Associated Press story puts antiretroviral programmes at risk
Reproduced, for non-commercial use, from:
HIV & AIDS Treatment in Practice #38, December 22, 2004
By Theo Smart
Officials of the US National Institutes of Health (NIH) have
been accused of covering up flawed research on the use of nevi-
rapine in the developing world.
The allegations, made in an "exclusive" series of articles pub-
lished last week by John Solomon of the Associated Press (AP),
concern the pivotal HIVNET 012 trial conducted in Kampala,
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 stud-
ies 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 tangen-
tially addressed in the AP series on HIVNET 012 - which seems
more intent on uncovering a US government scandal.
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 per-
ceived 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 sec-
tor. TAC activist Zachie Achmat says the drive to provide anti-
retroviral 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 re-
sulting from the recent press reports concerning nevirapine and
the HIVNET 012 trial, there is a real possibility that physi-
cians 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 treat-
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
>>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,
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 al-
ready 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 abso-
lutely false. Remonitoring reports of HIVNET 012 found no addi-
tional 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 experi-
enced 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 con-
firmed 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 pre-
scribed 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 re-
search with international sites.
These changes are not always welcome - fulfilling American regu-
latory 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 reduc-
ing 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 poten-
tial benefit that a simple, inexpensive and discreet option for
PMTCT could offer women and infants in resource limited set-
>>A death in Memphis
Without any evidence that sdN is associated with serious toxic-
ity, 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 danger.
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 regu-
larly thereafter. If any moderate or severe abnormalities in
liver enzymes occur, nevirapine should be interrupted immedi-
The woman in question entered a PMTCT study in Memphis, Tennes-
see 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 patients
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 lit-
tle 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
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 dis-
cussed at any length. But this too, needs to be put in perspec-
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
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 ini-
tiation 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 anti-
retroviral therapy - particularly if they have low viral loads
anyway (and are thus less likely to transmit the virus to the
Other women only discover their infection as they go into labour
and there is no time to start combination therapy before deliv-
Still others must first to deal with issues at home such as bias
and HIV disclosure and cannot risk being caught taking antiret-
roviral 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 con-
tinue to be made available for women who want to prevent the
transmission of HIV to their infants.
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