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Once-Daily Nevirapine Noninferior to Twice-Daily Dose in Treatment Naive
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ICAAC: 48 Week Efficacy, Pharmacokinetics, and Safety of Once a Day 400 mg Nevirapine (Viramune) Extended Release Formulation for Treatment of Antiretroviral Naïve HIV-1 Infected Patients (09/15/10)
ICAAC: 24 Wk Efficacy and Safety of Transitioning Virologically Stable HIV-1 Patients from IR Nevirapine 200 mg BID to Nevirapine XR 400 mg QD (TRANxITION) - (09/15/10)
50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12-15, 2010, Boston
Mark Mascolini
Once-daily extended-release nevirapine (NVP XR) proved noninferior to immediate-release nevirapine (NVP IR) in a week-48 analysis of study participants with a viral load below 50 copies [1]. Neither the response rate nor nevirapine trough concentrations varied by gender, race, region, or pretreatment viral load stratum. Response rates did drop off in people with nevirapine troughs below 1000 ng/mL, and more so in the NVP XR group than the NVP IR group. Side effects were less common with NPV XR.
VERXVE was an international, double-blind, double-dummy trial that enrolled antiretroviral-naive adults with a pretreatment viral load above 1000 copies and a pretreatment CD4 count below 400 in men and below 250 in women. People with a CD4 count below 50 were excluded from the trial. All study participants began treatment with 200 mg of NVP IR once daily for 14 days. At day 14, VERXVE investigators randomized them to 200 mg of NVP IR twice daily or 400 mg of NVP XR once daily. Everyone also took tenofovir/emtricitabine. The primary endpoint was a sustained virologic response at week 48, defined as a viral load below 50 copies before and at week 48 without a virologic rebound or change in antiretrovirals.
The analysis included 505 randomized and treated people in the NVP XR arm and 506 in the NVP IR arm. Age averaged 38 years, 85% of study participants were men, and about 20% were black. Half of study participants enrolled in Europe, about 30% in North American or Australia, about 10% in Latin America, and about 10% in Africa. Pretreatment viral load averaged 50,000 copies in both groups, while pretreatment CD4 count averaged 229 in the NVP XR group and 227 in the NVP IR group. Only 5% to 6% in each arm had an AIDS diagnosis.
By week 48, 84 people (16.6%) had dropped out of the NVP XR arm and 97 (19.2%) left the NVP IR arm. Thirty-two people (6.3%) quit the NVP XR arm because of adverse events, compared with 45 (8.9%) who stopped NVP IR for that reason. Similar numbers stopped treatment for lack of efficacy--24 (4.8%) on NVP XR and 26 (5.1%) on NVP IR.
In the week-48 virologic response analysis, 409 of 505 people randomized to NVP XR (81%) and 384 of 506 randomized to NVP IR (76%) had a viral load below 50 copies. The adjusted between-arm difference of 4.9% favoring NVP XR established the noninferiority of the once-daily formulation to twice-daily NVP IR. Response rates were lower in both arms among people who began treatment with a viral load above 100,000 copies, but these rates were similar in the two arms--73% with NVP XR and 71% with NVP IR. People in the NVP XR group gained an average 192 CD4 cells through week 48, compared with an average 181-cell gain in the NVP IR group.
Geometric mean trough concentrations through 48 weeks averaged 3.35 mcg/mL with NVP XR and 4.11 mcg/mL with NVP IR. Response rates at 48 weeks did not differ between treatment arms in the four higher geometric mean trough brackets: 1000 to 2000 ng/mL, 2000 to 3000 ng/mL, 3000 to 4000 ng/mL, and 4000 or more ng/mL. Response rates were blunted in people with a geometric mean trough below 1000 ng/mL, and more so for people taking NVP XR (about 30%) than NVP IR (about 60%). Overall, 85% of people taking NVP XR and achieving a trough above 1000 ng/mL, compared with 80% taking NVP IR, sustained a viral load below 50 copies.
During the randomized phase of the trial, 88% of participants taking NVP XR and 89% taking NVP IR had any adverse event. Investigator-defined drug-related adverse events were somewhat less frequent with NVP XR (19.8%) than NVP IR (24.3%). Adverse events leading to discontinuation were marginally less frequent with NVP XR (6.3%) than NVP IR (8.9%). Stevens-Johnson syndrome caused three discontinuations with NVP IR and none with NVP XR. Total hepatobiliary events were less frequent with NVP XR (2.2%) than NVP IR (5.5%), as were treatment-related hepatobiliary events (1.8% versus 3.8%). Rash (10.5% NVP XR and 9.5% NVP IR) and treatment-related rash rates (5.7% NVP XR and 4.9% NVP IR) were similar with the two formulations.
Reference
1. Gathe J, Knecht G, Orrell C, et al. 48 Week Efficacy, Pharmacokinetics and safety of once a day 400 mg nevirapine extended release formulation for treatment of antiretroviral naive HIV-1 infected patients (VERxVE). 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 12-15, 2010. Boston. Abstract H-1808.
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