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ACTG 384 -- Complicated, but Worth the Work
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ACTG 384 -- Complicated, but Worth the Work
AIDS Clinical Care, January 2004
By Paul E. Sax, MD
In this large, multicenter study comparing 6 different initial treatment strategies, AZT + 3TC + efavirenz emerged clearly superior to the other 5 combinations, including 4-drug triple-class regimens.
What is the optimal initial therapy for HIV? Do certain initial regimens increase the likelihood of treatment success with future regimens (a hypothesis called "sequencing")? Answering these two important questions was the major goal of ACTG 384, the full results of which have now been published in two separate articles.
From October 1998 to November 1999, researchers at 58 sites in the U.S. and 23 sites in Italy randomized treatment-naive patients with viral loads of at least 500 copies/mL to 1 of 6 treatment arms:
- (1) d4T + ddI + efavirenz
- (2) d4T + ddI + nelfinavir
- (3) AZT + 3TC + efavirenz
- (4) AZT + 3TC + nelfinavir
- (5) d4T + ddI + efavirenz + nelfinavir
- (6) AZT + 3TC + efavirenz + nelfinavir
In the event of virologic failure or discontinuation of an entire regimen due to toxicity, patients in groups 1 through 4 received salvage therapy with the converse regimen; for example, patients with virologic failure on AZT + 3TC + efavirenz received d4T + ddI + nelfinavir. Overall, 980 subjects with a median follow-up of 2.3 years were included in these analyses. The mean baseline CD4 count was 278 cells/mm3, and the mean baseline viral load was 4.9 log (nearly 100,000 copies/mL); 82% of the participants were male, and approximately 45% were white.
Robbins and colleagues reported results of the 4 triple-drug arms. The primary endpoint of this part of the study was time to the second regimen failure, regardless of the cause. Secondary endpoints concerned the time to failure of the first regimen. Initial treatment with efavirenz, rather than nelfinavir, delayed the occurrence of the second-regimen failure when combined with AZT + 3TC, but not with ddI + d4T (hazard ratio for failure of second regimen, 0.71; 95% confidence interval, 0.48-1.06). Similarly, starting therapy with AZT + 3TC, rather than d4T + ddI, delayed second-regimen failure when combined with efavirenz, but not with nelfinavir (HR, 0.68; 95% CI, 0.46-1.01). For the secondary endpoints, which were focused on first-regimen failure, the results were much more striking: The initial combination of AZT + 3TC + efavirenz was vastly superior to the other 3 triple-drug regimens, whether because of virologic outcome or dose-limiting toxicity (overall HR for first-regimen failure, 0.39; 95% CI, 0.24-0.64). The time to occurrence of peripheral neuropathy was substantially shorter in those starting d4T + ddI than in those starting AZT + 3TC.
Shafer and colleagues reported on the comparison between the 4-drug and 3-drug regimens. In this part of the study, the impressive performance of AZT + 3TC + efavirenz held up: neither 4-drug combination was superior to this triple-drug combination. Further exploration of adverse events in the whole study showed that d4T + ddI was associated not only with a greater risk for neuropathy, but also with significantly higher rates of pancreatitis, elevated serum lipase levels, and hepatic abnormalities compared with AZT + 3TC. Moreover, all 9 subjects who developed lactic acidosis during the study were receiving d4T + ddI.
As summarized in an accompanying editorial, the results of this landmark study have several important implications for clinical practice (many of which have already been incorporated into treatment guidelines): First, among the regimens tested here, the combination of AZT + 3TC + efavirenz is preferred as initial therapy because of its superior virologic activity and toxicity profile. Second, the NRTI combination of d4T + ddI should be avoided as part of initial therapy because of the high rates of toxicities associated with this NRTI duo; indeed, a metabolic substudy of ACTG 384 presented in preliminary form (see ACC Meeting Notes Dec 2002 and Antiviral Ther 2002; 7:Abstract L18) previously demonstrated that this combination leads to a greater degree of fat atrophy compared with AZT + 3TC. Fourth, use of a 4-drug, 3-class regimen does not necessarily improve treatment responses -- most notably AZT + 3TC + efavirenz was just as good as AZT + 3TC + efavirenz + nelfinavir. Fifth, the initial antiretroviral regimen is the patient's best chance for treatment success; the concept of sequencing was not supported by the findings with the various strategies presented here.
In light of the changes in HIV medicine since ACTG 384 was designed, we find newer, unanswered questions. Will sequencing be more successful with the use of genotypic or phenotypic resistance testing? How generalizable are these results to other drugs in the same classes? Specifically, would nevirapine have been as successful as efavirenz? How would lopinavir/ritonavir, atazanavir, or fosamprenavir have performed in place of nelfinavir? How does the AZT + 3TC combination compare with tenofovir + 3TC or tenofovir + emtricitabine? Answers to some of these questions are now being explored in clinical trials.
Dr. Sax is Editor-in-Chief of ACC.
Robbins GK et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003 Dec 11; 349:2293-303.
Shafer RW et al. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 2003 Dec 11; 349:2304-15.
Skolnik PR et al. HIV Therapy -- What do we know, and when do we know it? N Engl J Med 2003 Dec 11; 349:2351-2.
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