A randomized, placebo-controlled trial of abacavir intensification in HIV-1-infected adults with virologic suppression on a protease inhibitor-containing regimen

Abstract

Background and objective: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure.

Methods: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels<500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs>200 copies/mL) and treatment discontinuation.

Results: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P=.77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P=.22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms.

Conclusions: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs.

Trial registration: ClinicalTrials.gov NCT00000885.

Figure 1

Disposition of study subjects. LFU = loss to follow-up.

Figure 2

Primary and secondary virologic time to event distributions (in weeks). (A) Primary endpoint (first of confirmed HIV-1 RNA level >200 copies/mL or treatment discontinuation) (P = .77). (B) Virologic failure (confirmed HIV-1 RNA level >200 copies/mL) (P = .22). (C) Virologic failure (confirmed HIV-1 RNA level >50 copies/mL) (P = .65). Treatment arms were compared using log rank tests. ZDV = zidovudine; 3TC = lamivudine; IDV = indinavir; ABC = abacavir.

Figure 2

Primary and secondary virologic time to event distributions (in weeks). (A) Primary endpoint (first of confirmed HIV-1 RNA level >200 copies/mL or treatment discontinuation) (P = .77). (B) Virologic failure (confirmed HIV-1 RNA level >200 copies/mL) (P = .22). (C) Virologic failure (confirmed HIV-1 RNA level >50 copies/mL) (P = .65). Treatment arms were compared using log rank tests. ZDV = zidovudine; 3TC = lamivudine; IDV = indinavir; ABC = abacavir.