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[e-drug] AP story puts antiretroviral programmes at risk

E-DRUG: AP story puts antiretroviral programmes at risk
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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. 

See: 
http://www.guardian.co.uk/uslatest/story/0,1282,-4673434,00.html
http://www.newsday.com/news/local/state/ny-bc-ct--aidsdrug1214dec14,0,1412100.story?coll=ny-region-apconnecticut
http://www.guardian.co.uk/worldlatest/story/0,1280,-4671613,00.html

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 
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 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 
square one."

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: 

http://www.pedaids.org/press_release_nevirapine_december_14_2004.htm;
http://www.niaid.nih.gov/Newsroom/Releases/global_stratgies.pdf
http://www.niaid.nih.gov/newsroom/Releases/project_inform.pdf

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 
sites. 

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 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 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 
patients about.

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 
http://www.aidsmap.com/en/news/C24D11DE-1C19-48B0-A216-1A62B1DADA9F.asp
http://www.aidsmap.com/en/news/09A83419-9455-438E-9481-318A4F6D58F5.asp
http://www.aidsmap.com/en/news/C1316A81-32F9-4AA9-A94F-93E3EB4E0D0E.asp

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.

>>Nevirapine resistance

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 
http://www.aidsmap.com/en/news/1E48C7B9-97EC-4FC8-B6EB-6435E0707609.asp . 

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 
http://www.aidsmap.com/en/news/24D285A4-1292-4306-A68A-45BE5ABBF2A9.asp).

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. 

-------------

ABOUT HIV & AIDS TREATMENT IN PRACTICE
*****************************************
'HIV & AIDS Treatment in Practice' is an email newsletter for doctors, nurses, 
health care workers and community treatment advocates working in 
limited-resource settings.

It is published twice every month by NAM, the UK-based HIV information charity 
behind www.aidsmap.com, in partnership with the Saint Stephen's AIDS Trust and 
the International HIV/AIDS Alliance.

The newsletter is edited by Theo Smart (Durban) and Keith Alcorn, NAM's Senior 
Editor (London).

For further information: 
http://www.aidsmap.com/en/docs/3AE9A2A9-558D-4319-A9E7-C9B896A67784.asp

===============================================================
    
Copyright NAM Publications 2004. All rights reserved. 
=============================================================== 

__________________________________________________


Leela McCullough, Ed.D.
Director of Information Services

SATELLIFE
30 California Street, Watertown, MA 02472, USA
Tel: +617-926-9400    Fax: +617-926-1212
Email: leela@healthnet.org
Web: http://www.healthnet.org


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