Generic Nevirapine Now Available -- But the Big One Is Next Year

May 25, 2012

Paul E. Sax, M.D.

Paul E. Sax, M.D., is director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston.

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that didn't stop it from being front page news -- and more -- which made it all the more heartbreaking when the paper was retracted 6 months later.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.

Paul Sax is Clinical Director of Infectious Diseases at Brigham and Women's Hospital. His blog HIV and ID Observations is part of Journal Watch, where he is Editor-in-Chief of Journal Watch AIDS Clinical Care.

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Reader Comments:

Comment by: Elliot (Brussels, Belgium) Thu., May. 31, 2012 at 4:59 pm UTC
I'd just like to put in a good word for NVP. I've been on it for 10 years now, with excellent results and no side effects whatsoever. For whatever reason (perhaps financial?), NVP seems to be much more widely used and accepted in Europe than in the US. The level of government involvement here regarding health care is much higher, resulting in a generally better health care system for virtually all people living here, and this applies equally to people with HIV/AIDS. When I hear stories about how some drug is "superior" or "inferior" in the US, and then discover that the opposite opinion (and all opinions are supposedly based on "facts" and "research") predominates in Europe, I have to wonder what other factors (economic, social, cultural, or even political) are at play in determining these evaluations. Based on my own experience and the information provided to me by the very competent doctors and hospitals here, I must say that, whatever the reasons mentioned above for NOT taking NVP, I for one will continue to use it (the "Don't fix it if it ain't broken" philosophy) and support its use as a first-line HAART therapy.
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Comment by: Grace (Germany) Sun., Jun. 3, 2012 at 2:02 pm UTC
I completely agree with you. It is also working well for me.The side effect was very mild at the beginning-just some rashes that disappeared within a week.The drug was administered the right way and I have been on it for 10 years in combination with two other drugs.I am doing perfectly well and looking forward to a healthier future.
Comment by: Mike (Los Angeles, California) Thu., Jun. 7, 2012 at 1:05 am UTC
For 9 years. NVP has very successfully suppressed my VL with no problems or side effects (that I know of).

Comment by: Cassandra Tue., May. 29, 2012 at 3:35 pm UTC
Not as educated or as optimistic as you, but the only "interesting question" I forsee is whether Gilead will first renew its patent on Truvada or triple its price, thus making most of this excitement moot.
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