers are small and should be interpreted cautiously.
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Table 5. Changes in Study Medication Susceptibility
in Patients With Virologic Failure*
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COMMENT
Effective management of patients with virologic failure receiving PI
therapy is a major challenge today.4, 6, 14
Drug options are limited for patients failing their second or third regimen
because of intraclass drug cross-resistance.15
Four drug classes are represented herein. Amprenavir may retain activity against
clinical isolates from patients failing therapy with other approved PIs.15 Abacavir is the most potent NRTI approved to date.62 The HIV-1 isolates with limited genotypic evidence
of resistance to other nucleoside analogs can retain abacavir susceptibility,
making the drug useful for salvage purposes.63
However, multiple nucleoside analog–associated resistance mutations
(4) limit abacavir activity in patients with extensive prior nucleoside
analog use.64 Some HIV-1 isolates with reduced
susceptibility to nevirapine and delavirdine may retain some in vitro susceptibility
to efavirenz, although its in vivo activity in this case is limited.65 Use of adefovir dipivoxil (the first NtRTI anti-HIV
compound66) in HIV disease has been halted
because of limited antiretroviral activity and nephrotoxicity,67
but the closely related tenofovir disoproxil fumarate has a more favorable
safety and activity profile68-69
and is now FDA-approved.
The results of ACTG 398, the largest prospective, randomized trial of
salvage therapy for PI failure reported to date, show that only 31% of patients
had virologic suppression as defined by a viral load below 200 copies/mL at
24 weeks. This proportion is less than would be desired but this suppression
level is a stringent test of a salvage regimen. The study group had advanced
disease with a median baseline viral load of 51 601 copies/mL and a median
baseline CD4 cell count of 202/µL, 79% had prior use of 2 or more PIs,
and 44% were NNRTI-experienced. The study group as a whole averaged a -1.44
log10 decline in viral load at 24 weeks, a change likely to confer
clinical benefit.42
A key finding is that combined dual PI-containing arms were superior
to the single PI-containing arm (placebo) regarding the proportion of patients
with virologic suppression (viral load <200 copies/mL at 24 weeks [35%
vs 23%, respectively; P = .002]). This is the first
study to our knowledge that shows superiority of dual vs single PI therapy
in a prospective, placebo-controlled trial in treatment-experienced patients.
A second key finding is that the NNRTI-naive subgroup had a higher rate
of virologic suppression (viral load <200 copies/mL) compared with the
NNRTI-experienced subgroup (43% vs 16%; P<.001).
This emphasizes the importance of having at least one (preferably more) potent
agent, against which little or no viral cross-resistance is likely to exist,
to use as the cornerstone of a salvage regimen.14
Surprisingly, the number of prior PIs used (1 vs 2) was not associated
with a significant difference in virologic outcome at 24 weeks. Mean (SD)
durations of prior PI use in the single and 2 or more PI-exposed groups were
82 (42) and 115 (49) weeks, respectively. One would expect that greater duration
of prior PI use would influence virologic outcome but both groups were extensively
exposed, possibly preventing detection of a difference.
Data showing that efavirenz lowers amprenavir levels by 30% or more
became available after the ACTG 398 study was under way.17
Concern about this possibility and lack of data on possible 3-way drug interactions
between amprenavir, a second PI, and efavirenz led to inclusion of a pharmacokinetic
substudy in this trial. This substudy showed that 12-hour AUC for amprenavir
in the placebo arm was about 50% of that in indinavir and nelfinavir arms,
and at the lower end of the range described for prior pharmacokinetic studies
of amprenavir in the absence of efavirenz.17, 34-35
Interestingly, amprenavir AUC in the saquinavir arm was also about 50% of
that in indinavir and nelfinavir arms and comparable to that in the placebo
arm. Efavirenz lowers amprenavir AUC, presumably by inducing cytochrome P-450
(CYP) 3A4.43, 70 Saquinavir, indinavir,
and nelfinavir all inhibit CYP3A4 and amprenavir metabolism in vitro,43, 70-71 and would therefore
oppose the efavirenz effect. Saquinavir, however, is the weakest inhibitor
of CYP3A4; thus, it may not have opposed the efavirenz effect on amprenavir
levels to the same extent as indinavir and nelfinavir in vivo.43, 72
Although lower amprenavir levels in the placebo arm may have contributed to
virologic failure in that arm, lower amprenavir levels do not fully explain
the overall study results as illustrated by the virologic failure rates in
the 4 arms of the pharmacokinetics substudy (Table 4).
The extent of resistance to the assigned treatment regimen, as defined
by the baseline phenotypic sensitivity score using a 10-fold cutoff, was predictive
of suppression at 24 weeks. Hypersusceptibility to NNRTIs has been reported
in HIV-1 isolates from patients with nucleoside analog–associated resistance
mutations and limited data sets have suggested it is associated with better
response to NNRTI-containing regimens.50-51
Data herein, however, are the first to firmly establish the importance of
efavirenz hypersusceptibility in long-term virologic response to salvage regimens.
The rates of virologic success seen in this study are comparable to
or better than those seen with other approaches to salvage therapy, including
multidrug rescue therapy (a regimen containing at least 6 agents73),
structured treatment interruptions, and the use of nucleoside-adjunctive agents
such as hydroxyurea or mycophenylate mofetil.74-77
Salvage therapy results from NNRTI-naive patients receiving lopinavir, a PI
with high serum levels in the presence of low-dose ritonavir, suggest successful
viral suppression is possible with prior PI use if drug levels exceeding the
IC50 of resistant strains can be achieved.32, 78
The findings herein have shown progress and limitations in the challenging
therapeutic arena of providing effective salvage therapy in the setting of
virologic failure with PIs.
AUTHOR INFORMATION
Financial Disclosures: Dr Hammer is a consultant
or site investigator for Boehringer Ingelheim, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Roche-Trimeris, Shionogi, Shire Biochem, Tibotec-Virco,
Triangle. Dr Sheiner has Pharsight Corp stock; is a consultant for Alza (Johnson
& Johnson), Genentech, Novartis, Pfizer, Servier; is an advisor for Pharsight;
and receives grants/research funding from NIGMS and NIAID. Dr Eron is a principal
investigator for University of North Carolina research contracts from Abbott,
Merck & Co, Roche/Trimeris, and Pharmasett; consultant to, receives research
grant funding or honoraria for ad hoc consulting, sponsored talks, or CME
programs from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, NIH-NIAID, Substance Abuse and Mental Health Services
Administration, Triangle Pharmaceuticals, Trimeris, ViroLogic, and Tibotec-Virco;
Dr Wheat receives research grants/funding, honoraria, lecture sponsorships,
assay kits/reagents (Director of Histoplasmosis Reference Lab) from (or is
an advisor to) Abbott, Bristol-Myers Squibb, Chiron, Council of Health Care
Advisors for Gerson Lehrman Group, Fujisawa, Gilead Sciences, Glaxo, Lilly,
Merck, Ortho, Pfizer, Roche, Schering-Plough, Trimeris, and government grants/funding
(ACTG, SOCA, VA merit review on histoplasmosis). Dr Mitsuyasu receives honoraria
from medical education groups for CME programs sponsored by Bristol-Myers
Squibb and Roche. Dr Gulick receives research grants/funding or speaker honoraria
from or is an ad hoc consultant to Abbott, Boehringer Ingelheim, Bristol-Myers,
GlaxoSmithKline, Merck, Shionogi, Trimeris, ViroLogic. Dr Aberg receives research
grants/funding from Abbott, Agouron, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Merck, Roche, Pfizer. Dr Rogers has GlaxoSmithKline stock
options. Dr Karol is employed by and has stock in Roche. Dr Saah is employed
by and has stock and stock options in Merck. Dr Lewis is employed by and has
stock in Agouron. Dr Bessen is employed by and has stock options in Bristol-Myers
Squibb. Dr Brosgart is vice-president of clinical research at and has stock
and stock options in Gilead Sciences. Dr DeGruttola is a consultant for Glaxo
for Resistance Collaborative Group work and Bristol-Myers, and receives government
grant/research funding (Statistical and Data Analysis Center contract). Dr
Mellors has stock, stock options, research grants/funding, honoraria, consultancies,
assay kits/reagents, or CME program honoraria from numerous pharmaceutical
companies/other commercial entities, government grants/research funding from
the Veterans Affairs, NIH, NIAID, NCI, and has patents filed January 22, 1999
(Technology Transfer #2 [for a method for treating HIV that includes administering
beta-D-D4FC or its pharmaceutically acceptable salt or prodrug]), and December
22, 2000 (Technology Transfer #3 [for methods for treating viral infection
involving administering one or more lipid analogs of phosphonoformate or thiophosphonoformate]).
Author Contributions: Dr Hammer, as principal
author, had full access to all of the data and takes full responsibilty for
the integrity of the data and the accuracy of the data analyses. Study concept and design: Hammer, Vaida, Holohan, Eron, Valentine,
Rogers, Karol, Lewis, Bessen, Brosgart, DeGruttola, Mellors.
Acquisition of data: Vaida, Bennett, Holohan,
Eron, Mitsuyasu, Gulick, Valentine, Aberg, Brosgart.
Analysis and interpretation of data: Hammer,
Vaida, Bennett, Sheiner, Eron, Wheat, Saah, Brosgart, DeGruttola, Mellors.
Drafting of the manuscript: Hammer, Vaida,
Bennett, Holohan, Wheat, Lewis, Brosgart, Mellors.
Critical revision of the manuscript for important
intellectual content: Hammer, Vaida, Bennett, Sheiner, Eron, Mitsuyasu,
Gulick, Valentine, Aberg, Rogers, Karol, Saah, Bessen, Brosgart, DeGruttola,
Mellors.
Statistical expertise: Vaida, Bennett, Sheiner,
DeGruttola.
Obtained funding: Holohan, Valentine, Rogers,
Karol, Lewis.
Administrative, technical, or material support:
Holohan, Wheat, Rogers, Saah, Brosgart, Mellors.
Study supervision: Hammer, Vaida, Holohan,
Eron, Mitsuyasu, Gulick, Valentine, Aberg.
AIDS Clinical Trials Group 398 Study Sites and Contributors: Indiana University, Bloomington: Kristin
Todd, Michael Frank; University of California, Los Angeles
Medical Center: Ann Johiro, Mario Guerrero; Kaiser
Permanente Los Angeles Medical Center, Calif: Paul A. Turner; Weill Medical College of Cornell University, New York:
Todd Stroberg, Marshall Glesby; New York University:
Jane Dowling, Richard Hutt, Deborah Tolenaar; University
of California, San Francisco: Joann Volinski; University of Rochester, NY: Jane Reid, Carol Greisberger,
Richard Reichman; University of Colorado, Denver:
M. Graham Ray, Beverly Putnam, Sally Canmann; University
of Hawaii: Scott Souza; University of Washington,
Seattle: Sheryl S. Storey, Ann C. Collier; Tulane
University: Juan J. L. Lertora, Rebecca A. Clark, Russell A. Strada; Beth Israel Deaconess Medical Center: Mary Albrecht, Carol
DeQuattro; Massachusetts General Hospital: Kathy
Habeeb; University of Minnesota: Henry Balfour; University of Southern California: Fred R. Sattler, Holly
Boyd; Case Western Reserve University: Hernan Valdez,
Ron Johnson, Ann Conrad; Mount Sinai Medical Center:
Henry Sacks, Donna Mildvan; Stanford University:
Debbie Slamowitz, Sandra Valle, Pat Cain; University of
California, San Diego: Susan Little, Jill Kunkel; Washington University: Pablo Tebas, Kim Gray, Genice Hamilton; University of Alabama: Stephanie Johnson; The Johns Hopkins University, Baltimore, Md: Melody Higgins, Andrea
Weiss; University of Cincinnati, Ohio: Judith Feinberg,
Pamela Daniel, Patricia Kohler; University of Texas, Galveston: Richard B. Pollard; University of Miami, Fla:
Jose Castro, Margaret A. Fischl; Duke University Medical
Center: Gary M. Cox; Northwestern University Medical
School: Baiba Berzins; Cook County Hospital:
Joseph Pulvirenti; University of Puerto Rico: Jorge
L. Santana; University of Pennsylvania: Robert Gross,
Joseph Quinn; Ohio State University: Michael F. Para,
Charlotte Mills, Jane Russell; University of North Carolina: Charles Van der Horst; Howard University:
Lisa Alexis; National Hemophilia Foundation: Rita
Barsky; Division of AIDS: Ana Martinez; ACTG Operations Center: Sue Sepelak; Frontier Science
and Technology Research Foundation Data Management Center: Linda Gedeon,
Mary Jo Werder, Philip Vecchione; and ViroLogic:
Nick Hellmann.
Funding/Support: This work was supported by
grants AI46386, AI48013, AI42848, AI38855, AI27660, RR00865, AI46386, AI27665,
AI27742, and RR00083 from the National Institutes of Health.
Disclaimer: The data analysis was performed
by an academic group at the Harvard School of Public Health under contract
to the National Institutes of Health (NIH) to analyze ACTG data, in conjunction
with Frontier Science as data manager, also under NIH contract. The authors
were sponsored by the NIH and had complete control of the data. Industry support
from Agouron, DuPont, Gilead Sciences, GlaxoSmithKline, Merck, and Roche was
in the form of supplying study drugs and as part of the protocol, participated
in comment on the study. ViroLogic performed the resistance testing.
Corresponding Author and Reprints: Scott
M. Hammer, MD, Division of Infectious Diseases, Columbia University College
of Physicians and Surgeons, 630 W 168th St, New York, NY 10032 (e-mail: smh48{at}columbia.edu).
Author Affiliations: Department of Medicine,
Columbia University College of Physicians and Surgeons, New York, NY (Dr Hammer);
Department of Biostatistics, Statistical and Data Analysis Center, Harvard
School of Public Health, Boston, Mass (Drs Vaida and DeGruttola, and Ms Bennett);
AIDS Clinical Trial Group Operations Center, Silver Spring, Md (Ms Holohan);
Department of Laboratory Medicine (Dr Sheiner) and Department of Medicine
(Dr Aberg), University of California, San Francisco; Department of Medicine,
University of North Carolina, Chapel Hill (Dr Eron); Department of Medicine,
Indiana University, Bloomington (Dr Wheat); Department of Medicine, University
of California, Los Angeles (Dr Mitsuyasu); Department of Medicine, Weill Medical
College of Cornell University, New York, NY (Dr Gulick); Department of Medicine,
New York University, New York (Dr Valentine); Department of Medicine, University
of Pittsburgh, Pa (Dr Mellors); GlaxoSmithKline, Research Triangle Park, NC
(Dr Rogers); Hoffman-LaRoche, Nutley, NJ (Dr Karol); Merck Research Laboratories,
Blue Bell, Pa (Dr Saah); Agouron Pharmaceuticals, La Jolla, Calif (Dr Lewis);
DuPont Pharmaceuticals, Wilmington, Del (Dr Bessen); and Gilead Sciences,
Foster City, Calif (Dr Brosgart). Dr Bessen is now at Bristol-Myers Squibb.
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