Preliminary results from a prospective clinical trial of once-daily 3TC (lamivudine, Epivir), tenofovir (Viread) and nevirapine (Viramune) have shown a high rate of early virologic failure, leading to discontinuation of the study. The results of the French study were presented last week at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.
Several combinations of one non-nucleoside (NNRTI) plus two nucleosides (NRTI) have been validated as first-line antiretroviral options. The “DAUFIN” study was a prospective, randomised, open-label clinical trial conducted at several centres in France, which compared a twice-daily combination of nevirapine (200mg) and Combivir (300mg AZT plus 150mg 3TC) to a once-daily combination of 300mg 3TC, 400mg nevirapine, and 245mg tenofovir. (The poster presented at CROI did not explain why tenofovir was not dosed at the more typical 300mg daily.)
Enrolment began in May 2005 with a target of 250 participants; results were available for 71 participants enrolled by May 2006, when the study was prematurely terminated. Of the 71 participants, 35 were randomised to the “bid” (twice-daily AZT/3TC/NVP) arm and 36 to the “qd” (once-daily 3TC/TDF/NVP) arm.
Characteristics were similar between the two groups: the participants overall were antiretroviral naïve, 75% male, with an average age of 41.4 years, median CD4 cell count of 209 cells/mm3 (44% with a CD4 cell count below 200 cells/mm3), and median viral loads of 80,282 copies/ml (in the bid group) and 71,500 copies/ml (in the qd group).
“Early virologic failure” was defined as either a less than 2 log10 copies/ml decrease by week twelve, or a rebound of greater than 1 log10 after an initial decrease. Eight such early failures were seen, all in the qd (3TC/NVP/TDF) group. Two further viral rebounds occurred after week twelve, one in each group. A total of 9/36 failures (25%) were seen in the qd arm. Also, high discontinuation rates due to adverse events and other causes (17 dropouts in bid group: ten due to adverse events, seven other; eight dropouts in qd group: six due to adverse effects, two other) resulted in low intent-to-treat (ITT) success rates for both groups.
The researchers then analysed the baseline characteristics of patients in the qd group. Those with virologic failure had lower baseline CD4 cell counts (110 vs. 223 cells/mm3) and higher baseline viral loads (262,747 vs. 51,189 copies/ml) than those with virologic success (p=.004 and .002, respectively). High rates of NNRTI resistance mutations were seen among the virologic failures (K65R mutation in 6/9, Y181C/A in 7/9, two or more mutations in 5/9). Plasma trough concentrations of nevirapine were judged not low enough to explain the failures.
These results were similar to those presented from a previous study (Towner, 2004). The researchers concluded that, in treatment-naïve patients, “the once daily lamivudine, tenofovir and nevirapine regimen resulted in an unexpected high rate of early nonresponse with a high incidence of K65R and M184V. The reasons for the failures seen remain currently unclear... The trial steering committee decided to stop the trial and recommended that all [3TC/TDF/NVP] patients be switched to another ARV regimen.”
Rey D et al. Early virologic non-response to once daily combination of lamivudine, tenofovir and nevirapine in antiretroviral naïve HIV-infected patients: preliminary results of the DAUFIN study. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 503, 2007.
Towner W et al. Efficacy of a once daily (QD) regimen of nevirapine (NVP), lamivudine (3TC) and tenofovir (TDF) in treatment-naive HIV infected patients: a pilot study. Seventh International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P49, 2004.