Douglas J. Ward, MD Disclosures

Barcelona, Spain; Tuesday, July 9, 2002 -- With 15 antiretroviral agents now in common use, there is a myriad of potential 3- and 4-drug combinations available. Most commonly, treatment is given as 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 or 2 protease inhibitors (PIs), a nonnucleoside reverse transcriptase inhibitor (NNRTI), or a third NRTI. The choice of which drug class to use is difficult, let alone the choice of which specific drug, and at present there are few comparative data on their relative merits.

The CLASS trial, also known as ESS40001, has engaged with this problem, comparing a PI-based vs an NNRTI-based vs a triple-NRTI regimen in treatment-naive patients. John A. Bartlett, MD,[1] of Duke University, Durham, North Carolina, presented initial 48-week data from this planned 96-week trial. Patients were randomly assigned to receive abacavir and lamivudine as the NRTI backbone, plus either ritonavir-boosted amprenavir (PI), efavirenz (NNRTI), or stavudine (triple-NRTI). Second-line regimens for patients experiencing toxicity or failure are preplanned in the protocol: PI patients switch to efavirenz/zidovudine/didanosine; NNRTI patients switch to amprenavir/ritonavir/zidovudine/didanosine; and triple-NRTI patients to amprenavir/ritonavir/efavirenz. Each patient starting a second-line regimen is also randomly assigned to continue abacavir or to discontinue it. The trial end point is the percentage of patients with plasma HIV-1 RNA < 400 copies/mL at 96 weeks.

A total of 297 patients were enrolled, with similar baseline demographic distribution between the 3 groups. Of interest, the patients enrolled were 70% black or Hispanic. Baseline viral load was relatively high, with a median of 4.9 log10 copies/mL; 44% of patients had viral load > 100,000 copies/mL. The median CD4+ cell count at baseline was approximately 300 cells/mm3, and 35% of subjects had < 200 cells/mm3.
In-class drug substitution was allowed, and occurred in 12-15 patients per group. This was mostly switches in NRTIs, although 4 patients switched from efavirenz to nevirapine.

By week 48, 6 NNRTI patients had been switched to the second-line regimen: 5 for adverse events (AEs) and 1 for virologic failure. In the PI group there had been 5 AEs and 5 virologic failures; and in the triple-NRTI group there had been 4 AEs and 8 virologic failures.

In an intent-to-treat (ITT) analysis, plasma HIV-1 RNA < 400 copies/mL was achieved in 83% of the NNRTI group, 75% of the PI group, and 80% of the triple-NRTI group. The equivalent proportions in an on-treatment analysis were 98%, 91%, and 90%, respectively. None of these differences was statistically significant.

When analyzed using a viral load assay with a limit of detection of 50 copies/mL, the proportions achieving undetectable viremia were 76% for NNRTI, 59% for PI, and 62% for triple-NRTI by ITT analysis (P = .047 in favor of the NNRTI arm). In the on-treatment analysis, the proportions were 89%, 72%, and 71%, respectively.
Among subjects with baseline viral load > 100,000 copies/mL, the proportions achieving viral load < 50 copies/mL by ITT analysis were 77% in the NNRTI arm, 53% in the PI arm, and 55% in the triple-NRTI arm. This was statistically significant.

Increases in CD4+ cell count ranged from 173 to 196 cells/mm3, with no significant difference between the arms. There were no significant differences in AEs.
Thus, in this patient population with a high baseline viral load, all 3 arms provided effective treatment, with a slight edge to the efavirenz-based regimen. These preliminary data provide reassurance that any of these 3 treatment regimens can provide similarly good outcomes, so that we can tailor treatment decisions to individual preferences. The final 96-week results of this trial will eventually provide even more robust data to help us decide between these approaches. "Back-up" regimens always need to be considered when making treatment choices, and by having preplanned second regimens, this trial may eventually provide information on the "salvageability" of these different treatment approaches.

Reference

1. Bartlett JA, Johnson J, Herrera G, et al. Abacavir/lamivudine (ABC/3TC) in combination with efavirenz (NNRTI), amprenavir/ritonavir (PI) or stavudine (NRTI): ESS40001 (CLASS) preliminary 48 week results. Program and abstracts of the XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Abstract TuOrB1189.

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