Emerging doubts about the nevirapine-tenofovir-emtricitabine/lamivudine combo?

[lydgate]

Matt (and anybody else of course): any thoughts on the DAUFIN study (CROI 2007, Abstract 503), and the Lapadula et al study (in Clinical Infectious Diseases)? I've been reading the Hopkins guide/site, and it would seem that doctors like Joel Gallant are dis-recommending this combo as initial treatment. I heard from a friend that the head-to-head study (Viramune-Truvada vs. boosted Reyataz-Truvada) was discontinued recently because of the fears of (a) early virological failure, and (b) high rate of mutations in the Viramune arm. True?

Jay   

[newt]

Indeed.

1. I have doubts about Viramune doesd in one go each day until after viral load is suppressed to <50 copies anyway

2. The studies in question are quite small and I do wonder in the case of #503 whether all the subjects were completely treatment naive. A past but unreported episode of treatment, especially if used with poor adherence/stopped suddenly, would influence baseline resistance, which in the case of NNRTI mutations might well go undetected.

3. These and other studies do suggest a high viral load should influence choice of combo - ie go for a bomb.

4. But...on an intent to treat basis, the proporrtion achieveing undecetable viral loads in both these studies is broadly speaking similar to all other combos judged by the results in clinical practice.

See: http://www.aidsmeds.com/articles/1961_11411.shtml

The Viramune/Reyataz head-to-head is the NEwArT study (NCT00552240) by Boehringer Ingelheim Pharmaceuticals.  It uses Viramune 2 x day. I have no idea if it has been halted, it only started recruitment in November last year.

- matt

[lydgate]

Well, I wrote to Dr. DeJesus, the lead investigator (and also the subject of a thread in the Off Topic forum). My question and his reply below:

Dr. DeJesus,

I've heard that the NEwArT study, of which you are the lead investigator, has been halted or soon will be halted because of concerns about the Viramune arm. (The study compares Viramune-Truvada with boosted Reyataz-Truvada.) The concerns, specifically, being: (a) higher rates of early virological failure; (b) higher mutation rates (conferring cross-class resistance or intra-class only?); and (c) evidential support from small studies such as DAUFIN and Lapadula et al.

Is this true? If so, can you explain, elaborate -- especially since nevirapine is the NNRTI most widely used in less-developed countries (and used, also, by those wishing to avoid the potential psychiatric side-effects of efavirenz)?

Thanks!

* * *

Thanks for you question, and a very good one! The short answer is "No". There is no validity to any rumors suggesting that the sponsor of this trial is plannin--at the time of this response-- to stop this study. For this to occur, the DSMB will have to meet and find evidence that this regimen is associated with less efficacy and safety. This DSMB will be conveying soon to make that determination, on a protocol defined time-point (after certain amount of pts have achieved Week 12 data--which by the way will be occurring very soon).

The reason why the board did not conveyed earlier to make this determination for this study after the recent reports is because on a similar study been conducted in other countries, the ARTHEN study, the DSMB did not find any unknown safety or efficacy concerns.

Regarding the reports by Daufin and Lapadula, raising concerns on the efficacy and safety of nevirapine, FTC and TDF combination, there are a few things we need to keep on mind. For example, in those studies nevirapine was given once daily (instead of twice a day), which may have accounted for a higher rate of AE's; also at least on one study, 3TC was used instead of FTC, which is known to have a shorter half-life.

Today, there is no reports from any large, randomized study that could definitively confirm the findings and concerns raised by those smaller studies; reason why the conduction of the NEwArT trial is critical to understand any potential unfavorable interactions. I will assure you, that if any significant safety or efficacy concerns is identified during the conduction of this study, we will immediately notify the investigators to prevent placing any future patients at risk.

Thanks again for sharing your questions and concerns.