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Single-Dose Theory

November/December 2004

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Like a tsunami propagating across oceans, political shockwaves reverberated across continents as news broke in December 2004 about a U.S. government official's alleged cover-up of faulty data from an African AIDS trial of single-dose nevirapine to prevent mother-to-child transmission of HIV. The accusation, made by a disgruntled employee turned whistleblower at the National Institutes of Health (NIH), was quickly trumpeted by political figures as evidence that Africans had been made unknowing guinea pigs in a vast experiment with an unproven and unsafe drug.

Facing a media spasm of confusion, misinformation and opportunism, representatives of the HIV research and activist communities desperately tried to correct the facts, fearing an irrational backlash against a simple and affordable treatment that had saved possibly hundreds of thousands of newborns from HIV infection and early death. At stake was the future of one of the few successful programs for intervening in the runaway world AIDS crisis. Or was it?

HIV/AIDS is a slow but persistent disaster, washing over the continents of Africa and Asia with the deadly impact of a new tsunami every few weeks, killing 8,000 people per day, leaving decimated families and legions of orphans in its wake. Children are especially hard hit. An infected infant in a resource-poor setting will likely suffer from intestinal illness and poor nutrition and will generally lack access to pediatric formulations of antiretroviral (ARV) medicines, even in the few places where drugs are available for the parents. Few live to be five. Without treatment, about one in four infected mothers will deliver an infected infant. A baby fortunate enough to be born without HIV runs a high risk of acquiring the virus during the first few months of life if breast-fed by an untreated mother. With nearly 2,000 infants infected each day, the search for practical interventions to reduce this number has been a passionate quest.

One of the most important early government-sponsored HIV studies investigated using an ARV during pregnancy to reduce the risk of a mother passing the virus to her child. The trial, ACTG 076, reported its dramatic findings in 1994: using AZT during the last six months of pregnancy and during the first six weeks of the infant's life could reduce mother-to-child transmission (MTCT) of HIV by nearly two-thirds. The results immediately changed the standard of care for women with HIV in the U.S. and Europe and rates of infections at birth soon plummeted. But the AZT regimen called for diagnosing the mother's HIV status and starting treatment as part of routine prenatal care. What about women who do not have access to pre-natal care? What about women with HIV who only appear for medical attention on the day they go into labor? What about women who give birth at home?

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About half of mother-to-child HIV infections occur during labor and delivery; about 15 percent to 20 percent occur earlier in the pregnancy; and the rest occur through breast-feeding. Research has shown that the risk of transmission during labor and delivery is strongly associated with the mother's viral load, and that reducing viral load temporarily -- for example with a single dose of nevirapine -- can reduce the risk by about half. Other drug regimens with longer dosing durations can reduce the risk further and regimens that extend therapy to the mother and baby during the initial months of breast-feeding can lower infection rates even more.

In 1997, a study was designed to test a drug that could be given as one pill to the mother during labor and one pill to the baby, for use in situations where the standard regimen was not feasible. The drug to be studied, nevirapine, was selected because it was quickly absorbed and distributed throughout the body (including the neonate in utero and breast milk); because it could rapidly lower levels of detectable virus circulating in the blood; and because it had a long half-life in the body, meaning it could sustain its effective concentration throughout labor and delivery. Importantly, nevirapine, when tested in pregnant animals, had not been observed to cause birth defects. This strongly distinguished it from efavirenz, a drug in the same class as nevirapine with similar pharmacokinetic properties, but which had produced a high rate of severe birth defects when monkeys were exposed during early pregnancy.

Because AZT had made mother-to-child transmission of HIV rare in the developed world, it would be unethical and impractical to test single-dose nevirapine where proven methods were available. Since the greatest need for a simpler regimen for prevention of mother-to-child transmission (PMTCT) was in Africa, a "proof of concept" study was designed by researchers from Johns Hopkins University to compare single-dose nevirapine with a short course of AZT in 600 mothers in Kampala, Uganda. The trial was called HIVNET 012.

It was a great day when interim results were published in 1999 showing that single-dose nevirapine could reduce MTCT by half during the first 14-16 weeks in a breast-feeding population at a cost of about $4.00. Soon, a crusade was launched to bring the drug to every village and township. But nothing is as wonderful as it seems and the rollout of PMTCT has been painfully slow. It is estimated that less than five percent of women who will need PMTCT treatment in 2005 will have access to it.


Resistance Is Fatal

South Africa, a country with one of the world's most explosive HIV epidemics has suffered through one of the least rational responses to the threat. President Thabo Mbeki has said publicly on several occasions that he does not believe HIV is the cause AIDS. He is suspicious of what he sees as Northern pharmaceutical solutions to African problems and is wary of a conspiracy by multinational companies to dump their poisonous products on his people. For several years he and his health minister actively resisted allowing PMTCT programs to operate in South Africa until lawsuits brought by the country's Treatment Action Campaign (TAC) finally forced the government to begin treating its citizens. PMTCT programs, including some that use nevirapine, are now underway in some parts of South Africa. But a long propaganda campaign against them makes assuring the continuation and expansion of treatment in South Africa a constant struggle for TAC. Bad news about an AIDS drug is always big news in South Africa. Nevertheless, getting the story straight about nevirapine has been especially challenging. The non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine is used in two very different ways. Single-dose nevirapine, as is used for PMTCT, is generally accepted as safe and nontoxic. Indeed, there are proposals to treat all pregnant women with the drug in circumstances where HIV prevalence is high and testing impractical.

Continuously dosed nevirapine, however, used for chronic therapy for HIV infection, is another story. As blood levels of nevirapine build up with continuous dosing, some people, perhaps five percent, will have a reaction to the drug in the form of a rash or liver problems. In a small proportion of those who have reactions, if the drug is not stopped, the result can be deadly. In the words of the FDA:

"Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, has been reported in patients treated with VIRAMUNE [nevirapine]. These events are often associated with rash. Women, and patients with higher CD4 counts, are at increased risk of these hepatic events. Women with CD4 counts >250 cells/mm3, including pregnant women receiving chronic treatment for HIV infection, are at considerably higher risk of these events."

These rare but serious complications of chronic nevirapine therapy came to light after a series of tragic events, including a few health care workers who took nevirapine for post-exposure prophylaxis after a needle stick accident and subsequently died or required liver transplant. Typically, the victims were women. Part of the confusion arising from the recent news reports about the NIH "cover up" was the report of a woman in a NIH-sponsored clinical trial who continued to receive nevirapine after blood tests showed that she was having a reaction. She subsequently died. And the difficult climate for treatment in South Africa was complicated by the nevirapine-associated deaths of two women in a clinical trial there in 2000.

Although single-dose nevirapine does not lead to these kinds of serious reactions, a smoldering problem with drug resistance has started to flare up. Currently available NNRTI drugs, which include nevirapine and efavirenz (trade named Sustiva or Stocrin) have a low genetic barrier to resistance and HIV can quickly find an escape mutation if allowed to replicate in the presence of sub-therapeutic concentrations of these drugs. The problem with single-dose nevirapine is that the very long half-life that makes it ideal for reducing viral load during labor and delivery, also gives HIV a chance to start spinning off drug resistant mutants as the drug's concentration slowly tapers off. Some studies suggest that over half the women who take single-dose nevirapine may develop resistant HIV, thereby compromising their chances to someday benefit from continuous nevirapine therapy for their own health. In the starkest terms, some say that saving the baby means sacrificing the mother.


The Orphan Machine

There seem to be two fundamentalist strains of opinion in the international medical community about using single-dose nevirapine. Some say that since the drug is ideally suited for PMTCT, it should be reserved for that purpose and not rolled out in the general population as first-line therapy. Widespread population resistance, it is argued, could compromise one of the few effective MTCT interventions available. Others hold that, if nevirapine is available in affordable, fixed-dose generic forms to treat everyone, then use in single dose for PMTCT may save a child, but will ultimately doom the mother if she acquires resistance to the only practical first-line therapy available to her. Some commentators have gone as far as to suggest that there is little point in saving a child who is destined to become an orphan.

Among prevention fundamentalists these arguments take on a kind of pro-life versus pro-choice tinge, with one side championing the most innocent victims at all costs and the other protesting the treatment of women as no more than incubation vessels, consigned to the graveyard when their genetic duty is done. Most researchers involved in these issues, though, are looking for practical solutions. They admit that single-dose nevirapine has limitations but see it as the thin end of the wedge that helps a treatment program get on its feet, gives staff experience with antiretroviral drugs, provides an incentive for voluntary counseling and testing and can be replaced with more demanding regimens once capacity is built and trust is established with the community. Already, programs such as MTCT-Plus, which aims to treat the parents as well as the child, are widely considered much more sustainable solutions.

New ideas are emerging for improving the controversial regimen, such as covering the "tail" of dwindling nevirapine concentration with a few days of another antiretroviral drug, such as Combivir. But it's also becoming clear that the investment in infrastructure required to make even simple single-dose nevirapine work as well as it does in a clinical trial setting, is just as well suited for introducing more effective and less problematic regimens. This field is constantly in flux and with new data expected in 2005, the consensus about the minimally acceptable PMTCT regimen may be expected to shift.


Data Dump

In 2001, after the success of nevirapine in HIVNET 012, the drug's manufacturer, Boehringer-Ingelheim, decided to apply to the U.S. FDA to extend the approved indication for the drug from chronic use (approved in 1996) to single-dose use for PMTCT. However, problems became evident as the FDA began to examine the data collected at the Kampala study site. There were problems uncovered with how adverse events were judged and recorded. There were changes in the protocol seemingly made on the fly, without notice to the sponsor or to the participants. As the problems came to light, the NIH suspended research at the site in early 2002 while audits were conducted and procedures examined.

Although the conditions under which the trial was conducted were not necessarily unusual for that setting and may have been adequate for the limited purpose the trial set out to achieve, HIVNET 012 was never intended to provide data to support a submission to the fastidious FDA. It became clear that to obtain approval the sponsor would have to conduct another trial to back up the first. This was judged not practical and the application quietly withdrawn.

Despite the sketchy safety database in the Kampala study, audits by the FDA, Boehringer-Ingelheim and by the NIH all agreed that single-dose nevirapine did prevent mother-to-child transmission of HIV. Furthermore, there were no suggestions of safety problems in any other studies of single-dose nevirapine. Given the delicate status of PMTCT programs in South Africa, officials at the NIH felt it was important to keep the message straight: while HIVNET 012 did not supply the kind of pristine data that the FDA requires to approve a drug in the U.S., this did not mean the conclusions were flawed or that the drug was unsafe when used for PMTCT.

One of the problems the FDA found was that reports of adverse events in the study case files could not be confirmed with original hospital records. An investigator familiar with the trial site at Mulago Hospital has described the hospital's records as stacked along hallways and down a staircase in public areas, noting that these conditions were not unusual for hospitals in the developing world. It seems clear there was avoidable sloppiness in the research practices in HIVNET 012, but there were also practical limits to how strictly the investigators could adhere to ideal procedures. If the FDA's standards are to be met, in effect it will mean recreating much of the infrastructure of Western hospitals at every African site. But what would be the point of such research, some wondered, if the conditions of the research were so completely divorced from the realities of the regions they were operating in? How meaningful would the results be? More compelling perhaps is the thought of how many people would die if research stood still while waiting for the FDA's standards to be reached.

The NIH is in the process of improving its capacity to do HIV research in developing world settings by retooling its clinical trials networks to begin cooperating with international sites. On one level, this has been criticized as a "Willie Sutton" ploy, an attempt to sustain the flow of grant money to U.S. investigators by taking the research to where the patients are. Some also worry that building a high-tech research infrastructure in resource-poor regions is not a sustainable solution; that it will be vulnerable to collapse when U.S. interest inevitably shifts to other projects. But the main investment in building a quality clinical research organization is in establishing consistent procedures for performing routine medical tests and recording the data; ultimately it is about training, education and building the capacity of the staff. This may be what it takes to satisfy the FDA's standards, but achieving this level of quality is not cheap or easy. Furthermore, macro-economic factors in the developing world have tended to make retaining skilled staff difficult when there are creditor mandated caps on health care spending by governments and Northern markets for cheap skilled labor that lure employees away as quickly as they are trained.


Just Put Your Lips Together

Whistleblower Dr. Jonathan Fishbein was hired by the NIH to develop and implement quality standards for clinical research in its AIDS studies. He was trained in transplant surgery research and had worked in the pharmaceutical industry overseeing the quality of high stakes commercial research designed to secure FDA approval of new products. The cultural gap between his experience with kidney transplant medicine and conditions at the Mulago hospital must have sent him spinning. (Why the Division of AIDS (DAIDS) hired an expert in organ transplantation to monitor quality in clinical trials increasingly conducted in developing nations is not clear.) Fishbein joined DAIDS in the summer of 2003, two years after the problems with HIVNET 012 were detected and many months after the audits were completed. By that time consensus within the AIDS research community had accepted that, while some conclusions from the study were limited by flaws in methodology, the essential findings were not in dispute: single-dose nevirapine was safe and could help prevent babies from becoming infected with HIV at birth.

The Kampala research site had been closed for a year and a half while the audit was underway and was preparing to reopen about the time that Fishbein took over his position as director of the newly created Office for Policy in Clinical Research Operations. One of his first acts on the job was to question whether the site was really ready to reopen and he asked Edmund Tramont, the chief administrator of DAIDS, to let him establish his department's authority by claiming the responsibility to make the decision. In an email made public by Fishbein, Tramont implies Fishbein's role is advisory and states that he wants the Kampala site opened "ASAP because the site is now the best in Africa run by Black Africans."

Fishbein remained critical of the Kampala site and began pressing to reopen an investigation of the flaws in HIVNET 012. Tramont expressed his frustration in a brief email to the DAIDS staff, "Folks, HIVNET 012 has been reviewed, re-monitored, debated and scrutinized. To do anymore would be beyond reason. It is time to put it behind us and move on."

As is evident from internal memos released by Fishbein, Tramont was concerned about a pending visit by President Bush to the Kampala site during an African tour to promote his Emergency Plan for AIDS Relief (PEPFAR). Tramont might also have been concerned about the fragile state of NIH's capacity building efforts in Africa and about the potential damage to emerging PMTCT programs in South Africa and elsewhere if the situation was not carefully managed. Jonathan Kagan, Tramont's deputy, advised him to let Fishbein conduct his investigation lest it appear that it "look like we have something to hide." Furthermore, Kagan wrote, "We should NOT be motivated by political gains. ..."

At some point during the initial 16 months of his employment, Fishbein apparently learned that he was to be fired before his two-year probationary period ended. To protect his job (at a reported salary of $178,000 per year -- stratospheric by NIH standards) Fishbein invoked the Federal Whistleblower Protection Act, intended to shield employees who uncover government waste, fraud and abuse. He claimed he was the victim of retaliation after refusing to go along with a cover-up of the flawed study, which, he later testified, could have "fatal implications." An NIH spokesperson said he was being fired for "poor performance." Fishbein's bid for whistleblower status was denied by an administrative law judge in November and he went public with his charges in a series of Associated Press articles in mid-December. Fishbein says he is simply trying to defend his reputation and that his exposure of the cover-up at NIH should be seen as a public service. He makes this case on his website, HonestDoctor.org, with a list of 19 allegations, including sexual harassment and bid rigging.

When the story broke, reaction was swift. Senator Charles Grassley called for a Justice Department Investigation. Jesse Jackson called it a "crime against humanity" and said, "Research standards and drug quality that are unacceptable in the U.S. and other western countries must never be pushed onto Africa. We should stop discounting the lives of Africans." Most ominously, the South African ruling party, the African National Congress (ANC), published an attack on the NIH accusing them of conspiring with Boehringer-Ingelheim to promote the sale of nevirapine in Africa, treating Africans like "guinea pigs." The article was unsigned, but President Thabo Mbeki was assumed to be supportive of the paper's conclusions. The ongoing PMTCT programs in South Africa have been mandated by the courts, but it remains unclear what impact this episode may have on their future.

Lies and misinformation are difficult to call back once launched, especially when they are tied to inflammatory rhetoric. Unfortunately, the fallout from Fishbein's bid to keep his job may end up killing far more people than nevirapine ever will.


From a Statement by the Treatment Action Campaign (TAC), South Africa

It is critical that public confidence in a life-saving treatment used in many public facilities throughout South Africa and the developing world should not be undermined without due cause. Therefore, the TAC points out the following:

  • All available evidence demonstrates that nevirapine is safe and effective for single-dose mother-to-child transmission prevention.

  • Evidence confirming the safety and efficacy of nevirapine for mother-to-child transmission when used as a single-dose or in combination with other antiretrovirals comes from multiple trials around the world including ones conducted in South Africa, Thailand and Uganda.

  • Tens of thousands of pregnant women and infants have taken single-dose nevirapine. Not a single life-threatening adverse event has been recorded.

  • No new evidence has been offered to question the safety and efficacy of nevirapine for single-dose mother-to-child transmission prevention following the news story that has broken in the last two days. The questions raised relate to the conduct of the NIH.

  • It is however more effective to prevent mother-to-child transmission using a combination of antiretroviral medicines which may include nevirapine. Where possible, clinics and hospitals should switch over to combination therapy. This has been done in the Western Cape but is occurring too slowly in the rest of South Africa.

  • Single-dose nevirapine is associated with a resistant strain of HIV developing in a high percentage of women. However, it is not clear if this has a long-term consequence for the ARV treatment regimens available to such women when they begin treatment, or if other commonly used but more effective regimens are subject to the same problem.


Back to the GMHC Treatment Issues November/December 2004 contents page.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 

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