E-DRUG: AP story puts antiretroviral programmes at risk
Reproduced, for non-commercial use, from:
HIV & AIDS Treatment in Practice #38, December 22, 2004
MAIN ARTICLE: Associated Press story puts antiretroviral programmes at risk
By Theo Smart
Officials of the US National Institutes of Health (NIH) have been accused of
covering up flawed research on the use of nevirapine in the developing world.
The allegations, made in an "exclusive" series of articles published last week
by John Solomon of the Associated Press (AP), concern the pivotal HIVNET 012
trial conducted in Kampala, Uganda.
HIVNET 012 was the first clinical study to show that giving a single dose of
nevirapine (sdN) to both mother and baby was a very safe and effective way to
prevent the mother to child transmission (PMTCT) of HIV.
Since the first edition of HATIP in March 2003, many other studies have
explored the optimal PMTCT regimen and HATIP has spent much of the past year
discussing these studies and more recent nevirapine data. We should note that
many of the clinicians and treatment advocates on our advisory panel have
voiced concerns about the ongoing use of sdN used described by the HIVNET 012
study. But it is a complex issue, and one that is only tangentially addressed
in the AP series on HIVNET 012 - which seems more intent on uncovering a US
In fact, the AP report simply rehashes old news and appears, to this writer at
least, to be deliberately misleading. A cynic could see the NIH story as kind
of a me-too series, drafted to take advantage of current hullabaloo in the
States over the perceived failure of the Food and Drug Agency to protect the
public from the dangers of approved marketed pharmaceuticals such as Vioxx.
Like the FDA issue, the NIH/HIVNET story even comes with its own
"whistle-blower," the disgruntled consultant hired by the NIH to review the
HIVNET 012 study and who has now set up his own website www.honestdoctor.org.
Regardless of whether the AP NIH articles are really news or not, the alarm the
story has spread is genuine enough. What's worrisome is that such fearmongering
has a way of snowballing and taking on a life of its own.
Accepting the allegations as fact, some web-based blogs/newsgroups have
concluded that the US used Africans as guinea pigs in the study, and writers
have decried nevirapine PMTCT programmes as modern day Tuskeegee experiments.
Meanwhile, in South Africa, the report plays into the hands of AIDS denialists
in the government who would like to turn back the roll-out of antiretroviral
drugs in the public health sector. TAC activist Zachie Achmat says the drive to
provide antiretroviral treatment in that country is danger of "going back to
And back in the US, also apparently believing the AP story, Jesse Jackson has
reacted with outrage, issuing a press release declaring that the NIH officials
have conducted "a crime against humanity" and accusing the Bush administration
of trying to foist a "deadly drug" upon Africa.
According to the NIH: "As a result of distortions of facts resulting from the
recent press reports concerning nevirapine and the HIVNET 012 trial, there is a
real possibility that physicians and health care providers in developing
countries will not use the lifesaving single-dose nevirapine regimen to block
mother-to-infant transmission of HIV in situations where there are no other
options, such as multiple drug antiviral treatments."
Community-based advocacy organizations agree and are desperately trying to set
the record straight. See:
The AP NIH story misconstrues so many facts that it is difficult to tackle them
all, but we will try to address some of the key points.
>>Data management issues in HIVNET 012
The AP report starts off by claiming that, in 2002, "top U.S. health officials
were warned that research on the key drug was flawed and may have underreported
thousands of severe reactions, including deaths."
The study in question, HIVNET 012, began in 1997 and results from the trial
were published in the Lancet in 1999. At that point, the NIH and much of the
HIV treatment community were already well aware that there were record keeping
inconsistencies in HIVNET 012. The issue also kept cropping up whenever the
South African government made a case against supplying the drug to pregnant
women through the public health system.
The data management problems did not affect HIVNET 012's primary conclusions.
They also should not be interpreted to mean that single dose nevirapine caused
any serious side effects - though that is what the AP article implies.
According to the NIH press release: "This implication is absolutely false.
Remonitoring reports of HIVNET 012 found no additional serious adverse
reactions related to nevirapine. The original published study and the multiple
subsequent reviews of the HIVNET 012 trial that have carefully scrutinised its
data have found only a very small number of serious adverse reactions that
potentially might be due to nevirapine."
In the 320 infants who received nevirapine, 35 infants experienced serious
adverse events, only two of which were thought to be "possibly" due to
nevirapine. Of the 306 mothers who received nevirapine, 16 experienced serious
adverse events, and only one was thought "possibly" to be due to nevirapine.
The safety of single dose nevirapine has subsequently been confirmed by half a
dozen other studies.
The 2002 "warnings" referred to in the AP article, came about when
Boehringer-Ingleheim became interested in applying to the FDA for an expanded
indication to allow nevirapine to be prescribed for PMTCT in the US because of
the unexpected benefit seen in the study.
As part of the evaluation of the HIVNET 012 trial for this new indication,
NIAID and NIH initiated several reviews and re-reviews of the study and
investigated whether the data could be "cleaned up" to meet the rigorous
standards the FDA requires in order to consider a drug for approval. It could
not and it was too late to retrofit the study.
This resulting analysis of the "procedural flaws in the study" led NIAID to
make changes in how it conducts collaborative research with international
These changes are not always welcome - fulfilling American regulatory
requirements is not usually the first priority of HIV clinicians and
researchers treating HIV patients abroad.
>>The "Cover up"
The AP story also claims that the procedural flaws in HIVNET 012 were
deliberately concealed so as to not detract from President Bush's public
relations/AIDS funding tour of Africa. Email quotes used to justify such claims
in the piece don't provide enough context to be certain what the NIH officials
actually were saying. Again, it is left up to the reader to infer that the
officials' comments are in support of the authors assertion. Full transcripts
of the emails would have been more telling.
But what would have been the point in a cover up? Most of the news on HIVNET
012 procedural problems was already out there. Furthermore, support for sdN as
PMCTC no longer rested solely on the HIVNET data. Several other studies had
already validated HIVNET 012 primary conclusions.
Besides, nevirapine-based PMTCT programmes were really only a small part of the
President's projected $15 billion Emergency Plan For AIDS Relief (PEPFAR).
In fact, if the aim of the AP NIH series was to criticise the Bush
administration's AIDS efforts, they should investigate whether the President
intends to stick to his five year funding promise given the costs of the war on
Iraq and calls for reducing the US government's budget deficit.
And given that there have been no significant serious adverse event findings in
any of the sdN studies or clinical use of the drug in thousands of women, the
conclusion by NIH officials, that the safety concerns about single doses of
nevirapine were overblown, seems a fair one, especially in light of the
potential benefit that a simple, inexpensive and discreet option for PMTCT
could offer women and infants in resource limited settings.
>>A death in Memphis
Without any evidence that sdN is associated with serious toxicity, the AP
recounted the tragic story of a pregnant woman who died in a different study of
nevirapine. Her death was probably due to a side effect that only occurs in
some patients who take the drug over an extended period of time.
Continued administration of nevirapine can be associated with certain
life-threatening side effects, namely Stevens Johnson Syndrome and serious
liver inflammation - both of which may be the result of severe allergic
reactions to the drug.
Reports of nevirapine's liver toxicity first began to surface in 1999 and 2000.
By 2000, regulatory authorities in both Europe and the US issued warnings about
The greatest risk of liver toxicity occurred in the first six weeks of
treatment and the regulatory agencies recommended that patients should receive
liver enzyme monitoring at baseline and every two weeks during the first month
of treatment and regularly thereafter. If any moderate or severe abnormalities
in liver enzymes occur, nevirapine should be interrupted immediately.
The woman in question entered a PMTCT study in Memphis, Tennessee in 2003 - at
a time when enough was known about nevirapine's risks that her death should
have been avoidable.
It is not clear whether she was adequately advised of the early signs of this
side effect. The AP article points out that the toxicity is first mentioned on
page 6 of a sixteen-page informed consent form - however it was the very first
nevirapine-related potential adverse event that the consent form warned
What is clear is that the trial site failed to check the results of her liver
function tests when they should have.
Her death was truly heartbreaking and senseless. But it has little to do with
the HIVNET 012 story, other than to serve as a cautionary tale of what can
happen if clinical research is not held to the highest of standards.
Four weeks of a drug, any drug, is usually very different from a single dose of
the drug. One cannot deduce harmful effects of a short-term course of
nevirapine based on studies that examine long-term, continued use of the drug.
Furthermore subsequent data suggest that the toxicity is more likely to affect
patients with higher CD4 cell counts (above 250) or percentages (above 25%).
Inherited characteristics may also play a role.
For more on the risks of toxicity on extended nevirapine see
The fact that nevirapine is very safe when administered as a single dose
appears to have been lost on many readers of the AP NIH story.
The only real danger in the ongoing use of sdN as PMTCT is that it could lead
to the development of resistance to nevirapine and the related drug efavirenz
in some patients. Resistance has been observed in the virus of some patients
exposed to just a single dose of nevirapine. Earlier this year, data from a
clinical study also showed that some women who took sdN had a less robust
virologic response to subsequent antiretroviral therapy (see
Some experts quite reasonably fear that the use of sdN could significantly
limit future treatment options for a woman - and if infected despite PMTCT,
possibly her infant as well.
This danger is cited in the AP story but it isn't really discussed at any
length. But this too, needs to be put in perspective.
Persistent resistance (lasting more than a few months) has only been observed
in a minority of patients - and is only really relevant in those in need of
immediate treatment. Furthermore, preliminary clinical data suggest that
resistance can be avoided simply by adding Combivir to sdN for four to seven
days after childbirth.
But more study is needed to see whether this is a feasible and effective option
for most women in resource limited settings (see
Combination therapy not always a woman's best option
It is a mistake to thing that sdN is a lower standard of care foisted upon the
developing world simply because it is cheap.
There are many other reasons besides expense that make the initiation of longer
and/or more complex antiretroviral regimens for PMTCT difficult in many parts
of the world.
First and foremost, not all pregnant women with HIV need to go on
antiretroviral therapy for their own health. Many don't want to make their
pregnancy more challenging with combination antiretroviral therapy -
particularly if they have low viral loads anyway (and are thus less likely to
transmit the virus to the infant).
Other women only discover their infection as they go into labour and there is
no time to start combination therapy before delivery
Still others must first to deal with issues at home such as bias and HIV
disclosure and cannot risk being caught taking antiretroviral medications by
potentially violent husbands or others.
For all of these women, sdN may represent an attractive option for PMTCT. Their
interests are not well served by irresponsible journalism that implies that the
strategy is neither safe nor effective when a large body of evidence shows that
it is. Until better options are found or can be administered, sdN should
continue to be made available for women who want to prevent the transmission of
HIV to their infants.
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