The nevirapine case
The present article was written in an attempt to put a little order to the situation, starting with a chronicle of the NVP case, and then placing the use of this drug in a correct context.
October 2004: A brief chronicle of the NVP case
Over the years, NVP has been marked down as being less powerful than the other agent from the same drug class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV; Sustiva®). Specifically, comparing different widely commented studies seemed to reveal that in people who have yet to start treatment and with a basal viral load (at treatment initiation) above 100,000 copies/ml, EFV was more effective than NVP. This idea has become so accepted that some governmental health agencies in Europe, for instance in Spain, have excluded the use of NVP as a firstline option in favor of EFV as far as NNRTIs are concerned, in people with a high viral load.
However this was in complete contradiction with clinical practice in this country, where NVP has been largely prescribed, and this despite warnings on the drug’s hepatotoxicity (see below) and the high number of people coinfected with HIV and hepatitis C virus (HCV).
The manufacturer of NVP, the German multinational Boehringer-Ingelheim (BI), has insisted that the studies evaluating EFV and NVP separately were not comparable. If this was so, a head-to-head protocol between the two non-nucleosides was needed. The 2NN study results made public at the Retrovirus Conference 2003 show data that have been presented over and over again to the public in several ways, but with the same conclusion: NVP is equally effective as EFV, including in people with a high basal viral load.
December 2004: A star reporter or a falling star?
Boehringer-Ingelheim’s happiness only lasted a few months. In December, the Associated Press published a series of articles written by a journalist called John Solomon, that uncovered a potential scandal: in Africa and under the context of a study, pregnant women had been given a drug to avoid mother–to-child transmission of HIV infection that had deadly effects and could cause the mothers to develop resistance to HIV drugs. On top of all of this the participants were not even informed on the possible risks to their health. The drug in question was nevirapine.
These notes referred to the HIVNET 012 study held between 1997 and 1999 in Uganda, and whose results, later confirmed by many other studies, established the current standard for the prevention of mother-to-child HIV transmission in developing countries: one dose of NVP for the mother and another for the baby before 72 hours have passed after the birth. The expansion of its use has caused an amazing decrease in the number of newborns with HIV in many areas of the developing world.
The issue never came to light until BI tried to register NVP in the USA for the prevention of HIV vertical transmission. The health authorities began to review the study protocols and found many errors in the data collection and follow-up processes. This information was given by Jonathan M. Fishbein, an employee of the U.S. National Institutes of Health (NIH) who was later fired, and published on the Internet at www.honestdoctor.org. On the other hand, it seems there is no report that women received information that the drug they were taking put them at a great risk of developing resistance to all the other NNRTIs available: HIV transmission to the child was prevented, but at the expense of the mother having her treatment options reduced, if she had access to them.
Yet there is more. Solomon also reported about the case of a pregnant woman in Memphis (Tennessee, USA) who died in 2003 while taking NVP as part of her antiretroviral regimen in the context of another mother-to-child prevention study, and related it to the Ugandan trial. In reality the two things have nothing to do with each other: the U.S. patient suffered from an inflamed liver and Stevens-Johnson syndrome. Those are two adverse effects which commonly occur in the first weeks of taking NVP. They are easily recognized and easily treatable by stopping the treatment when the first symptoms are noticed, which is something that has been well known since 2003. The case was actually one of medical negligence.
Together with the protocol violations -that in no way tainted the final conclusions of the study, as Fishbein himself admitted-, and the avoidable death of a patient from Tennessee, Solomon and his agency believed they had an exclusive piece of news: the U.S. government had promoted a drug in Africa with terrible side effects, life-threatening and causing resistance.
January 2005 (part one): Don’t let reality ruin a good piece of news!
Press agencies began to spread the news of the ”scandal“ created by Associated Press and it quickly shot through the Internet like a bullet. Amongst the printed press a good example is that of Spain where newspapers like La Vanguardia, El Mundo and El PaÃÂs translated and edited Solomon’s piece of news without even crosschecking data, which created an unnecessary commotion among those who were taking NVP as part of their antiretroviral regimen. This appears to have also occurred in other countries throughout Europe.
The articles made NVP look like nothing more than a lethal venom with almost no beneficial factors. This was and will always be an unfounded assertion, and a very irresponsible thing to do. In fact, members of the South African Government, encouraged by the AIDS denialists, took advantage of the situation to place new doubts on the benefits of access to antiretroviral drugs to one of the most HIV/AIDS affected populations in the world.
January 2005 (part two): Activists’ move to stop the panic
Activists had to urgently write press releases and make declarations to the medias that were willing to listen to them. As an example, the veteran community activist John S. James in New York reminded everybody that: ”everyday 1,800 babies are born with HIV, generally to women who have no available treatment for themselves or to prevent the transmission of the infection to their children. There is no reason to doubt that the one-time dose of nevirapine works and can stop half of the transmission cases. If we take into account the resistance issue, the one-time dose of NVP is not the best first option, but sometimes it is the only possible one“.
Continuing with the Spanish example, on January 25th the newspaper El PaÃÂs finally published a letter by Pablo Rivas, from the Development NGO Doctors of the World, in which the latter stated that: ”nevirapine [...] has been used for many years in developing countries in order to prevent mother-to-child transmission of HIV infection. Also it is commonly used by thousands of patients in our country and the rest of the world. We believe that the tone of this article on the dangers of this drug may have deeply worried its users and organizations like Doctors of the World that conduct mother-to-child prevention programs based on this treatment.“
There were many more reactions, but all of them will not fit in this article.
January 2005 (part three): A new warning on an old topic
To stop the tornado of information, the U.S. Food and Drug Agency (FDA) published an official warning in which it is recommended not to prescribe NVP in women with CD4 counts above 250 cells/mm3. The reason being that symptomatic liver toxicity are more common with NVP than other antiretrovirals.
Indeed, follow-up data indicates that people with high CD4 counts are more at risk of experiencing liver toxicity if they start NVP. Furthermore, women are at a three-time higher risk than men of developing symptomatic liver toxicity, and women with a CD4 count higher than 250 cells/mm3 are at a twelve-time higher risk of experiencing symptomatic liver toxicity than women with a CD4 count lower than 250 cells/mm3 (11% versus 0.9%).
When it happens, liver toxicity usually appears during the first weeks of treatment and is detected by transaminase level elevations and at least one moderate to serious symptom (rash or symptoms similar to those related to the flu or a high fever).
In reality, the FDA was not giving more than an already known precaution message: one year earlier, in January 2004, and on the insistence of the regulatory organization, Boehringer-Ingelheim had sent a letter to doctors warning them on these risks that we have gradually been getting news of.
Epilogue
Nevirapine, which was the first non-nucleoside on the market, may have passed its moment of glory, but it is still a viable treatment alternative. Not everybody tolerates well protease inhibitors or the effects of EFV on the nervous system, for example.
The adverse effects of NVP are well known, and extreme cases are very rare, easily recognized, treatable and do not happen with one single dose. Generally, symptoms disappear when NVP is interrupted and only in some very exceptional cases have they remained after the drug’s interruption.
If you are taking NVP as part of you antiretroviral treatment, there is no reason to be alarmed. As in the case of any other drug, a regular follow- up and talking with your doctor will help control possible problems.
Joan Tallada
EATN - European AIDS Treatment News, Volume 13, I – Spring 2005
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