Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Jonas L, Meibohm A, Holder D, Schleif WA, Condra JH, Emini EA, Isaacs R, Chodakewitz JA, Richman DD. Simultaneous vs Sequential Initiation of Therapy With Indinavir, Zidovudine, and Lamivudine for HIV-1 Infection100-Week Follow-up. JAMA. 1998;280(1):35-41. doi:10.1001/jama.280.1.35
From the Department of Medicine, New York University School of Medicine, New York (Drs Gulick and Gonzalez); Department of Medicine, University of Pittsburgh School of Medicine and Pittsburgh VA Medical Center, Pittsburgh, Pa (Drs Mellors and McMahon); Departments of Pathology and Medicine, University of California and San Diego VA Medical Center, San Diego (Drs Havlir and Richman); Department of Medicine, University of North Carolina, Chapel Hill (Dr Eron); and Merck Research Laboratories, West Point, Pa (Drs Meibohm, Holder, Condra, Emini, Isaacs, and Chodakewitz, Ms Jonas, and Mr Schleif).
Context.— Combination antiretroviral therapy can markedly suppress human immunodeficiency
virus (HIV) replication but the duration of HIV suppression varies among patients.
Objective.— To compare the antiretroviral effect of a 3-drug regimen started simultaneously
or sequentially in patients with HIV infection.
Design.— A multicenter, randomized, double-blind study, modified after at least
24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up
through 100 weeks.
Setting.— Four clinical research units
Patients.— Ninety-seven patients with HIV infection who had taken zidovudine for
at least 6 months with serum HIV RNA level of at least 20000 copies/mL and
CD4 cell count of 0.05 to 0.40×109/L.
Interventions.— Patients were initially randomized to receive 1 of 3 antiretroviral
regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours
and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks
of blinded therapy, all patients received open-label 3-drug therapy.
Main Outcome Measures.— Antiretroviral activity was assessed by changes in HIV RNA level and
CD4 cell count from baseline. Data through 100 weeks were summarized.
Results.— Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed
HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL
and increased CD4 cell count to a median of 0.209×109/L above
baseline at 100 weeks. When these 3 drugs were initiated sequentially, only
30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine
group and 13 of 29 in the indinavir group, respectively) had a sustained reduction
in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased
to 0.101 to 0.163×109/L above baseline at 100 weeks.
Conclusions.— A 3-drug combination of indinavir, zidovudine, and lamivudine started
simultaneously has durable antiretroviral activity for at least 2 years. Sequential
initiation of the same 3 drugs is much less effective.
IN CLINICAL trials of adults with human immunodeficiency virus (HIV)
infection, antiretroviral therapy with a combination of 2 nucleoside analogue
reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside
reverse transcriptase inhibitor has suppressed viral load and increased CD4
cell count for a year.1,2 These
results have prompted panels convened by the International AIDS Society-USA3 and the US Department of Health and Human Services4 to recommend a combination of 2 nucleoside analogue
reverse transcriptase inhibitors and a potent protease inhibitor as the preferred
treatment of established HIV infection. However, durability of antiretroviral
activity of these combination regimens is unknown.
Recently, several groups reported that 30% to 66% of patients taking
protease inhibitor–containing antiretroviral regimens fail to maintain
viral suppression in clinical practice settings.5- 8
A possible explanation for this failure is the sequential, rather than simultaneous,
initiation of the antiretroviral drugs, resulting in incomplete viral suppression
and the selection of drug-resistant virus. This hypothesis has not been evaluated
prospectively in a randomized clinical study.
In a clinical trial comparing a 3-drug combination of indinavir, zidovudine,
and lamivudine to indinavir monotherapy or the 2-drug combination of zidovudine
and lamivudine,1 all patients were offered
open-label 3-drug therapy when the 3-drug regimen proved to be superior in
a preliminary analysis. Patients initially randomized to indinavir monotherapy
or the combination of zidovudine and lamivudine received their original regimens
for 24 to 52 weeks before receiving open-label 3-drug therapy with indinavir,
zidovudine, and lamivudine. After changing to open-label 3-drug therapy, patients
continued to be followed for 100 weeks from the time of initial randomization
in an ongoing study. This provided an opportunity to compare the use of 3-drug
antiretroviral therapy started simultaneously or sequentially. The magnitude
and duration of HIV suppression and increase in CD4 cell count, as well as
development of drug-resistance mutations, were compared between simultaneous
and sequential triple-therapy groups.
The study was originally designed as a randomized, double-blind comparison
of 3 oral antiretroviral regimens: indinavir (Crixivan, Merck, West Point,
Pa), 800 mg every 8 hours (indinavir monotherapy group); zidovudine (Retrovir,
Glaxo-Wellcome, Research Triangle Park, NC), 200 mg every 8 hours, combined
with lamivudine (Epivir, Glaxo-Wellcome), 150 mg every 12 hours (zidovudine/lamivudine
group); or all 3 drugs together at the same doses (3-drug group).1 The study patients were adults with HIV infection
who had taken zidovudine for at least 6 months but had not taken lamivudine
or any protease inhibitor, with serum HIV RNA levels of at least 20000 copies/mL
(Amplicor HIV Monitor Test, Roche Diagnostic Systems, Branchburg, NJ) and
CD4 cell counts between 0.05 and 0.40×109/L at screening.
Randomization followed a permuted block design stratified by site and CD4
cell count (either 0.050-0.250×109/L or 0.251-0.400×109/L). Patients were enrolled between April and December 1995.
The planned duration of the original blinded study was 52 weeks, but
because of preliminary findings of superior activity of the 3-drug regimen,
the study design was amended to provide open-label 3-drug therapy for all
patients after at least 24 weeks of blinded, randomized therapy. The 3-drug
group continued taking all 3 antiretroviral agents, while zidovudine and lamivudine
were added by the indinavir monotherapy group, and indinavir was added by
the zidovudine-lamivudine group. Blinding of the original treatment assignment
was maintained through March 1997. After initiating open-label 3-drug therapy,
patients have been monitored for 100 weeks or more from time of initial randomization
(Figure 1 and Figure 2). Results from the first 100 weeks are reported herein.
The study and the amendment were approved by the internal review boards at
each site, and all patients gave written informed consent.
Patients had study visits weekly for the first 4 weeks, every 2 weeks
through week 16, every 4 weeks through week 52, and every 8 weeks through
week 100. At baseline and at each visit, medical history was taken, a physical
examination performed, and standardized laboratory tests conducted. Serum
was processed, stored at−70°C, and subsequently assayed for HIV
RNA (Amplicor assay). The assay lower limit of quantification was 500 HIV
RNA copies/mL. Assay values were reported as numerical values greater than
or equal to 500 copies/mL, "less than 500 copies/mL," or "negative" if an
amplification signal above background was not detected. Plasma samples from
week 52 were assayed and for all patients (n = 47) whose serum HIV RNA value
was less than 500 copies/mL, the plasma HIV RNA value was also less than 500
copies/mL. Samples with less than 500 copies/mL were assayed with an investigational
ultrasensitive polymerase chain reaction assay with a consistent cutoff of
detection of about 50 copies/mL of HIV RNA, as described.1
T-lymphocyte subgroups were quantified using flow cytometry.1
Genotypic analysis of serum viral RNA was done as described.9 Amino acid substitutions present in 50% or more of
independent molecular clones were identified. Substitutions in reverse transcriptase
at positions 41, 67, 70, 215, and 219 were scored as correlates of zidovudine
in reverse transcriptase at position 184 served as a marker for lamivudine
and substitutions in protease at residues 10, 20, 24, 46, 54, 71, 82, 84,
and 90 were scored as correlates of indinavir resistance.9
Virologic failure was defined as never achieving an HIV RNA level less
than 500 copies/mL, or for those patients who achieved an HIV RNA level less
than 500 copies/mL, the occurrence of 2 consecutive HIV RNA levels of at least
500 copies/mL. Time to virologic failure was defined as number of weeks of
therapy prior to first occurrence of 2 consecutive HIV RNA levels of at least
500 copies/mL. For patients who never had an HIV RNA level less than 500 copies/mL,
virologic failure occurred at week 0. Number of days of missed doses was the
sum of number of days the patient was not taking the study drug and the number
of days the patient took less than the full prescribed daily dose.
The primary measure of antiretroviral drug activity was the proportion
of patients with serum HIV RNA levels less than 500 copies/mL by the Amplicor
assay. Proportion of patients with serum HIV RNA levels less than 50 copies/mL
was also calculated; in these calculations, it was assumed that those with
at least 500 RNA copies/mL by standard assay had at least 50 copies/mL.
Analyses were performed on an intention-to-treat basis. Using only observed
data may overestimate the proportion of patients with an HIV RNA level below
the specified level, as patients who were virologic failures may be more likely
to discontinue the study. Therefore, patients discontinuing the study for
therapy-related reasons (eg, increase in HIV RNA level, drug-related adverse
experience) were considered to have RNA levels greater than or equal to 500
copies/mL at time points subsequent to their discontinuation (ie, imputed
as a virologic failure). All those discontinuing with viral RNA levels of
at least 500 copies/mL at time of discontinuation were imputed as failures
at subsequent time points. Patients discontinuing for other reasons (eg, contraindicated
medications, patient request) with viral RNA levels less than 500 copies/mL
at time of discontinuation were not included in analysis of subsequent time
points. When an HIV RNA level was missing at a time point while the patient
was still being followed, the missing value was assumed to be less than 500
copies/mL if the HIV RNA levels immediately preceding and following the missing
value were measured to be less than 500 copies/mL; otherwise the missing value
was assumed to be at least 500 copies/mL. Estimated proportions of patients
with serum HIV RNA levels less than 500 copies/mL at week 100 were compared
among treatment groups using the Cochran-Mantel-Haenszel test, stratifying
by site and CD4 cell count stratum.
Patients withdrawing and imputed as virologic failures for analysis
of proportions with HIV RNA levels less than 500 copies/mL were also imputed
as virologic failures for analysis of proportions with HIV RNA levels less
than 50 copies/mL. For isolated missing values, rules similar to those for
values less than 500 copies/mL were applied. In analyses of proportions of
patients with HIV RNA levels less than 500 or 50 copies/mL, at any time point
the denominator may include both patients with actual viral load determinations
and those with imputed values; thus, the denominator is referred to as "contributing
Median changes from baseline in HIV RNA levels (based on the Amplicor
assay) and CD4 cell counts were calculated. Patients discontinuing the study
for therapy-related reasons or with HIV RNA levels of at least 500 copies/mL
at the time of discontinuation had the last observed value carried forward
at subsequent time points. For calculation of changes from baseline, RNA values
reported as "less than 500 copies/mL" were regarded as equivalent to 500 copies/mL,
and values reported as "negative" were regarded as equivalent to 250 copies/mL.
Before analysis, HIV RNA values underwent log10 transformation.
One patient did not have a baseline HIV RNA value and was not included in
these analyses. Distribution of changes from baseline was compared between
each pair of treatment groups using analysis of variance on the ranks; the
model included treatment group, site, and CD4 stratum.
For all analyses, nominal, unadjusted, 2-sided P
values were reported.
Ninety-seven patients with baseline median HIV RNA level of 43190 copies/mL
(range, 4900-262070 copies/mL) and CD4 cell count of 0.144×109/L (range, 0.035-0.480×109/L) were enrolled.1 Baseline characteristics were similar across the 3
original treatment groups. Patients received open-label 3-drug therapy after
a median of 40 weeks of blinded, randomized therapy (range, 24-52 weeks).
Of the 97 enrolled patients, 92 completed 24 weeks, 87 completed 52 weeks,
and 70 completed 100 weeks of study treatment.
Reasons for early discontinuation are listed in Figure 2. Fewer patients discontinued from the group originally
randomized to receive 3-drug therapy than from the other 2 groups. The most
common reason for early discontinuation was increase in HIV RNA levels (16
patients); more patients randomized to the indinavir monotherapy and the zidovudine-lamivudine
groups discontinued for this reason than in the 3-drug group.
Compliance, as assessed by median percentage of days on which the recommended
dosage of study medications was taken, was similar among the 3 treatment groups
during both open-label and blinded study periods, and exceeded 91% during
both study periods (data not shown).
All therapies were generally well tolerated; 1 patient in each group
discontinued study medications for a clinical or laboratory adverse event.
Two deaths occurred, both in patients originally randomized to receive zidovudine
and lamivudine (Figure 2). One death
was due to Pneumocystis carinii pneumonia; this was
the only AIDS-defining illness occurring in any group during 100 weeks of
follow-up. The other death was caused by myocardial infarction.
The group originally randomized to receive simultaneously initiated
3-drug therapy continued to receive the same 3 drugs throughout 100 weeks
of follow-up. In this group, the median decrease in serum HIV RNA level from
baseline was 2.0 log10 by week 8, which was sustained through week
100 (Figure 3). In this group, 28
(88%) of 32 contributing patients had HIV RNA levels less than 500 copies/mL
at week 16, and 25 (78%) of 32 at week 100 (Figure 4, A). Similar virologic responses were shown with the investigational
ultrasensitive assay; 21 (66%) of 32 contributing patients had HIV RNA levels
less than 50 copies/mL at week 24, and 21 (66%) of 32 at week 100 (Figure 4, B). Median increase in CD4 cell
count above baseline in this group was 0.127×109/L at week
24, 0.155×109/L at week 52, and 0.209×109/L
at 100 weeks (Figure 5).
In those consistently achieving a serum viral RNA level less than 500
copies/mL, the pattern of results was variable with the investigational ultrasensitive
assay, which has a consistent detection cutoff of about 50 copies/mL (data
not shown). Most patients had more than 1 HIV RNA level of at least 50 copies/mL
during the period that their HIV RNA levels were consistently less than 500
copies/mL. Some had 2 or 3 consecutive HIV RNA levels of at least 50 copies/mL
followed by a return to less than 50 copies/mL.
Seven of 33 patients originally randomized to receive simultaneous 3-drug
therapy had HIV RNA values greater than 500 copies/mL by week 100 (Table 1). Four of these virologic failures
occurred during the first 20 weeks of the study and 3 others occurred at 32,
40, and 100 weeks of follow-up. Review of these cases revealed that 1 patient
never had a reduction of HIV RNA to less than 500 copies/mL, 1 had intestinal
amebiasis 2 months prior to virologic failure, and 1 missed drug doses on
15 (36%) of 42 days and another on 56 (25%) of 224 days prior to virologic
failure. No obvious reason for virologic failure was identified in the other
3 patients, including the patient in whom therapy failed at 100 weeks. All
3 patients in whom therapy failed after week 20 had at least 1 serum RNA level
less than 50 copies/mL.
Patients randomized to the indinavir monotherapy and zidovudine-lamivudine
groups crossed over to open-label 3-drug therapy(Figure 1). Results for the first 24 weeks of study were obtained
while patients were on original randomized regimens. Results obtained between
weeks 24 and 52 reflect patients either on their original regimen or the open-label
3-drug regimen. All crossed over to open-label 3-drug therapy by week 52.
Indinavir, Followed by Addition of Zidovudine and Lamivudine. Over the first 24 weeks, patients received original blinded therapy.
Patients randomized to the indinavir monotherapy group had a maximal median
decrease in HIV RNA from baseline of 1.7 log10 at week 12 and the
median decrease rose to 1.0 log10 below baseline at week 24 (Figure 3). In this group, 13 (43%) of 30
contributing patients had reductions in HIV RNA to less than 500 copies/mL
and 9 (30%) of 30 to less than 50 copies/mL at week 24 (Figure 4). Median increase in CD4 cell count in this group was 0.111×109/L over baseline at 24 weeks (Figure
After patients added zidovudine-lamivudine, maximum additional median
decrease in HIV RNA was 0.6 log10 (data not shown). There was a
1.4-log10 median decrease in HIV RNA from baseline at week 52 and
at week 100 (Figure 3). Thirteen
(45%) of 29 contributing patients in this group had HIV RNA levels less than
500 copies/mL at week 100, which is similar to the proportion prior to the
addition of zidovudine-lamivudine (Figure
4, A). After adding zidovudine-lamivudine to indinavir, the median
increase in CD4 cell count was 0.127×109/L above baseline
at week 52 and 0.163×109/L above baseline at week 100 (Figure 5).
Zidovudine and Lamivudine, Followed by Addition of Indinavir. Patients originally randomized to the 2-drug zidovudine-lamivudine combination
had a maximal median decrease of HIV RNA from baseline of 1.4 log10
at week 2, and the median decrease rose to 0.6 log10 below baseline
at week 24(Figure 3). No patients
taking zidovudine-lamivudine had HIV RNA reductions to less than 500 copies/mL
at week 24 (Figure 4, A). Median
increase in CD4 cell count was 0.013×109/L above baseline
in this group at 24 weeks (Figure 5).
After patients added indinavir, maximum additional median decrease in
HIV RNA was 1.5 log10 (data not shown). There was a sustained median
decrease in HIV RNA from baseline of 1.5 log10 at week 52 followed
by an increase to 1.3 log10 below baseline at week 100 (Figure 3). In this group, 10 (30%) of 33
contributing patients had HIV RNA levels less than 500 copies/mL at week 100
(Figure 4, A). Median increases
above baseline in CD4 cell counts in this group were 0.106×109/L above baseline at week 52, and 0.101×109/L at week
100 (Figure 5).
The HIV RNA and CD4 cell count responses were compared among the patients
originally randomized to 3-drug therapy, those who added zidovudine-lamivudine
to indinavir, and those who added indinavir to zidovudine-lamivudine. In this
way, simultaneous initiation of indinavir, zidovudine, and lamivudine could
be compared with sequential initiation of the same 3 drugs.
At 100 weeks, proportions of patients in the simultaneous 3-drug group
with HIV RNA levels less than 500 (P≤.006) and
50 (P<.05) copies/mL, changes in HIV RNA levels
from baseline (P≤.004), and changes in CD4 cell
count above baseline (P<.05) were statistically
significantly greater than those in either of the sequential 3-drug therapy
groups. There was no difference in changes from baseline in HIV RNA level
(P=.71) or CD4 cell count (P=.54)
between the 2 sequential therapy groups at 100 weeks.
To better understand the reasons why simultaneous 3-drug therapy was
superior to sequential therapy, detailed genotypic analysis of viral resistance
markers was undertaken. Analyses were performed on specimens obtained on entry
into the study and at time of crossover to open-label 3-drug therapy. Consistent
with the enrollment requirement that patients had received prior zidovudine
therapy, 75 (82%) of 91 patients at study entry had circulating virus with
substitutions in the reverse transcriptase gene associated with zidovudine
resistance.10,11 These patients
were evenly distributed among the 3 study arms. Even though no patient was
to have taken prior lamivudine therapy, 1 patient at study entry yielded virus
with the M184 mutation responsible for lamivudine resistance12- 14;
this patient was randomized to the indinavir monotherapy group. None of the
patients at study entry had virus with substitutions in the protease gene
associated with indinavir resistance.9
Regarding the indinavir monotherapy group at the time of crossover to
open-label 3-drug therapy, 22 of 28 patients yielded amplifiable viral RNA
from serum. Of these, 17 (77%) had reverse transcriptase substitutions associated
with zidovudine resistance, none had the substitution associated with lamivudine
resistance, and 14 (64%) had substitutions in the protease gene associated
with indinavir resistance.9 The patient who
had evidence of lamivudine resistance at study entry did not have amplifiable
viral RNA from serum at time of crossover.
Of 32 patients in the original zidovudine-lamivudine group with amplifiable
viral RNA from serum at time of open-label crossover, 26 (81%) had evidence
of zidovudine resistance, 30 (94%) had evidence of lamivudine resistance,
and none had evidence of indinavir resistance.
Genotypic analyses were also done at the time of virologic failure in
the 7 patients originally randomized to simultaneous 3-drug therapy. Five
patients had evidence of zidovudine resistance, all had substitutions associated
with lamivudine resistance, and 5 patients had acquired substitutions associated
with indinavir resistance (Table 1).
Genetic patterns of resistance were consistent with those previously described
for indinavir, zidovudine, and lamivudine.9- 14
The effect of the 3-drug combination of indinavir, zidovudine, and lamivudine
initiated simultaneously was a reduction in viral load in 78% of contributing
patients to less than 500 copies/mL and in 66% of contributing patients to
less than 50 copies/mL for 2 years. Most patients with this degree of viral
load suppression at week 24 continued to have viral load suppression at week
100. At 100 weeks of follow-up, patients had a median increase in CD4 cell
count of 0.209×109/L above baseline. This study has the longest
follow-up to date of a combination antiretroviral regimen producing this magnitude
of sustained viral load reductions, and the results imply that most patients
with suppression of viral load to less than 500 copies/mL by week 24 will
have continued suppression through at least 2 years of follow-up on this regimen.
The durable antiretroviral effect associated with simultaneous initiation
of the 3-drug regimen likely results from ability of the combination to suppress
emergence of drug-resistant HIV variants. Most patients initiating simultaneous
3-drug therapy not only had reductions in HIV RNA below 500 copies/mL, but
also below 50 copies/mL. It has been shown that a greater therapy-induced
reduction of viral load corresponds with a more durable antiretroviral response.15,16 It is important to note, however,
that it was common to find isolated serum viral RNA levels of at least 50
copies/mL even in those patients who consistently achieved a serum viral RNA
level less than 500 copies/mL.
In contrast to initiating the 3 drugs simultaneously, when sequential
3-drug combination therapy was used, either adding indinavir to regimens of
patients already taking zidovudine and lamivudine, or adding zidovudine and
lamivudine for those already taking indinavir, an inferior antiretroviral
effect was seen with only 30% to 45% of patients having sustained reductions
in viral load levels to less than 500 copies/mL at 100 weeks. The marked sustained
antiretroviral response seen in the original 3-drug group was likely due to
the fact that none of the patients had prior use of lamivudine or any protease
inhibitor, and when the study began, the drugs were begun simultaneously.
In the current study, detailed genotypic analysis of viral resistance
helped explain the mechanism of failure of sequential antiretroviral therapy.
Of the group originally randomized to zidovudine-lamivudine, no patient experienced
a sustained decrease in HIV RNA to less than 500 copies/mL, and by the time
of open-label crossover, 94% of patients had developed virus with the reverse
transcriptase substitution at position 184 associated with lamivudine resistance.12- 14 Using lamivudine
as part of an antiretroviral regimen that fails to maximally suppress HIV
permits ongoing viral replication, allowing the rapid emergence of lamivudine-resistant
virus.17,18 When this group added
indinavir to zidovudine-lamivudine, the proportion of patients with HIV RNA
levels reduced to less than 500 copies/mL at week 100 was similar to that
observed in the indinavir monotherapy group prior to crossover. Similarly,
of the group originally treated with indinavir monotherapy, at the time of
crossover to open-label 3-drug therapy, 64% of patients had selected for virus
with substitutions associated with indinavir resistance. Consequently, sequential
addition of zidovudine and lamivudine to this group occurred in the presence
of considerable indinavir resistance.
The practice of adding antiretroviral agents sequentially after an initial
antiretroviral regimen fails is similar to using monotherapy. Monotherapy,
even with a potent agent, is commonly associated with subsequent virologic
failure due to emergence of drug-resistant virus.9,15,19,20
In contrast, simultaneously adding at least 2 new potent antiretroviral agents
inhibits HIV replication more effectively and thereby inhibits emergence of
drug-resistant mutant viruses, increasing the likelihood that antiretroviral
effect is maintained.
Use of sequential monotherapy with antiretroviral agents has occurred
commonly in clinical practice as a consequence of the sequential approval
of drugs for clinical use. Lamivudine was approved by the US Food and Drug
Administration in December 1995, and ritonavir and indinavir were approved
in March 1996. Clinicians with limited therapeutic options often added the
drugs sequentially as they became available. In their retrospective chart
review, Deeks et al5 found that for most patients
in whom combination antiretroviral therapy failed, a protease inhibitor had
been added to their regimens without changing other antiretroviral drugs.
In the patient subset for whom a new nucleoside analogue together with a protease
inhibitor were simultaneously added, about 80% had reductions in HIV RNA levels
to less than 500 copies/mL at 24 weeks,5 similar
to our findings. The use of sequential antiretroviral therapy has likely played
a major part in causing drug failure in community settings.
The simultaneous initiation of indinavir, zidovudine, and lamivudine
was associated with an initial rapid increase in CD4 cell count over the first
4 to 12 weeks of therapy. After the initial rise, CD4 cell count then continued
to increase steadily for at least 2 years. The CD4 response in the sequential
3-drug groups was inferior to that seen with the simultaneous 3-drug group.
Several groups have noted not only increases in CD4 cell numbers, but also
associated returns in immunologic function with other potent antiretroviral
therapy regimens over the first year of therapy.21,22
In persons with diagnoses of autoimmune disease or cancer who have received
intensive chemotherapy or radiation therapy, CD4 cell counts recover slowly
and it may take 3 years or more for normal levels to be attained.23- 25 Further study is
required to determine the level of immunologic restoration that is ultimately
possible with potent antiretroviral therapy administered over the course of
There is evidence that patients with more advanced HIV disease than
in those in our study (ie, higher viral load or lower CD4 cell count at baseline)
may have less consistent responses to 3-drug antiretroviral regimens, with
fewer patients having sustained viral load suppression.26,27
Patient populations with more advanced HIV disease may require more intensive
antiretroviral therapy. Studies of 4-drug combinations using combinations
of protease inhibitors and other agents are in progress. Results from the
current study support the concept that antiretroviral treatment initiated
by patients in earlier stages of HIV disease may have a greater likelihood
of sustained beneficial virologic effects. Recent reports of the isolation
of replication-competent HIV from lymphocytes of patients taking antiretroviral
therapy with prolonged viral suppression28- 30
imply that despite marked, sustained viral load reductions, long-term antiretroviral
treatment will be necessary in most, if not all, patients.
In summary, use of indinavir, zidovudine, and lamivudine therapy initiated
simultaneously was associated with a marked antiretroviral response, sustained
for at least 2 years, in 78% of contributing patients. This sustained antiretroviral
effect was accompanied by a substantial and continuing increase in CD4 cell
count. The antiretroviral effects of simultaneous 3-drug therapy contrast
with those resulting from the use of the same drugs added sequentially over
months, where substantial viral suppression occurred in only 30% to 45% of
contributing patients. Overall, observations from this study support current
guidelines3,4 that recommend simultaneous
introduction of at least 2, or preferably 3, new potent antiretroviral agents,
including a protease inhibitor, either as initial therapy or when changing
a failing antiretroviral regimen.