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Treatment Options for Antiretroviral-Naive Patients

The 14th Retrovirus Conference advanced our understanding of which antiretroviral regimens are best for treatment-naive patients.

Does directly observed therapy improve outcomes in treatment-naive patients? Is a once-daily regimen more effective than a twice-daily one? In ACTG 5073, 402 treatment-naive patients were randomized to receive a lopinavir/ritonavir-based regimen in one of three ways: self-administered, once daily; self-administered, twice daily; or directly observed, once daily [Abstract 138]. Overall, no differences were seen between study arms in time to virologic failure. An unanticipated finding was that the once-daily self-administered regimen had reduced efficacy (compared with the twice-daily regimen) in patients with baseline viral loads >100,000 copies/mL, a result not seen in prior studies of once-daily lopinavir/r. As with many studies that were conducted several years ago but are only now being published or presented, an unavoidable limitation was the use of the older soft-gel lopinavir/r formulation, which had substantial gastrointestinal side effects when given once daily.

AZT and ddI are currently the only two antiretrovirals available in generic formulations in the U.S. However, these formulations are rarely used because AZT comes as part of fixed-dose AZT/3TC, and relatively few data are available on ddI as initial therapy. In the GESIDA study, fixed-dose AZT/3TC was compared with ddI + 3TC, both with efavirenz as the third drug, in 369 treatment-naive subjects [Abstract 504]. The ddI group had slightly higher rates of virologic suppression to <50 copies/mL at 24 weeks than did the AZT group (71% vs. 66%, a nonsignificant difference) and significantly greater CD4-cell increases, likely representing the absence of AZT-induced bone marrow suppression. The combination of ddI, 3TC, and efavirenz may be especially useful in developing countries, given concerns about AZT-related anemia and d4T-associated toxicity.

The 2NN study previously demonstrated that when given with d4T and 3TC, once-daily nevirapine is as effective as twice-daily nevirapine (ACC Jun 1 2004); however, these data have not led to widespread use of once-daily nevirapine in the U.S., and the drug is not FDA-approved for this mode of administration. In the DAUFIN study, 250 treatment-naive patients were randomized to a standard twice-daily regimen of AZT/3TC + nevirapine or to a once-daily regimen of tenofovir, 3TC, and nevirapine [Abstract 503]. After only 71 patients had been enrolled, the trial was halted because of seven early virologic failures in the once-daily arm; two additional failures occurred after the study was terminated. Trough concentrations in these failures did not demonstrate inadequate nevirapine concentrations. Furthermore, resistance analyses showed that six of the nine patients with failure had developed the K65R mutation, a rate much higher than that seen in other clinical trials of tenofovir. These results underscore the importance of avoiding novel regimens for treatment-naive subjects; the recommended regimens in the U.S. Department of Health and Human Services and International AIDS Society–USA guidelines all have extensive clinical-trial data supporting their efficacy.

Efavirenz was approved by the FDA in 1998, and, because of its high potency, safety, tolerability, and excellent pharmacokinetics, it has had relatively little within-class competition, at least compared with PIs and NRTIs. Rilpivirine (previously TMC278) is an investigational NNRTI that is also dosed once daily. In a phase IIb dose-finding study, three different doses of rilpivirine were compared with efavirenz in 368 antiretroviral-naive patients; all regimens were given with investigator-selected AZT/3TC or tenofovir/3TC [Abstract 144LB]. At 48 weeks, all four treatment groups had comparable rates of virologic suppression to <50 copies/mL (approximately 80%). In addition, rilpivirine recipients had a lower incidence of rash and CNS side effects than did efavirenz recipients. A potential limitation of this study is that the efavirenz was given in an open-label fashion, which raises the question of whether study participants were more likely to report CNS adverse events if they knew they were receiving efavirenz. A fully powered phase III study is planned of rilpivirine at 75 mg daily versus efavirenz.

— Paul E. Sax, MD

Published in Journal Watch HIV/AIDS Clinical Care April 2, 2007

2011 Year in Review