Background:  This is a pilot, open-label, multicenter study evaluating the efficacy and safety of once-daily trizivir (TZV) + Tenofovir DF (TDF) in antiretroviral naïve subjects with entry HIV-1 RNA >30,000 copies/mL.  A preliminary evaluation was performed to assess virologic response in this ongoing study due to the poor response previously reported with once-daily TDF + ABC/3TC in study ESS30009.

Methods:  Analyses were performed on data from 88 subjects with at least 8 weeks of HIV-1 RNA data.  Early virologic non-response (EVNR) was defined as:  <2.0 log drop in VL and >50 copies/mL by week 8 or >1.0 log rebound from nadir at or before 8 weeks. Viral RT genotype and phenotype (Virco) were determined at baseline and longitudinally following protocol-defined virologic non-response (PVNR), i.e. confirmed HIV-1 RNA >400 copies/mL at 24 weeks or later, until the subject withdrew from the study.

Results:  At baseline, median HIV-1 RNA and CD4⁺ cell count were 5.1 log₁₀ copies/mL and 226 cells/mm³, respectively.  At week 24, the proportion of subjects with HIV-1 RNA <400 copies/mL and HIV-1 RNA <50 copies/mL was 78% (42/54) and 67% (36/54), respectively (observed analysis). Of 88 subjects, 10 (11%) met EVNR criteria, with most of these subjects (60%) having baseline HIV-1 RNA >100,000 copies/mL (High VL group).  At the time of this evaluation, 8/54 subjects (15%) had met PVNR:  7 in the High VL group and 1 with baseline HIV-1 RNA <100,000 copies/mL.  At baseline, 6/8 (75%) had wild-type virus and 2/8 (25%) had mutant virus (K103N and 215T/A reversion mutation).  At withdrawal or at the last post-week 24 visit, 1/8 (13%) had K65R, 2/8 (25%) had wild-type virus, 2/8 (25%) had >1 TAMs without M184V, and 3/8 (37%) had >1 TAMs with M184V.  To improve virologic response in subjects with HIV-1 RNA >50 copies/mL, the protocol is being amended to allow these subjects to optimize therapy.

Conclusions:  The poor virologic response observed with TDF + ABC/3TC (ESS30009) was not observed with the once-daily TZV + TDF regimen, despite ZDV being dosed once-daily.   In this study, virologic non-response appears to be associated with baseline HIV-1 RNA >100,000 copies/mL. This once-daily, PI- and NNRTI-sparing regimen shows promise in subjects with baseline HIV-1 RNA <100,000 copies/mL.  The resistance pattern to date includes less K65R or M184V than would have been predicted by ESS30009, suggesting a potential role of ZDV in resistance modulation.

Keywords: Trizivir; Tenofovir; Resistance