HIV and ID Observations

As I’m sure you’ve heard from your patients — as I did — lamivudine (3TC) is now available generically.

Now comes news of the release of several generic formulations of nevirapine (NVP), an effective but always somewhat overshadowed medication. Since its approval way back when in 1996, there has always been a solid reason to pick something else.

Why? Here are a few reasons, some scientific, some accidents of HIV history, some just gut responses:

1. The first studies of NNRTIs showed that resistance to the drugs developed very quickly, often within days. Since NVP was the first in this class of drugs approved, it always carried that baggage of “low resistance barrier” more than other drugs.
2. Remember this whole “convergent combination therapy” saga? The message was that if there was enough selective pressure on the same target — here reverse transcriptase, using AZT, ddI, and NVP — HIV could not grow in vitro at all, since the virus paid such a penalty for accumulating resistance mutations. The authors (many of whom are still colleagues of mine) urged caution in interpretation of results, but that didn’t stop it from being front page news — and more — which made it all the more heartbreaking when the paper was retracted 6 months later.
3. Nevirapine was approved right after indinavir, the first PI that really put combination antiretroviral therapy on the map. It didn’t matter that in hindsight NVP had many advantages over indinavir (fewer pills, fewer side effects, better metabolic profile, no need for a quart of water a day, easier to take) — NVP was hugely overshadowed. In hindsight, possibly the reason that indinavir seemed to be a more effective drug was that pivotal trials with indinavir included ZDV/3TC, but with nevirapine  ZDV/ddI. Which combination of NRTIs would you prefer?
4. The approval of efavirenz in 1998 was another reason not to pick NVP. Based on experience with NVP and delavirdine, I never thought any drug from this class could be more effective than a PI. Indeed, I was highly skeptical until this study, with its surprising finding that efavirenz was in fact better than indinavir. Now that efavirenz has pretty much become the gold standard “key third drug” in HIV treatment — still never beaten in a  primary analysis of any HIV study — I’m a believer!
5. Nevirapine hypersensitivity — rash, fever, hepatitis — is scary and potentially fatal, and the two-week dose escalation sounds simple but is not always so easy for patients to get right. Stevens-Johnson syndrome and toxic epidermal necrolysis are also concerns. Never mind that rates of these reactions are low when NVP is prescribed appropriately, these severe side effects obviously are a deterrent to using the drug. Anecdote: A patient once came to me with an ad from a magazine for NVP, saying “Don’t give me this one — I know someone who nearly died from it.”
6. Single-dose NVP for prevention of maternal to child transmission certainly works, is safe, cheap, and probably has saved the lives of hundreds of thousands of children in developing countries. But the take-home message for most clinicians reinforced the resistance problem. And no one would recommend it in settings that had access to fully suppressive regimens.
7. These weird reports (here for example, or more recently here) of virologic failure with resistance when NVP is given with TDF and 3TC remain mostly unexplained, but certainly would make me hesitant to use this combination, especially in patients with high viral loads.
8. Prior treatment failure with efavirenz doesn’t typically give a patient resistance to etravirine, the second-generation NNRTI. Nevirapine, however, often selects for Y181C, which along with other mutations makes etravirine substantially less active.

Among the above, probably the biggest challenge facing NVP was #4 — can we finally say that efavirenz is just a much better drug than nevirapine? Maybe not for all people, but for most of them. For further evidence, here’s Chuck Hicks’ nice summary of a large cohort analysis comparing the two drugs.

All in all, I therefore doubt that generic NVP is going to have a whole lot of influence on HIV prescribing in the United States. Those who are on branded NVP and doing well will switch to it (or more accurately, “be switched to it”) saving some drug costs.

But when efavirenz goes generic — some time next year or the year after? — that will be big news. And raise all kinds of interesting questions.