AIDS 2010: Once-daily Extended Release Nevirapine (Viramune) Equals Twice-daily Immediate Release Formulation

A once-daily extended-release formulation of nevirapine (Viramune) suppresses HIV viral load as well as the older immediate-release pill, and may cause fewer or milder side effects, according to a late-breaker presentation at the XVIII International AIDS Conference (AIDS 2010) last week in Vienna. The more convenient once-daily formulation is likely to be especially beneficial in resource-limited countries where the drug is still widely used.

The immediate-release formulation of nevirapine (Viramune IR) currently on the market is approved fortwice-daily dosing. Once-daily medications, however, are more convenient and associated with better adherence.

As described by Anne-Marie Quinson from Boehringer-Ingelheim, the VERxVE trial compared the safety and efficacy of extended-release (Viramune XR) and immediate-release nevirapine formulations for first-line HIV treatment.

The study enrolled 1011 treatment-naive HIV positive adults, mostly from North America, Europe, and Australia. Most (85%) were men and the average age was 38 years.

The median pre-treatment viral load was about 50,000 copies/mL, and participants were stratified into high and low viral load groups (above or below 100,000 copies/mL). The average CD4 cell count was 228 cells/mm3. (Based on studies showing that people with better immune function are more likely to experience nevirapine hypersensitivity reactions, men with CD4 counts above 400 cells/mm3 and women with levels above 250 cells/mm3 were excluded.)

During a 14-day lead-in period -- done to bring nevirapine up to therapeutic levels in the body -- all participants took 200 mg Viramune IR once-daily. They were then randomly assigned (1:1) to receive either Viramune IR at a dose of 200 mg twice-daily or the new Viramune XR at a dose of 400 mg once-daily, both in combination with tenofovir/emtricitabine (Truvada).

Results

• A 48 week analysis showed that 81% of patients taking the new Viramune XR achieved undetectable viral load (< 50 copies/mL) with no virological rebound, compared with 76% of those taking the Viramune IR.
• The adjusted difference of 4.9% fell within a predetermined margin of 10%, indicating that Viramune XR is non-inferior to the immediate-release formulation.
• Response rates were also similar among participants with high baseline viral load, at 73% vs 71%, respectively.
• Viramune XR was generally safe and well-tolerated.
• 17% of Viramune XR recipients and 19% taking Viramune IR discontinued treatment prior to week 48.
• 6% and 8%, respectively, did so due to adverse events.
• 20% of participants in the Viramune XR arm experienced drug-related adverse events compared with 24% in the Viramune IR arm, not a significant difference.
• 12% vs 11%, respectively, experienced serious adverse events.
• 6% and 9%, respectively, had adverse events leading to treatment discontinuation.
• Types of adverse events were similar in both arms but occurred somewhat less often with Viramune XR.
• Symptomatic liver toxicity was less common in the Viramune XR arm than in the Viramune IR arm (1.6% vs 2.8%).
• Skin rash occurred with similar frequency in the 2 arms (8.3% vs 8.7%, respectively).
• Both formulations demonstrated similar blood lipid profiles, lowering triglycerides and raising total, LDL ("bad"), and HDL ("good") cholesterol.
• Viramune XR, however, was associated with a slightly better total cholesterol-to-HDL ratio.
• Among a subset of participants in a pharmacokinetic sub-study, Viramune XR maintained a steady nevirapine concentration over the dosing interval, raising the minimum concentration seen with Viramune IR while lowering the maximum concentration.

This pivotal trial showed "non-inferior efficacy for Viramune XR to Viramune IR," the investigators summarized, with "similar safety and tolerability profiles for both formulations."

"Once-daily dosing with Viramune XR provides patients with a more convenient treatment regimen with comparable efficacy and safety to Viramune IR," they concluded.

"We are confident that the extended release formulation, once approved, will enable HIV patients and their physicians to choose an effective, tolerable and durable treatment option with a favourable lipid profile," Prof. Klaus Dugi, Boehringer Ingelheim Corporate Senior Vice President Medicine, said in a press release issued by the company. "This development is particularly important as it will give patients the convenience of a once daily antiretroviral drug that does not carry food or drink restrictions."

Boehringer Ingelheim indicated that it is working with regulatory authorities to make the nevirapine extended-release formulation available on a global basis as soon as possible.

Therapeutic Concepts, Houston, TX; Ludwig-Maximilians University, Munich, Germany; Care Resource, Miami, FL; Warsaw Medical University and Hospital of Infectious Diseases, Warsaw, Poland; Chelsea & Westminster Hospital, London, UK; Fundacion Huesped, Buenos Aires, Argentina; Antiguo Hospital Civil de Guadalajara, Guadalajara, Mexico; Toga Labs, Edenvale, South Africa; Boehringer-Ingelheim Pharmaceuticals Inc, Ridgefield, CT.

7/27/10

Reference

J Gathe, J Bogner, S Santiago, and others. Comparison of 48 week efficacy and safety of 400 mg QD nevirapine extended release formulation (Viramune XR) versus 200 mg BID nevirapine immediate release formulation (Viramune IR) in combination with Truvada in antiretroviral (ARV) naive HIV-1 infected patients (VERxVE).XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB202.

Other Source

Boehringer-Ingelheim. VERxVE study demonstrates efficacy and safety of 400mg once daily nevirapine (Viramune) extended release (NVP XR) formulation. Press release. July 22, 2010.