For several years, Boehringer Ingelheim and independent researchers have been looking into the possibility of once-daily Viramune® (nevirapine) dosing, to help simplify its use in the treatment of HIV. However, new research presented at the 14th Conference on Retroviruses and Opportunistic Infections (CROI) suggests that the approved twice-daily schedule will remain the necessary dosing option, especially for those starting therapy with high viral loads, based on a significantly greater number of virologic failures seen in a French study comparing the two dosing schedules.
The DAUFIN study randomized 71 HIV-positive patients to one of two treatment groups. In the first group, 36 patients took once-daily Viramune (400mg), Viread® (tenofovir; 245 mg), and Epivir® (lamivudine, 300 mg). In the second group, 35 patients took twice-daily Viramune (200 mg) and Combivir® (zidovudine plus lamivudine). All patients were treatment-naïve – new to treatment at the start of the study – and the men had to have CD4 counts below 350, whereas the women had to have CD4 counts below 250 (to reduce the risk of Viramune-related hypersensitivity).
The average viral loads at study entry were 71,500 in the once-daily group and 80,282 in the twice-daily group. Pre-treatment CD4 counts average 208 cells in both groups.
The study began in May 2005, with a planned target enrollment of 250 patients. However, by May of 2006, early virologic failure was documented in seven patients – all in the once-daily group – leading to early termination of the study. The data presented at CROI reflected results for 71 patients enrolled in the trial before it was discontinued.
In total, eight individuals – again, all in the once-daily group – experienced early virologic failure, defined as a viral load that failed to drop more than 2 log by week 12 or a greater than 1 log rebound in viral load by week 12. Two additional patients experienced virologic rebound later in the study, one in each study group.
It was not initially clear why patients in the once-daily group were much more likely to experience virologic failure compared to those in the twice-daily group. Trough concentrations of Viramune – a measure of the drug in the blood – were somewhat lower in the once-daily group, but not significantly so.
Two factors that did seem to play a role in early virologic failure were high viral loads and low CD4 counts at the time of study entry. The average pre-treatment viral load among those who maintained virologic control was 51,189. Among those who experienced virologic failure, the average pre-treatment viral load was 262,747. As for pre-treatment CD4 cells, the average count among those who continued to respond well to treatment was 223, vs. an average pre-treatment count of 110 among those who experienced virologic failure. These differences were statistically significant.
While discontinuation due to side effects was slightly more common among individuals in the twice-daily group compared to the once-daily group, the difference was not statistically significant.
Rey D, Schmitt MP, Hoizey G, et al. Early virologic non-response to once daily combination of lamivudine, tenofovir, and nevirapine in ART-naive HIV-infected patients: preliminary results of the DAUFIN study [Abstract 503]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.