Staszewski S, Keiser P, Montaner J, Raffi F, Gathe J, Brotas V, Hicks C, Hammer SM, Cooper D, Johnson M, Tortell S, Cutrell A, Thorborn D, Isaacs R, Hetherington S, Steel H, Spreen W, for the CNAAB3005 International Study Team . Abacavir-Lamivudine-Zidovudine vs Indinavir-Lamivudine-Zidovudine in Antiretroviral-Naive HIV-Infected AdultsA Randomized Equivalence Trial. JAMA. 2001;285(9):1155-1163. doi:10.1001/jama.285.9.1155
Author Affiliations: Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Germany (Dr Staszewski); University of Texas Southwestern Medical Center, and Department of Veterans Affairs, Dallas (Dr Keiser); St Paul's Hospital, Vancouver, British Columbia (Dr Montaner); CHRU de Nantes, Nantes, France (Dr Raffi); Houston Clinical Research Network, Division of Montrose Clinic, Houston, Tex (Dr Gathe); Servico Medicina 3, Hospital de Santo António dos Capuchos, Lisbon, Portugal (Dr Brotas); Duke University, Durham, NC (Dr Hicks); Beth Israel Deaconess Medical Center, Boston, Mass (Dr Hammer); St Vincent's Hospital, Sydney, Australia (Dr Cooper); Royal Free Hospital, London, England (Dr Johnson); Glaxo Wellcome Inc, Research Triangle Park, NC (Mss Tortell and Cutrell and Drs Hetherington, Steel, and Spreen); Merck & Co Inc, West Point, Pa (Dr Isaacs); and Glaxo Wellcome Research and Development, Greenford, Middlesex, England (Drs Thorborn and Steel).
Context Abacavir, a nucleoside analogue, has demonstrated suppression of human
immunodeficiency virus (HIV) replication alone and in combination therapy.
However, the role of abacavir in a triple nucleoside combination regimen has
not been evaluated against a standard protease inhibitor–containing
regimen for initial antiretroviral treatment.
Objective To evaluate antiretroviral equivalence and safety of an abacavir-lamivudine-zidovudine
regimen compared with an indinavir-lamivudine-zidovudine regimen.
Design and Setting A multicenter, phase 3, randomized, double-blind trial with an enrollment
period from August 1997 to June 1998, with follow-up through 48 weeks at 73
clinical research units in the United States, Canada, Australia, and Europe.
Patients Five hundred sixty-two antiretroviral-naive, HIV-infected adults with
a plasma HIV RNA level of at least 10 000 copies/mL and a CD4 cell count
of at least 100 × 106/L.
Interventions Patients were stratified by baseline HIV RNA level and randomly assigned
to receive a combination tablet containing 150 mg of lamivudine and 300 mg
of zidovudine twice daily plus either 300 mg of abacavir twice daily and indinavir
placebo or 800 mg of indinavir every 8 hours daily plus abacavir placebo.
After 16 weeks, patients with confirmed HIV RNA levels greater than 400 copies/mL
were eligible to continue receiving randomized treatment or receive open-label
Main Outcome Measure Virologic suppression, defined as HIV RNA concentration of 400 copies/mL
or less at week 48.
Results The proportion of patients who met the end point of having an HIV RNA
level of 400 copies/mL or less at week 48 was equivalent in the abacavir group
(51% [133/262]) and in the indinavir group (51% [136/265]) with a treatment
difference of −0.6% (95% confidence interval [CI], −9% to 8%).
In patients with baseline HIV RNA levels greater than 100 000 copies/mL,
the proportion of patients achieving less than 50 copies/mL was greater in
the indinavir group than in the abacavir group with 45% (45/100) vs 31% (30/96)
and a treatment diference of −14% (95% CI, −27% to 0%). The 2
treatments were comparable with respect to their effects on CD4 cell count.
There was no difference between groups in the frequency of treatment-limiting
adverse events or laboratory abnormalities. One death in the abacavir group
was attributed to hypersensitivity reaction, which occurred following rechallenge
with abacavir, approximately 3 weeks after initiating study treatment.
Conclusions In this study of antiretroviral-naive HIV-infected adults, the triple
nucleoside regimen of abacavir-lamivudine-zidovudine was equivalent to the
regimen of indinavir-lamivudine-zidovudine in achieving a plasma HIV RNA level
of less than 400 copies/mL at 48 weeks.
The current goal of antiretroviral therapy is to achieve prolonged suppression
of human immunodeficiency virus (HIV) replication. The rational selection
of antiretroviral agents used to initiate the treatment of HIV infection is
critical for 2 reasons. First, the magnitude and duration of antiretroviral
response is greatest for initial therapy, and second, sequencing of therapy
must allow for effective second-line treatment regimens if the initial therapy
fails. A conventional approach to initial antiretroviral treatment has been
with 2 nucleoside analogues and a protease inhibitor.1- 3
While protease inhibitor–containing regimens have contributed substantially
toward delaying progression of the acquired immunodeficiency syndrome (AIDS)
and increasing duration of survival,4- 7
several problems can limit their long-term effectiveness and contribute to
incomplete viral suppression. These problems include poor tolerability, metabolic
toxic effects, drug interactions due to inhibition or induction of cytochrome
P450 enzymes, and incomplete adherence due to the complexity of dosing regimens.8- 11 Incomplete
viral suppression in the presence of selective pressure exerted by antiretroviral
therapy promotes the development of resistance mutations, which may confer
cross-resistance to other drugs of the same class.
Abacavir is a potent inhibitor of HIV reverse transcriptase (RT),12,13 it does not rapidly select resistant
viruses in vitro, and multiple mutations are required to confer high-level
reduction (10-fold) in susceptibility of HIV strains.14- 17
Initial studies among therapy-naive HIV-infected patients demonstrated that,
as monotherapy, abacavir has antiretroviral activity comparable with that
of protease inhibitors, decreasing HIV RNA level by 1.7 to 2.2 log10 copies/mL.18 Marked antiretroviral activity
of abacavir also has been demonstrated in combination regimens with lamivudine
and zidovudine.19,20 This study
compares the efficacy and safety of a triple nucleoside analogue regimen of
abacavir-lamivudine-zidovudine with the conventional regimen of indinavir-lamivudine-zidovudine
in previously untreated HIV-infected patients.
Adults who were seropositive for HIV and who had not received previous
antiretroviral therapy were screened for enrollment. Additional criteria for
enrollment included a plasma HIV RNA level of at least 10 000 copies/mL
within 21 days of study drug administration, a CD4 cell count of at least
100 × 106/L within 21 days of study drug administration,
a hemoglobin level exceeding 10 g/dL (100 g/L) for men or 9 g/dL (90 g/L)
for women, a neutrophil count exceeding 1000/µL, a platelet count exceeding
75 000 × 103/µL, an estimated creatinine clearance
of greater than 40 mL/min (0.67 mL/s), a serum amylase level of less than
1.5 times the upper limit of normal, a total bilirubin level of less than
1.5 times the upper limit of normal, and levels of hepatic aminotransferases
of less than 5 times the upper limit of normal.
Patients were excluded from consideration for the study if they had
previously received any antiretroviral treatments, received any HIV vaccine
within 90 days before study entry, or received immunomodulatory drugs or treatment
with radiation therapy or cytotoxic chemotherapeutic agents within 30 days
before study entry (with the exception of local treatment for Kaposi sarcoma).
Patients were also excluded if they were pregnant or breastfeeding, had clinical
pancreatitis or hepatitis (within 6 months before study entry), or had active
HIV-related illness as defined by Centers for Disease Control and Prevention
This 48-week, double-blind, randomized, multicenter trial was conducted
at 73 centers in the United States, Canada, Australia, and Europe. The institutional
review boards and independent ethics committee at each site approved this
study, and all patients gave written informed consent before initiating the
Randomization was performed after screening using a block size of 8
and was stratified according to initial HIV RNA level (≤10 000-100 000
copies/mL or >100 000 copies/mL) by a centralized randomization procedure
(Figure 1). Study personnel called
a center established by Clinphone (Nottingham, England) to enter patients'
eligibility data and to receive treatment number assignment. Patients were
randomly assigned on a 1:1 ratio to receive a combination tablet containing
150 mg of lamivudine and 300 mg of zidovudine twice daily and either a 300-mg
tablet of abacavir twice daily plus indinavir placebo or 800 mg of indinavir
every 8 hours daily (200-mg capsule formulation) plus abacavir placebo. The
patient, the investigator, and the sponsor were blinded to treatment allocation.
Breaking the blind was permitted in cases of medical emergency only if knowledge
of a patient's treatment assignment was essential for appropriate clinical
management or upon diagnosis of a probable hypersensitivity reaction.
All patients received 16 tablets per day and followed the diet restrictions
and fluid requirements recommended for indinavir. In brief, indinavir (or
indinavir placebo) was administered with water 1 hour before or 2 hours after
a meal and patients were instructed to drink 1.5 L of water during the course
of 24 hours to ensure adequate hydration. Patients who had confirmed HIV RNA
levels of 400 copies/mL or higher on 2 occasions at week 16, or thereafter,
selected 1 of 3 options: (1) continuation of randomized therapy; (2) discontinuation
of randomized therapy to receive open-label therapy consisting of abacavir
or indinavir or both, with lamivudine plus zidovudine combination tablet (or
alteration of background therapy); or (3) discontinuation of all study medication
and withdrawal from the study. Patients who chose open-label therapy (as well
as those who completed the study per protocol) were able to receive treatment
until (1) they permanently withdrew from the study; (2) discontinued the study
for any reason; or (3) the last patient had completed 48 weeks of randomized
Patients were assessed every 2 weeks for the first 4 weeks and every
4 weeks through week 48. Plasma HIV RNA level was measured using a standard
RT polymerase chain reaction assay (Amplicor HIV Monitor, Roche Molecular
Systems, Branchburg, NJ) with a limit of quantification of 400 copies/mL.
The ultrasensitive PCR assay with a quantification limit of 50 copies/mL was
also used to analyze plasma samples collected at weeks 16, 24, 36, and 48.
CD4 cell counts were measured by flow cytometry. Safety assessments were based
on evaluations of medical histories, vital signs, hematology, clinical chemistry,
urinalysis, and clinical adverse experiences. Adverse events were evaluated
using the Division of AIDS Table for grading severity of adult adverse experiences.22
Ajudication of safety and adverse event data were performed by study investigators
blinded to patient treatment assignment, except in cases of medical emergencies.
All plasma samples for efficacy and safety laboratory evaluations were analyzed
by Covance Central Laboratories (Geneva, Switzerland; Indianapolis, Ind; and
Genotypic analysis was performed on plasma samples from patients with
confirmed HIV RNA levels of greater than 400 copies/mL. The HIV RT and protease
coding regions and gag cleavage sites were amplified
by RT polymerase chain reaction, as described previously.23
Mutations were also identified by the OpenGene genotyping system (Visible
Genetics, Toronto, Ontario).
The primary end point in the assessment of efficacy was virologic suppression
defined as a plasma HIV RNA level of 400 copies/mL or less at week 48. The
secondary end points included the proportion of patients with HIV RNA levels
of 50 copies/mL or less at week 48, changes in HIV RNA levels and CD4 cell
counts over 48 weeks, clinical progression, the proportion of patients with
moderate (grade 2) to severe (grade 4) adverse events, and time to viral rebound.
The time to viral rebound analysis was assessed for all patients using a standard
threshold level of 400 copies/mL, and a less stringent one evaluated previously
of 5000 copies/mL.24 Viral rebound was confirmed
when 2 consecutive HIV RNA values exceeded the threshold level. Patients who
did not have HIV RNA levels below the threshold level on randomized therapy
were considered virologic failures at time zero.
Efficacy variables were analyzed on an intent-to-treat basis (excluding
patients who were randomized but did not initiate therapy) and on an as-treated
basis. In the intent-to-treat analysis, patients were considered treatment
failures if they made any treatment changes, prematurely discontinued randomized
treatment for any reason, or had missing data for 2 consecutive evaluations.
In the as-treated analysis, only data from patients continuing randomized
treatment were considered for analysis.
As with HIV surrogate marker studies evaluating treatment interventions,
the established standard practice is to compare treatment groups with respect
to the proportion of antiretroviral-naive patients with undetectable plasma
viral loads. In this study, the viral load was measured using the Amplicor
HIV monitor (the only assay approved at the time this study was conducted),
which had a lower limit of detection of 400 copies/mL. The study was powered
to assess treatment equivalence for the primary end point (ie, a plasma HIV
RNA level of ≤400 copies/mL at week 48 for the intent-to-treat population).
For the primary end point, treatments were considered equivalent if the 95%
confidence interval (CI) was within the bound of −12% to 12%. As a result
of discussions with clinical investigators and with the Food and Drug Administration,
the margin for equivalence was preselected as the largest difference that
would be considered clinically acceptable.25
Based on these parameters, the study was designed to enroll approximately
550 patients, with 275 in each treatment group.The CIs were similarly generated
for secondary and subgroup analyses for descriptive purposes.
The HIV RNA values were log10 transformed before analysis.
The magnitude and duration of changes in HIV RNA levels and CD4 cell counts
were summarized by the average area under the curve minus baseline calculation.
The area under the curve minus baseline calculation difference between groups
and the corresponding 95% CIs were calculated using nonparametric methods.
The time to confirmed viral rebound was compared between groups using Kaplan-Meier
estimates and was stratified by the baseline HIV RNA level.
Five hundred sixty-two patients were enrolled in the study between August
1997 and June 1998. Thirty-five patients (6%) did not take study drugs at
the start of the trial (Figure 1).
The treatment groups were balanced with respect to demographic and baseline
characteristics (Table 1). Approximately
one third of patients enrolled had baseline HIV RNA levels greater than 100 000
copies/mL. There were no differences between groups in the reasons for premature
discontinuation from the study (Figure 1).
At week 48, the proportion of patients who had sustained suppression
of HIV RNA levels to less than 400 copies/mL in the abacavir-lamivudine-zidovudine
group was equivalent to that in the indinavir-lamivudine-zidovudine group
by the intent-to-treat analysis: 51% (133/262) vs 51% (136/265) with a treatment
difference of −0.6% (95% CI, −9% to 8%) (Figure 2A). In the as-treated analysis, proportions were 86% (125/145)
vs 94% (130/139) for the abacavir-lamivudine-zidovudine group vs indinavir-lamivudine-zidovudine
group with a treatment difference of −7% (95% CI, −14% to 0%)
(Figure 2A). No difference was observed
between the 2 groups in the proportion of patients with HIV RNA levels of
less than 400 copies/mL regardless of baseline HIV RNA level (Figure 2B).
At week 48, the proportion of patients who had HIV RNA levels of 50
copies/mL or less in the abacavir-lamivudine-zidovudine group was comparable
with that in the indinavir-lamivudine-zidovudine group by intent-to-treat
analysis: 40% (104/262) vs 46% (121/265) with a treatment difference of −6%
(95% CI, −15% to 2%) (Figure 2C).
By the as-treated analysis, proportions were 69% (104/150) vs 82% (121/147)
for the abacavir-lamivudine-zidovudine vs indinavir-lamivudine-zidovudine
groups with a treatment difference of −13% (95% CI, −23% to −4%)
In the intent-to-treat analysis, the proportion of patients in the high
baseline HIV RNA stratum who had HIV RNA levels of 50 copies/mL or less at
48 weeks was greater in the indinavir-lamivudine-zidovudine group than in
the abacavir-lamivudine-zidovudine group: 31% (30/96) vs 45% (45/100) with
a treatment difference of −14% (95% CI, −27% to 0%) (Figure 2D). This was not observed in the
low baseline HIV RNA stratum: 45% (74/166) vs 46% (76/165) with a treatment
difference of −2% (95% CI, −13% to 9%). In the as-treated analysis,
the proportion of patients who had HIV RNA levels of 50 copies/mL or less
was greater in the indinavir-lamivudine-zidovudine group for both strata:
76% (74/97) vs 88% (76/86) with a treatment difference of −12% (95%
CI, −23% to −1%) for the high baseline HIV RNA stratum and 57%
(30/53) vs 74% (45/61) with a treatment difference of −17% (95% CI, −34%
to 0%) for the low baseline HIV RNA stratum.
The median decreases in HIV RNA area under the curve minus baseline
calculation values were comparable between groups: −1.96 log10 copies/mL in the abacavir-lamivudine-zidovudine group and −1.84
log10 copies/mL in the indinavir-lamivudine-zidovudine group with
a median difference of −0.03 (95% CI, −0.15 to 0.08).
The median increases in CD4 cell count area under the curve minus baseline
calculation for CD4 cell counts were comparable between groups: 107 ×
106/L in the abacavir-lamivudine-zidovudine group and 93 ×
106/L in the indinavir-lamivudine-zidovudine group with a median
difference of −3 (95% CI, −24 to 19). At week 48, the median change
from baseline in CD4 cell counts was similar between groups (Figure 3).
At 48 weeks, there were no differences between groups in the proportion
of patients who did not have viral rebound with HIV RNA levels greater than
400 copies/mL or greater than 5000 copies/mL among all patients (Figure 4) or in the subgroups. In the high
baseline HIV RNA stratum, proportions for the abacavir-lamivudine-zidovudine
vs indinavir-lamivudine-zidovudine groups were 55% vs 61% (400 copies/mL)
and 75% vs 79% (5000 copies/mL), respectively. Likewise, no differences were
observed between groups in the low baseline HIV RNA stratum and were 68% vs
68% (400 copies/mL) and 84% vs 78% (5000 copies/mL).
Of the 59 patients who had confirmed HIV RNA levels exceeding 400 copies/mL
by week 48 of therapy, 47 had 2 plasma samples collected (at baseline and
at the time of confirmed failure). In both treatment groups, the RT mutation
most frequently observed was M184V, which was detected in viral isolates from
31 patients overall (66%), including 21 of 27 patients in the abacavir-lamivudine-zidovudine
group and 10 of 20 patients in the indinavir-lamivudine-zidovudine group.
Additionally, 22 (71%) of 31 patients had viral isolates with the M184V mutation
alone, including 15 of 21 patients in the abacavir-lamivudine-zidovudine group
and 7 of 10 patients in the indinavir-lamivudine-zidovudine group. Overall,
14 patients (30%) with viral rebound had wild-type virus, including 6 of 27
patients in the abacavir-lamivudine-zidovudine group and 8 of 20 patients
in the indinavir-lamivudine-zidovudine group. Two patients in the indinavir-lamivudine-zidovudine
group developed the protease mutation L10V or M461 without evidence of M184V.
Mutations selected also included other RT-associated mutations (6 patients
from the abacavir-lamivudine-zidovudine group) and protease-associated mutations
(5 patients from each group).
Four (<1%) of 562 patients had confirmed AIDS-defining events during
the study. Three patients in the abacavir-lamivudine-zidovudine group had
clinical progressions to Centers for Disease Control and Prevention category
C that included Kaposi sarcoma (2 patients) and cryptococcosis (1 patient).
One patient in the indinavir-lamivudine-zidovudine group had clinical progressions
to category C (lymphoma). In addition, there were 4 deaths that were not HIV-related
disease progressions as described below.
The study treatments were equally well tolerated for up to 48 weeks.
The most common (≥5%) drug-related adverse events that were of moderate
to severe intensity (grades 2-4) included nausea (with or without vomiting),
malaise and fatigue, headache, and renal signs and symptoms (Table 2). The proportion of patients with severe laboratory abnormalities
was similar between groups (Table 2).
Four deaths were reported during the study. In the abacavir-lamivudine-zidovudine
group, 1 death was attributed to hypersensitivity reaction that occurred following
rechallenge with abacavir approximately 3 weeks after initiating study treatment,
and 2 were attributed to cardiac arrhythmia and myocardial infarction occurring
30 to 35 weeks after initial study treatment. The latter 2 events were not
considered to be related to abacavir. In the indinavir-lamivudine-zidovudine
group, 1 death was attributed to drug overdose (heroin and cocaine), which
occurred approximately 6 weeks after initiating study treatment.
Nineteen patients (7%) in the abacavir-lamivudine-zidovudine group and
6 patients (2%) in the indinavir-lamivudine-zidovudine group were identified
as having symptoms that were consistent with or similar to a possible abacavir
hypersensitivity reaction. In the abacavir-lamivudine-zidovudine group, symptoms
generally occurred within 6 weeks of initiating abacavir, and included fever
and rash accompanied by gastrointestinal tract–related symptoms, such
as nausea, vomiting, and diarrhea. In the indinavir-lamivudine-zidovudine
group, symptoms were less severe, were gastrointestinal in nature, and included
rash or fever but not both concurrently.
This randomized trial is the first, to our knowledge, to evaluate the
antiretroviral equivalence of atriple nucleoside analogue regimen against
the conventional regimen of a protease inhibitor plus 2 nucleoside analogues
for initial treatment in antiretroviral-naive HIV-infected adults. Results
demonstrate that the abacavir-lamivudine-zidovudine regimen provides equivalent
virologic suppression to the indinavir-lamivudine-zidovudine regimen at 48
weeks based on the primary analysis of the proportion of patients with plasma
HIV RNA levels of 400 copies/mL or less. Secondary analyses by baseline HIV
RNA stratification demonstrated comparable antiretroviral activity among patients
with baseline HIV RNA levels below 100 000 copies/mL, as assessed by
the standard or ultrasensitive assays. A greater proportion of patients in
the high baseline HIV RNA stratum had undetectable HIV RNA levels with the
indinavir-lamivudine-zidovudine regimen than with the abacavir-lamivudine-zidovudine
regimen by the ultrasensitive assay. Kaplan-Meier analysis of the time to
viral rebound (>400 or 5000 copies/mL of HIV RNA) was not different between
groups when analyzed for all patients or by the subgroups.
The double-blind, randomized nature of this study and the use of CIs
to estimate treatment similarities provided a rigorous assessment of treatment
effects.26 The validity of the study conclusions
is further demonstrated by the consistency of results obtained from the various
analyses. Because of the placebo-control design of the study, all patients
were required to receive 16 tablets per day with the diet restrictions and
fluid requirements associated with indinavir therapy. Although treatment adherence
was not evaluated in the present study, other studies have demonstrated that
increased pill burden is correlated with decreased treatment adherence.10,11 Thus, the study results may underestimate
the potential impact of the abacavir-lamivudine-zidovudine regimen as the
increased pill count (16 tablets daily vs 2 tablets twice daily in clinical
practice) may have affected treatment adherence.
While cross-study comparisons are limited by differences in populations,
methods, and availability of long-term data, the results of this study of
a single-class regimen are generally comparable with those from several trials
of multiclass triple regimens. In these studies, triple therapy regimens containing
a protease inhibitor plus 2 nucleosides have reduced plasma HIV RNA levels
to less than 400 copies/mL in 41% to 70% of patients and 34% to 57% of patients
for 50 copies/mL or less by intent-to-treat analysis.27- 30
Median HIV RNA level reductions of 1.7 to 3 log10 copies/mL and
median CD4 cell count increases of 130 × 106/L to 227 ×
106/L were observed in these trials. Likewise, both groups in our
study showed substantial and sustained increases in CD4 cell counts over 48
In this study, few patients in either treatment group had confirmed
virologic failure. Genotypic resistance analyses of these patients indicated
that virologic failure was associated with the development of a single RT
mutation (M184V). Similar results have been seen in patients receiving protease
inhibitor–containing regimens.31- 33
The finding that patients with viral rebound had wild-type virus implies that
factors other than the selection of resistant mutant viruses may be responsible
for virologic failure.31 Our study showed that
viral isolates from most patients did not contain mutations that were associated
with resistance to other drugs, implying that virologic response to subsequent
treatments might be successful.
Several studies have shown that suppression of HIV RNA levels to less
than 20 to 50 copies/mL was associated with a more durable virologic response
compared with suppression to below 400 copies/mL.26,34,35
Our study showed no difference in the durability of response between treatment
groups despite a difference in the proportion of patients who had undetectable
HIV RNA levels by the ultrasensitive assay. Although the reason for this difference
is unclear, we speculate that treatment differences may take longer to emerge
or may be due to variability associated with the use of a single measure (as
in the proportion of patients with HIV RNA levels below the limit of detection
of the assay).
Among patients who had high baseline HIV RNA, less than 50% of patients
achieved viral suppression to below 50 copies/mL in both treatment groups,
although a better response was observed for patients receiving the indinavir-lamivudine-zidovudine
regimen. Several studies have shown that the likelihood of achieving undetectable
viral load with an initial treatment regimen is reduced if patients have high
HIV RNA levels and lower CD4 cell counts at baseline.7,36,37
The difficulty in achieving an undetectable viral load among patients with
high baseline HIV-1 RNA levels support the need to initiate antiretroviral
treatment in a manner consistent with treatment guidelines from the Department
of Health and Human Services (ie, CD4 cell count <350 or 500 × 106/L and HIV-1 RNA level >30 000 or 55 000 copies/mL).1,2
The hypersensitivity reactions to abacavir observed in this study were
consistent with the previously described clinical syndrome.18,19,38
In a few cases, investigators diagnosed a hypersensitivity reaction to study
drug based on the presence of rash only; all subjects were receiving indinavir.
This finding highlights the lack of specificity of rash alone as an indicator
of a hypersensitivity reaction to abacavir. The observed frequency of hypersensitivity
reaction to abacavir was higher than noted in other studies.38
The 1 fatality reported followed a rechallenge with abacavir after resolution
of an initial reaction. The reasons for the rechallenge are not known because
rechallenges were prohibited by the protocol. This case demonstrates the rapid
onset of a reaction after rechallenge and the risk for a fatal outcome.
The results of this study provide some practical implications for treatment
strategies. The selection of an antiretroviral regimen must be tailored to
the individual patient profile, including consideration of baseline HIV RNA
level and CD4 cell count.1,2 The
abacavir-lamivudine-zidovudine regimen may be an appropriate option for first-line
treatment of antiretroviral-naive HIV-infected subjects. However, as this
study suggests, the abacavir-lamivudine-zidovudine regimen may be less efficacious
than the indinavir-lamivudine-zidovudine regimen for patients with high baseline
RNA levels. Morever, it remains to be seen whether the abacavir-lamivudine-zidovudine
regimen will continue to provide long-term virologic suppression comparable
with the indinavir-lamivudine-zidovudine regimen.
The virologic benefit derived from an HIV treatment regimen also must
be balanced against other factors that impact treatment strategy including
possible increased serious adverse effects, tolerability, potential drug interactions,
likelihood of nonadherence, treatment costs associated with managing adverse
effects, an emerging resistance profile, and availability of future treatment
options.39,40 Given these considerations,
the abacavir-lamivudine-zidovudine regimen offers several potential advantages,
including twice daily dosing, low pill burden, low drug interaction risk,
and the potential to reserve other drug classes for future therapy. However,
this regimen also has several potential disadvantages including limited data
on long-term efficacy, clinical progression, or toxicity, and the risk for
hypersensitivity reactions. Recent data also suggest that another nonprotease
inhibitor–containing triple therapy is an option for patients who are
treatment-naive or who are moderately treatment experienced.30
In conclusion, the results of this 48-week randomized trial demonstrate
that in previously untreated HIV-infected adults, the triple nucleoside combination
regimen of abacavir-lamivudine-zidovudine administered twice daily is equivalent
to a conventional regimen of indinavir-lamivudine-zidovudine in achieving
plasma HIV RNA levels of less than 400 copies/mL at 48 weeks, and is comparable
with respect to their CD4 cell count effects.