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Past Issues
Volume 18, number 11/12
November/December 2004
Single-dose Nevirapine
Will whistleblower flap kill kids?
Birth, Death and Resistance
In Between
Emerging data on response after single-dose exposure
The Limits of Simplicity
Disappointing data on simple PMTCT regimen in the field
Four More Years
Outlook for HIV/AIDS Policy during second term
Goal is Better Access to Better
Therapies
Pediatric AIDS Foundation on single-dose nevirapine
More on Resistance
Statement from Global Strategies for HIV Prevention
The Rolls-Royce and the Túk-Túk
Gregg Gonsalves on research standards for the developing world
Single Dose Theory
By Bob Huff
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
(Viramune) 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 prenatal
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?
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 (now about 27 cents). 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
of 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 an 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.
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 aim 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 in flux, and new data expected in 2005 will likely help
shape the consensus about the minimally acceptable PMTCT regimen.
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; and the outcome of too
many patients was simply unaccounted for. As these 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 FDA application was quietly withdrawn.
Despite the sketchy safety database in the Kampala study, audits
by the FDA, Boehringer-Ingelheim, and 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 re-creating
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.
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. Fishbein joined the Division of
AIDS (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 e-mail
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 e-mail to the DAIDS staff: "Folks,
HIVNET 012 has been reviewed, re-monitored, debated and scrutinized.
To do any more 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 "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 learned that he would not be rehired at the end of his
two-year probationary period. 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 2004. Fishbein said he was simply trying
to defend his reputation and that his exposure of the cover-up
at the NIH should be seen as a public service.
He makes this case on his Web site, HonestDoctor.org, with a list
of 19 allegations, including sexual harassment and bid rigging.
When the story broke, reaction was swift. Sen. 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 used for political effect are difficult
to call back once launched, especially when they are tied to inflammatory
rhetoric that feeds on fear. The danger in this case is that the
fallout from one person's fight to save 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.
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Single-dose Jeopardizes
Long-term Therapy
By Polly Clayden
HIV i-Base
Results from a Thai study (PHPT-2) designed to evaluate whether
greater mother-to-child transmission efficacy could be gained by
adding single-dose nevirapine to standard zidovudine prophylaxis
found that efficacy came with the risk of resistance.1
In the study, 1,844 women were enrolled and mother and infant
pairs randomized to three arms: single 200mg nevirapine dose to
the mother in labor and 6mg to the baby within 72 hours of birth
(the nevirapine-nevirapine arm); nevirapine dose to the mother
and placebo to the infant (nevirapine-placebo) and both mother
and baby receiving placebo (placebo-placebo). Additionally all
mothers received zidovudine from 28 weeks of gestation and infants
one week of zidovudine and formula feeding. The study endpoint
was HIV infection of the infant.
Presenting author Marc Lallemant reported that the placebo-placebo
arm was discontinued following the trial's first interim analysis
due to the highly significant 80% reduction in transmission among
those receiving the additional drug: 1.1% in the nevirapine-nevirapine
arm and 6.3% in the placebo-placebo arm (p=0.00026). Subsequent
analysis showed that transmission rates between the nevirapine-nevirapine
and the nevirapine-placebo arms did not differ dramatically: 2.0%
and 2.8%, respectively.
Subsequent Treatment Compromised
In a second presentation, Gonzague Jourdain assessed the effect
of nevirapine exposure in PHPT-2 on the response to subsequent
NNRTI-containing HAART regimens.2 Genotypic analysis
was performed on 90 randomly selected, 12-day postpartum samples
from trial participants. Eighteen percent of the women sampled
were found to have detectable NNRTI mutations.
Ultimately, 25 percent of the women who participated in the PHPT-2
study initiated antiretroviral therapy and subsequently received
an NNRTI-containing regimen (nevirapine/3TC/d4T). Of the 255 women
who started HAART, 42 had not, and 213 had, been exposed to nevirapine.
At six months, 75% of the unexposed, 53% of the exposed/no detectable
mutations and 34% of the women exposed/with detectable mutations
had a viral load below 50 copies. Initiation of therapy six months
or more after nevirapine exposure was associated with a modest
but non-significant improvement in virological response.
In a comment from the floor after this presentation, John Mellors
remarked that these findings echoed those from ACTG 398, in which
patients receiving efavirenz-containing regimens had responded
less well if previously exposed to an NNRTI, even without detectable
resistance.3 These reports suggest that prior NNRTI
exposure can select minor resistant variants not detectable by
standard genotype assays, but which can nevertheless contribute
to the failure of subsequent NNRTI-containing regimens.
Problem May be Widespread
In a surveillance study nevirapine resistance in Kwazulu-Natal,
South Africa, Gordon and colleagues examined nevirapine resistance
patterns in 30 mother and infant pairs (including one set of
twins) with HIV-1 subtype C who had participated in a single-dose
(to mother and infant, respectively) prevention of mother-to-child
transmission (PMTCT) program at a clinic in Hlabisa, South Africa.4
At six weeks following the nevirapine prophylaxis, 12/30 (40%)
of women and 40% of infants had detectable resistance. The K103N
mutation was the most common mutation in 10/12 (83%) of the mothers.
Other mutations reported in the mothers included: Y181C in 3/12
(25%), Y188C in 3/12 (25%), V106M in 2/12 (17%) and G190A in 1/12
(8%) Two or more mutations were found in 4/12 (33.3%) mothers.
Among the infants, the Y181N was the most common mutation and was
present in 11/12 (92%) of the children (including one of the twins).
Additionally 2/12 infants (17%) had the K103N and another 1/12
(8%) had a subtype C associated V106M mutation.
The investigators concluded: "Given the high rate of resistance
in mothers and infants after single dose nevirapine, the search
for safer regimens to prevent MTCT should be intensified."
Persistence of Resistance
A resistance substudy of the Ditrame Plus trial in Abidjan, Côte
d'Ivoire — in which women received single-dose nevirapine
in addition to short course zidovudine to reduce MTCT and the infants
short course zidovudine and single-dose nevirapine syrups — evaluated
nevirapine resistance at four weeks post partum.5,6
Baseline and four week samples were available for 63 women. The
investigators reported 21/63 (33.3%) of women had developed nevirapine
resistance at week four, with the K103N being the most common mutation.
They also reported that mothers with infected and uninfected infants
developed resistance at the same rate (33.3%), 7/21 and 14/42,
respectively. No zidovudine resistance was detected in this group.
Analysis of nevirapine plasma concentrations revealed wide inter-patient
variability with a median concentration of 648 (range 417–954)
ng/mL. Resistance was significantly associated with a higher plasma
concentration of nevirapine; among women who received two doses
of nevirapine, 3/4 (75%) acquired resistance.
Additionally, 6/26 (23%) of the infected infants developed nevirapine
resistance at four weeks post partum, and follow-up samples in
two children — one at 3 and one at 12 months old — detected
archived mutations.
The investigators note that the association between high nevirapine
plasma concentrations and resistance suggests, "That a high level
of nevirapine concentration induced a prolonged viral replication
under suboptimal drug selective pressure which promotes the emergence
of resistant strains." Concerning the infants they write: "Recent
studies have reported a negative impact of nevirapine resistance
on a subsequent treatment including nevirapine; our results raise
anxiety for those very young children presenting with resistant
viruses."
Resistance in HIVNET 012
A resistance substudy of the HIVNET 012 trial presented by Susan
Eshleman and colleagues examined the impact of HIV subtypes A
vs. D on the selection and "fading" of nevirapine associated
mutations K103N and Y181C in a group of women following a single
dose of nevirapine to reduce mother to child transmission.7 Genotypes
were obtained at 7 days and at 6–8 weeks; paired data were
available for 159 women. Of this group, 83 women had subtype
A and 57 had subtype D.
The investigators found a significantly higher overall rate of
resistance (i.e., any nevirapine mutation) at 6–8 weeks than
at 7 days, 47/140 (34%) and 31/140 (22%), respectively, in women
with either A or D subtypes (p=0.013). There was a higher rate
of accumulation of mutations for subtype D vs. A. The K103N mutation
was detected at a higher rate in the 6–8 week samples: 41/140
(29%), than the 7 day samples: 18/140 (13%), (p=0.0001) across
both subtypes. Conversely the detection rate for the Y181C mutation
was higher at 7 days than at 6–8 weeks overall, 26/140 (19%)
and 15/140 (11%), respectively (p=0.0145). The investigators added: "Furthermore,
Y181 faded quickly in subtype A with little or no fading in subtype
D."
The report suggests that nevirapine mutations are better tolerated
by subtype D HIV than subtype A and that HIV-1 subtype should be
considered in the design and interpretation of studies to determine
whether single-dose nevirapine compromises subsequent NNRTI containing
treatment.
Comment
These reports signal bad news for highly active drugs with long
half-lives, given as monotherapy (or effectively as monotherapy).
Although nevirapine resistant variants "faded" from detection
in women in HIVNET 012 by 12–24 months using population
sequencing methods, resistant variants will surely still persist
as minority variants and rapidly return when drug pressure is
reintroduced. "Fading" is an incongruous term to use in a room
full of virologists who have warned of the risks from archived
resistance for many years.
Jourdain et al. showed dramatically reduced response in women
receiving NNRTI containing regimens following acquisition of nevirapine
resistance after receiving single-dose nevirapine to reduce MTCT
(at six months 75% unexposed, 53% of exposed but with no detectable
mutations and 34% of exposed with detectable resistance were below
50 copies). Additionally when Mellors, et. al., evaluated the role
of minor NNTRI mutations, failure to achieve viral suppression
was associated with previous NNRTI experience and NNRTI mutations
at baseline. Although genotyping failed to detect NNRTI mutations
in 50/216 (23%) baseline samples in the NNRTI experienced patients,
this group performed no better than those with detectable NNRTI
resistance and much worse that the NNRTI-naïve group who similarly
showed no mutations.
Furthermore, as the Thai study demonstrated, adding nevirapine
to background zidovudine is not associated with significantly less
nevirapine resistance. The early emergence of the Y181C in HIVNET
012 may help to explain the different rates of NNRTI mutations
seen in mothers compared to infants, as previously reported. The
more rapid "fading" of the Y181C would seem to suggest that this
mutation is "less fit" relative to both K103N and wild-type virus,
at least in sub-type A virus. Better news is that no resistance
was reported for zidovudine as prescribed in the DITRAME study.
These studies confirm the efficacy of nevirapine to contribute
to the reduction mother-to-child transmission. But they also confirm
the likelihood of rapidly selecting resistance mutations when less-than-suppressive
concentrations of the drug are allowed to persist. The finding
that single-dose nevirapine exposure can negatively impact future
outcomes to such a dramatic extent should lead to a rapid change
in policy, especially in countries rolling out combination therapy.
The potential benefit of nevirapine or efavirenz as part of a subsequent
regimen for the mother must be protected, and the use of nevirapine
for prevention of mother-to-child transmission (PMTCT) of HIV restricted
to effective combinations only and with due consideration for its
prolonged clearance from the body, which varies considerably between
individuals.
This article originally appeared in: HIV Treatment Bulletin Volume
3 and Volume 5. www.i-base.org.uk
- Lallemant M, Jourdain G, Le Coeur S et al. A randomised, double-blind
trial assessing the efficacy of single-dose perinatal nevirapine
added to a standard zidovudine regimen for the prevention of
mother-to-child transmission of HIV-1 in Thailand. Program and
Abstracts of the 11th Conference on Retroviruses and Opportunistic
Infections. Abstract 40LB.
- Jourdain G, Ngo-Giang-Huong N,Tungyai P et al. Exposure to
intrapartum single-dose nevirapine and subsequent maternal six-month
response to NNRTI-based regimens. Program and Abstracts of the
11th Conference on Retroviruses and Opportunistic Infections.
Abstract 41LB.
- Mellors J, Palmer S, Nissley D et al. Low frequency NNRTI-resistant
variants contribute to failure of efavirenz-containing regimens.
Program and Abstracts of the 11th Conference on Retroviruses
and Opportunistic Infections, 8–11 February 2004, San Francisco.
Abstract 39.
- Gordon M, Graham N, Bland R et al. Surveillance of resistance
in KZN South Africa, including mother-infant pairs six weeks
after single dose nevirapine. XIII Intl Drug Resistance Workshop,
Abstract 71. Antiviral Therapy 2004; 9:S80.
- Dabis F, Ekouevi DK, Rouet F et al. Effectiveness of a short
course of zidovudine and lamivudine and peripartum nevirapine
to prevent HIV-1 mother-to-child transmission. The ANRS 1201
DITRAME Plus trial, Abidjan, Cote d'Ivoire. 2nd IAS Conference.
Abstract 219.
- Chaix ML, Ekouevi DK, Peytavin G et al. Persistence of nevirapine
resistant virus and pharmacokinetic analysis in women who received
intrapartum NVP associated to a short course zidovudine (ZDV)
to prevent perinantal HIV-1 transmission: the Ditrame Plus ANNRS
1201/02 Study, Abidjan, Cote d'Ivoire. Abstract 160. Antiviral
Therapy 2004; 9:S176.
- Eshleman SH, Wang L, Guay LA et al. Distinct patterns of selection
and fading of K103N and Y181C are seen in women with subtype
A vs D HIV-1 after single dose nevirapine: HIVNET 012. XIII Intl
Drug Resistance Workshop, Abstract 50. Antiviral Therapy 2004;
9:S59.
What is to be Done?
Adding Combivir to single-dose nevirapine for PMTCT
significantly reduces resistance
At the World AIDS Conference in Bangkok, James McIntyre
from the University of Witwatersrand, Johannesburg, South
Africa, presented an interim analysis from the currently
ongoing TOPS (Treatment Options Preservation Study). [1]
The study was originally planned to enroll 300 treatment-naïve
women and their infants and randomizes mothers and babies
to one of three arms. Arm 1 involves single-dose nevirapine
given to mothers at onset of labor and single-dose to the
baby. Arm 2 involves single-dose nevirapine to mother and
baby plus 4 days twice-daily Combivir (zidovudine/lamivudine
combined pill) to mother and baby starting during labor and
within 24–72 hours of birth, respectively. Arm 3 involves
single-dose nevirapine to mother and baby plus 7 days twice-daily
Combivir. Enrollment and informed consent is at 34 weeks
and women are randomized in labor.
The objective is to determine whether adding either 4 or
7 days Combivir can reduce the occurrence of nevirapine resistance
in treatment-naïve HIV-positive pregnant women, which
would in turn preserve their future treatment options.
At the time of this interim analysis 156 women had entered
the trial and six week resistance data was available for
61 (18, 20, 23 mothers in the single-dose nevirapine, single-dose
nevirapine plus 4 days Combivir and single-dose nevirapine
plus 7 days Combivir arms, respectively).
The investigators reported that at 2 weeks, 57.1% of the
mothers receiving single-dose nevirapine had detectable nevirapine
resistance vs. 0% in either of the other two arms. At 6 weeks,
resistance was detected in 53.3%, 5.00% and 13.6% of mothers
receiving single-dose nevirapine, single-dose nevirapine
plus 4 days Combivir and single-dose nevirapine plus 7 days
Combivir, respectively. They noted that 9/18 (50%), 1/20
(5%) and 3/23 (13%) of mothers from the three groups had
detectable resistance at any time after baseline. Overall,
resistance was detected in 50% receiving single-dose nevirapine
and in 9.3% of those receiving nevirapine plus Combivir (p=0.001).
The most frequently detected mutations at any time were the
K103N and the Y181C. There was no resistance to either zidovudine
or lamivudine.
Following these dramatic results, enrollment into the single-dose
nevirapine arm of the study was closed in June 2004. McIntyre
explained: "The trial was originally powered expecting 20%
resistance in the nevirapine arm but emerging data, notably
Neil Martinson's Retrovirus report of 39%, suggest the real
figure is much higherÉ" The trial is continuing with adjusted
sample size (150 mothers in each arm) to compare 4 and 7
days of Combivir as the optimal duration of this supplementation
is uncertain.
Polly Clayden (HIV Treatment Bulletin, Volume 5, Number
7, Aug/Sep 2004.)
1. McIntyre J et al. Addition of short course Combivir
(CBV) to single dose Viramune (sdNVP) for prevention of
mother-to-child transmission of HIV-1 can significantly
decrease the subsequent development of maternal NNRTI-resistant
virus. XV Intl AIDS Conference. LbOrB09.
|
Time to Move On
More Questions about Single-dose Nevirapine
By Polly Clayden
HIV i-Base
A cost effectiveness analysis published in the August 20, 2004,
edition of AIDS reports that the efficacy of the single-dose nevirapine
regimen for reducing mother-to-child transmission in a field setting
is much lower than desired and despite the low cost of the drug
itself, requires significant financial resources to implement successfully.
[1]
Although in the developed world, use of effective interventions
has meant that MTCT has been virtually eliminated, in developing
countries interventions have been difficult to implement due to
high costs and lack of health care infrastructure. Single-dose
nevirapine to the mother and a single dose to the infant — according
to the HIVNET 012 results published in 1999 — have been the
most widely discussed strategy. The authors also emphasize that
although in a trial setting this intervention has been shown to
reduce MTCT by approximately 47%, for very little cost, in a field
setting clinics frequently need additional financial and technical
resources to implement the protocol. "Thus, the benefits of low
cost and simplicity of the intervention may not always be realized
in practice," they write.
The primary research question was: "What are the health benefits
for national health care systems to invest in a short-course nevirapine
intervention for HIV infected pregnant women, and what reduction
in adult HIV prevalence and reduction in the number of HIV-infected
women who become pregnant, would yield equivalent reductions in
infant HIV transmission as the nevirapine intervention?"
Data from antenatal clinics from Botswana, Cote D'Ivoire, Kenya,
Rwanda, Tanzania, Uganda, Zambia and Zimbabwe were used. These
countries were selected because they have high HIV prevalence among
pregnant women and great differences in uptake of the various stages
involved in accessing the nevirapine intervention. The investigators
report wide variation in cost outcomes across countries.
In this analysis the average cost per HIV infection averted was
$3,813, ranging from $1,808 in Botswana to $9,258 in Cote d'Ivoire.
The cost per disability adjusted life year (DALY) saved ranged
from $58 in Botswana to $310 in Cote d'Ivoire. The authors noted
that health care systems accounted for most program expenses, followed
by HIV testing and counseling but drug costs accounted for a very
small proportion of the overall costs. Besides the very low cost
of the drug (the model uses a drug cost of $0.27 for the nevirapine),
this also reflected the low numbers of eligible women taking up
all the interventions and in turn receiving the nevirapine.
Impact of HIV Prevalence and Unplanned Pregnancy
They report that lowering HIV prevalence by just a small amount
among women of childbearing age would have an equivalent impact
to the nevirapine intervention in reducing infant infection. In
Cote d'Ivoire, prevalence would only need to be reduced by 1% from
10% to 9% and in Botswana — where the most cost effective
nevirapine intervention was found — a reduction from 43% to
39% would be necessary to produce an equivalent reduction.
Similarly, a minimal reduction in unplanned pregnancies in HIV-positive
women would lower the rate of infant infection by the same rate
as the nevirapine intervention. The authors cite Kenya and Zambia,
lowering the pregnancy rate by 5.6% and 6.6%, respectively would
have the equivalent impact. In countries where the nevirapine intervention
was more cost effective, such as Rwanda, a greater reduction would
be needed, in this case by 35% to achieve the same reduction in
infant infection.
The authors state that, overall, short course nevirapine should
be considered cost effective, although variable across countries
and less so than previously reported. They also found that programs
could spend up to $152 per woman on an antiretroviral drug that
had 70% efficacy and achieve the same cost effectiveness as the
current nevirapine programs, concluding: "Therefore spending more
on the eligible women who actually make it through the system and
receive the antiretroviral drug would be more efficient and effective."
How Well Does It Work in the Real World?
A research letter in the September 3, 2004, edition of AIDS discusses
the effectiveness of single-dose nevirapine in reducing mother
to child transmission in a field setting in Mombasa, in which
mother to child transmission rates were similar to those found
using no intervention. [2] The authors point out that although
the HIVNET 012 regimen has been widely recommended, data to validate
the effectiveness of this strategy outside a research setting
are lacking.
In the study — conducted between April 2001 and October 2003 — HIV-positive
women received nevirapine and instructions to use it at the onset
of labor, and were invited to participate in the follow up study.
The program enrolled 482 women, and 172 presented for follow up
at 6 or 14 weeks. The investigators report, over 58% of the women
delivered at the hospital, 19% delivered at home, and 22% delivered
in another hospital. More than 85% of the women (147/172) reported
taking the maternal dose, 86.0% of babies (148/172) received the
nevirapine suspension, and 82% (141/172) reported the administration
of both the maternal and neonatal dose.
Samples were available for 127 babies, and the authors report
a transmission rate of 18.1% at 14–16 weeks. They write that
there was no correlation between the maternal dose intake only,
intake by the baby only, or the intake of nevirapine by both mother
and baby, and the transmission rates at 14 weeks (p=0.887, p=0.336
and p=0.529, respectively).
The authors write that this transmission rate is similar to a
perinatal transmission rate at 14 weeks of 21.7% using no intervention
in this Mombasa setting, and does not compare well to the HIVNET
012 reported rate of 13.1% at 14 weeks.
The authors add: "These data, suggesting a rather limited effect
of the widely recommended HIVNET 012 intervention, call for further
research on the long-term efficacy of the HIVNET 012 regimen in
a field setting. Taking into account the low coverage of the nevirapine
regimen, the lack of benefit for maternal health, the concerns
about resistance, the enormous deployment of resources needed to
provide nevirapine within the current voluntary counseling and
testing paradigm, and the reported lack of efficacy in real life
conditions, the true health gains of the intervention should be
reconsidered."
Comment
These two articles present data and analysis which result in assessments
of the potential financial cost and clinical effectiveness of
single-dose maternal plus single-dose infant nevirapine for the
prevention of mother-to-child transmission of HIV-1 that differ
from earlier studies. The findings are not particularly surprising
and will continue the swing of the pendulum away from this approach
which might have begun when the first reports of nevirapine resistance
in mothers following single-dose exposure were reported — by
Eshleman et al. — from HIVNET 012 but certainly gained momentum
in February 2004 when Jourdain et al. reported the negative impact
of these mutations on maternal treatment at six months.
It is clear to most that single-dose nevirapine is not the panacea
for PMTCT. The trick now is not to throw the baby out with the
bath water. Nevirapine is a highly effective HIV inhibitor which
efficiently crosses the placenta and which has a long plasma half-life
that can be used to advantage. Lallemant et al. showed that used
in combination with zidovudine monotherapy from 28 weeks single-dose
nevirapine contributes significantly to reducing pre/intrapartum
transmission to 2%. While McIntyre et al. demonstrated the addition
of Combivir for 4 – 7 days post-partum dramatically limits
the development of detectable nevirapine resistance mutations in
plasma at 12 days. Whether these two approaches can be successfully
combined and the determination of the optimal duration and components
of therapy to preserve the use of nevirapine is the next priority.
Meanwhile we should not forget that the prevention of pediatric
HIV infection as well as the survival of HIV uninfected children
starts with prevention of HIV infection in their parents and with
treating those mothers already infected if this is indicated for
their own HIV. The point is already implicit in the cost effectiveness
analysis but could stand a little more emphasis; some have speculated
that the infrastructure needed to implement the 012 protocol is
just about what is needed to offer continuous therapy. The study
also reminds us: "The goal in the Declaration on HIV/AIDS of the
UN General Assembly Special Session is bold in its mandate, 'reduce
the proportion of infants infected with HIV by 20% by 2005, and
by 50% by 2010'." We are very unlikely to reach this goal if we
concentrate on PMTCT single-dose nevirapine interventions in isolation.
This article originally appeared in:HIV Treatment Bulletin, Volume
5, Number 9/10, Oct/Nov 2004.
1. Sweat M, O'Reilly KR, Schmid GP et al. Cost-effectiveness of
nevirapine to prevent mother-to-child HIV transmission in eight
African countries. AIDS: Volume 18(12), 20 August 2004, pp 1661–1671.
2. Quaghebeura A, Mutungab L, Mwanyumbac F et al. Low efficacy
of nevirapine (HIVNET012) in preventing perinatal HIV-1 transmission
in a real life situation. AIDS: Vol 18(13), 3 September. Research
Letters 1855.
Impact of the Second Bush
Administration on National HIV/AIDS Public Policy
GMHC Public Policy Department
The election of George W. Bush to a second term as President of
the United States, combined with an increase in the Republican
majority in both houses of Congress and an increase in the conservative
faction of the majority, is likely to continue ominous conditions
for HIV/AIDS service organizations and for national HIV/AIDS public
policy. While the specific details of any negative impact cannot
be ascertained fully at this time, there is a nearly universal
consensus within the HIV/AIDS community that the fight against
AIDS will be threatened seriously, domestically and globally, by
a second Bush term in office. The very real difficulties, attacks,
and outright setbacks that were experienced in the first term give
credence to the concerns over what will happen over the next 2 – 4
years.
Key factors affecting the overall impact of a Bush second term
on HIV/AIDS will be the degree to which Mr. Bush's and his administration's
tendency towards right-wing conservative ideological principles
prevail and the degree to which a hard line, regressive approach
on HIV/AIDS, especially the domestic HIV agenda, is promulgated
to reward social conservatives and Christian fundamentalists for
their support in the 2004 elections and appease those constituencies
for their continued support. Again, the first term and some post-election
actions suggest that conservative ideology and social conservative
and religious viewpoints will continue to have a heavy influence
on how the administration and Congress responds to the HIV/AIDS
pandemic, here and abroad.
The impact on national HIV/AIDS public policy of a second term
likely will be across the board and emerge over time. The impact
on three areas, however, likely will be more immediate and very
negative. These areas are Federal appropriations for HIV/AIDS,
reauthorization of the Ryan White CARE Act, and health care access,
specifically Medicare.
Budget/Appropriations
Mr. Bush's first term saw a marked reversal of the fairly steady
increases (albeit at times incremental) in discretionary Federal
funding for HIV/AIDS. For the past few fiscal years, Mr. Bush's
Budget Requests basically have called for flat-funding for domestic
HIV/AIDS programs and funding for global AIDS programs well below
needed levels. Overall, Congress has adhered closely to the President's
requests in passing the actual appropriations. When inflation
and rising caseloads are taken into account, there has been an
effective cutback in funding for domestic HIV/AIDS programs.
The recently enacted omnibus appropriations bill for FY 2005
exemplifies this trend.
Nearly all Federal budget experts agree that the administration's
FY 2006 Budget Request will call for an overall cut, for some individual
programs deep cuts, in non-defense discretionary funding. With
a strengthened Republican majority, Congress likely will continue
to adhere closely to the administration's budget as it enacts appropriation
legislation. The reduction in non-defense discretionary funding
will be driven by the impact of the already enacted tax cuts, Mr.
Bush's stated intent to make permanent many of the tax cuts, the
record level deficit, the continuing and growing costs of the military
campaign in Afghanistan and the war in Iraq, and the costs of homeland
security. This reduction trend likely will continue in the out-years
(FY 2007 and thereafter). According to a paper published by GalleryWatch
and Federal BudgetObserver, the Federal Office of Management and
Budget itself projects that over the next four years non-defense
discretionary funding will be cut by $11.6 billion. If Mr. Bush
is successful in achieving his goals of overhauling the Federal
income tax and restructuring Social Security, the need for further
cuts in non-defense discretionary funding may well exceed the OMB's
$11.6 billion projection.
Given this context, Federal spending for domestic HIV/AIDS programs
will be at best flat-funded and may well experience actual reductions
(the Federal HOPWA program already has experienced a nearly $13
million reduction in funding, after the across-the-board recision,
in the FY 2005 omnibus spending bill). Actual or effective reduced
funding for the CARE Act and for domestic HIV prevention can be
expected under the Bush second term.
Reauthorization of the Ryan White CARE Act
The current authorization of the Ryan White CARE Act expires on
September 30, 2005.
While work on reauthorizing the Act has been underway, especially
among HIV/AIDS public policy advocates, for the past 18 months,
actual proposals from the administration were not expected until
after the 2004 elections. Likewise, Congressional action was not
expected until the new 109th Congress convenes in January.
With a second Bush term now a reality, the administration's thinking
will have a major, if not overwhelming, influence on reauthorization.
The most salient likely influence will be a further move towards
the "medicalization" of CARE Act services, especially under Title
I. If this trend is realized, then the result could be to render
ineligible many or all of the mental health and social supportive
services now funded under Title I. This would have a drastic, negative
impact on the funding to AIDS service organizations, and other
community-based organizations.
The administration, with the support of the majority in Congress,
is also expected to call for changes in the funding formulas for
Titles I and II. The stated intent of the administration's proposed
formula changes will be to achieve greater funding equity among
Title I jurisdictions and among the states, the District of Columbia,
and the territories funded under Title II. A revision or outright
elimination of current hold harmless provisions is expected to
be proposed or at least supported by the administration and the
Congressional leadership. If such proposals are enacted, and when
applied to the above described funding scenarios, then the effect
of the formula changes could be a major reduction in Title I and
Title II funding to Northeast and West Coast jurisdictions, smaller
reductions to Mid-West jurisdictions, and significant funding gains
for Southern jurisdictions.
A further potentially negative factor for reauthorization is the
election of Tom Coburn to the Senate. Mr. Coburn is a hard-core
political and social conservative. As a U.S. Representative from
Oklahoma, Mr. Coburn was a key player during the previous reauthorization
of the Act. He is expected to try to play a similar leadership
role even as a freshman senator. Mr. Coburn can be expected to
propose changes and amendments to the Act that would promote abstinence-only
programs, enhanced partner notification and contact tracing efforts,
and the "medicalization" of HIV/AIDS services.
Health Care Access: Medicaid
Medicaid is the largest source of health coverage for people living
with HIV/AIDS. In 2003, President Bush proposed to change the
financing of Medicaid to a block grant, which would have eliminated
the entitlement nature of the program in exchange for states
receiving lump sums of Federal dollars. A block grant approach
effectively would cap Federal Medicaid spending. A capped Medicaid
program would essentially leave states "holding the bag" for
increases in their Medicaid costs, especially during economic
downturns or disasters/emergency situations. It is widely held
by advocates that a capped Medicaid program would lead to capped
enrollment, reductions in benefits, increased cost-sharing and
increased numbers of the uninsured. Through tireless advocacy,
consumer groups, including strong support from the HIV/AIDS community,
across the country working closely with Congressional allies
helped stop the President's proposal in 2003.
Health care experts widely expect Mr. Bush to revive his Medicaid
capped entitlement and block grant proposal early in his second
term. The common assumption is that the administration's Medicaid
proposal will be entwined in the FY 2006 budget process. By "burying" Medicaid
changes in the budget process and with a bigger Republican majority
in Congress, the administration's Medicaid proposal will be much
harder to defeat. In addition, the nationwide pressure on the states
to cut their Medicaid costs may make many governors willing to
support the administration in exchange for relief on their state
budgets.
If Mr. Bush's proposals are enacted, then the impact on thousands
of people living with HIV/AIDS likely will be negative to a significant,
perhaps life-threatening, degree.
Impact on Other HIV/AIDS Public Policy Areas
Medicare. Medicare is increasingly growing in importance
to people living with HIV/AIDS, and is the second largest source
of funding for HIV care. In late 2003, Congress passed the Medicare
Modernization Act of 2003, which added a drug benefit (Part D)
to Medicare. The law allows private drug plans to administer the
drug benefit and create formularies and approval processes for
accessing drugs. The most immediate concern to PWAs is the loss
of Medicaid drug coverage on January 1, 2006 for dual eligibles
(there are about 80,000 in the U.S. with HIV) without an immediate
fall back for drug coverage in case they are not enrolled in a
Part D plan. Other major concerns include the availability of antiretroviral
and non-HIV prescriptions for PWAs, whether off-label use of medications
will be covered, the appeals process for PWAs who are denied medications
through their plans, and the ability of ADAP to wrap around Part
D.
Prior to the 2004 elections, an advocacy hope was to influence
the new administration's implementation of the Part D benefit and
to work with Congress to make actual changes in the law that would
mitigate negative impacts. The election results make changes in
the law a dim prospect, at best. The administration's Mark McClellan
seems amenable to addressing some of the concerns of the HIV community,
but it is quite clear that implementing the benefit will take some
time to work out, and PWAs run the risk of having their regimens
interrupted while the problems in the system are fixed.
Prescription Drug Pricing. The increasing costs of prescription
drugs is the biggest factor in keeping the increases in overall
health care costs above the rate of inflation. The close relationship
between the Bush administration and the pharmaceutical industry
and the industry's strong lobbying efforts in Congress have blocked
efforts to effect Federal drug price control policies. Again, the
election results are not likely to change this situation. The lack
of drug price controls is squeezing public programs and causing
more and more employer-based plans to pass on costs their employees.
States are forced to deal with the high price of prescription drugs
in varying ways, some of which have the effect of limiting access
to drug treatment. While New York State enjoys a relatively solid
safety net to ensure access to needed medications, especially for
people living with HIV/AIDS, New York is not immune to pressures
to control rising drug costs. Attempts to enact a preferred drug
list under Medicaid are an example.
Domestic HIV Prevention. Beyond the likely impact of
flat or reduced funding for domestic HIV prevention programs, the
second term of the Bush administration likely will continue the
trend towards a more politically and socially conservative approach
to HIV prevention that minimizes or even disregards sound public
health science. The administration likely will continue to push
for an increased emphasis on abstinence-only-to-marriage programs
(which received a $30 million increase in the FY 2005 omnibus spending
bill). The shift in priorities at the Federal Centers for Disease
Control and Prevention away from primary prevention likely will
continue. This will result in decreased funding support for efforts
to reach and intervene with at-risk communities, especially among
men who have sex with men, drug users, and women of color. Enactment
of proposed guidelines for the review of HIV prevention materials,
unless changed in light of comments from GMHC and others in the
HIV/AIDS community, will also have a negative, chilling effect
on the ability of community-based programs to produce materials
that are appropriate for targeted audiences.
HIV/AIDS Research. After a ten year period during which
the NIH budget has doubled, a period of stagnant funding is likely
with annual increases that are below the rate of biomedical inflation.
For HIV/AIDS research, this likely will mean that little new research
will be funded unless current projects are de-funded. An additional
negative impact of a second Bush administration is the likely continuation
of outright hostility towards the NIH's HIV/AIDS research program
by the leadership at the Department of Health and Human Services
and, some members of Congress.
Global AIDS. A generally perceived impact of the last
four years of the Bush administration has been an increase in the
Federal government's attention to the global AIDS crisis. Mr. Bush's
announcement of a major $15 billion initiative in his 2003 State
of the Union Address and Congress's enactment of his proposed initiative
underscored the administration's attention to the global AIDS pandemic.
All too often, however, this has been more of a shift in attention
from the domestic HIV/AIDS agenda to a focus on global AIDS. Moreover,
the administration's approach to global AIDS has been characterized
as being more unilateral than multilateral, as evidenced in the
administration's stance towards generic antiretroviral drugs that
have been approved by the World Health Organization. Also, funding
for the President's global AIDS program has been well below expectations
and even below the annualized amounts authorized by Congress. The
administration has also allowed its approach to be guided by political
and social ideologies over sound public health and the local needs
of recipient countries.
These trends are very likely to be continued in the second term.
An ominous indication of this was the recent strong opposition
of the administration to the Global Fund's starting a fifth round
of funding to initiate new programs.
Human Rights. A Bush second term and the results of the
Congressional elections likely will stall any efforts to lift the
immigration bar on entry to the United States by HIV-positive individuals.
The administration is also expected to continue, and perhaps expand,
the policy of discriminating against HIV-positive personnel in
the military. Negative impact on HIV-positive immigrants was foreshadowed
by the administration during its first term ending of PRUCOL, a
previous option to petition the government for lawful stay used
by many HIV-positive immigrants. Finally, the administration, in
its first term, moved away from forceful Federal enforcement under
the American with Disabilities Act (ADA) of disability discrimination
laws, leaving enforcement to the states. Again, these trends are
likely to continue, if not increase, in the second term.
Pediatric AIDS
Foundation on Single-dose Nevirapine
The Elizabeth Glaser Pediatric AIDS Foundation supports
providing the safest, most effective regimen of drugs to
prevent mother-to-child transmission in all instances. In
the United States and other developed world settings, mother-to-child
transmission has been dramatically reduced through aggressive
prevention and treatment programs that are widely available.
In the developing world, due to poor infrastructure and the
high cost of other regimens, nevirapine, administered as
one dose to the mother at the onset of labor and one dose
to the child within 72 hours of birth, is frequently the
only option feasible and available. There is considerable
scientific data demonstrating that this short-course nevirapine
regimen is safe and effective and should continue to be used
to prevent mother-to-child transmission in settings where
more complex regimens are not available.
The AP article raises concerns about the safety of short-course
nevirapine for prevention of mother-to-child transmission.
It is important to understand that there are no data demonstrating
that significant NVP-induced toxicities occur in women or
infants receiving short-course nevirapine for PMTCT. Although
studies have shown a risk of toxicity with long-term use
of nevirapine for HIV treatment, it is scientifically inaccurate
to deduce harmful effects of a short-term course of nevirapine
based on studies that examine long-term, continued use of
the drug.
The single-dose nevirapine regimen to prevent mother-to-child
transmission has been used in hundreds of thousands of women — both
in practice and in clinical trials — without any significant
toxicity for mothers or babies. Including the HIVNET 012
study, referenced in the AP article, single-dose NVP regimen
has been studied in three large, randomized, comparative,
phase III clinical trials including over 1,600 HIV-infected
women and their infants. PACTG 316 was a phase III, randomized,
double-blind clinical trial conducted in the U.S., Europe,
Brazil, and the Bahamas. The South African Intrapartum Nevirapine
Trial (SAINT) trial was a phase III, randomized trial comparing
a combination of drugs to single-dose nevirapine. No significant
clinical or laboratory toxicity was observed in any of these
three studies. In addition, reports from clinicians administering
this regimen in the field confirm what these studies demonstrated:
that nevirapine, when taken in a short-course for PMTCT,
does not cause significant toxicity in mothers or babies.
It is true that resistance has been shown to occur in those
receiving short-course nevirapine. However, to date, there
is no evidence of negative clinical outcomes as a result of
subsequent antiretroviral therapy. The Foundation strongly
supports further research about resistance issues. We are currently
partnering with the Centers for Disease Control and Prevention
to examine the long-term effects of a single dose of nevirapine
for prevention of mother-to-child transmission on a woman's
subsequent response to ARV therapies containing nevirapine.
However, in the absence of evidence of negative clinical outcomes
for future treatment, it would be premature to withdraw the
only safe and effective regimen to prevent mother-to-child
transmission of HIV that is currently available throughout
large parts of Africa and other portions of the developing
world.
UNAIDS estimates that 1,900 children worldwide are infected
with HIV each day, the vast majority through mother-to-child
transmission. Yet, services to prevent mother-to-child transmission
are available to less than 10 percent of the women who need
them. We must continue to work aggressively to expand access
for pregnant women to scientifically-based services to prevent
mother-to-child transmission and support research that will
guide the very best implementation of these lifesaving programs.
As one of the world's largest funders of PMTCT programs,
the Foundation is committed to using the best available science
to prevent as many infant infections as possible and safeguard
the health of HIV-positive mothers.
In making any decision about drug regimen use, we should
rely on the scientific facts. It would be premature and inappropriate
to withdraw nevirapine as an option for mother-to-child transmission
at a time when so many pregnant women throughout the world
have no other option to save the lives of their babies. At
this point in time, based on all existing scientific evidence,
nevirapine should continue to be one of several interventions
available to prevent mother-to-child transmission.
However, it is important to remember that safer, more effective
drug regimens, including a combination of AZT and single-dose
nevirapine and long-term combination therapy for the mother,
exist and are already being used in some parts of the developing
world. Rather than focus on withdrawing nevirapine from those
who urgently need it, the entire world should focus on how
we can provide the funding for infrastructure improvements,
training, and drug purchase costs so that more and more women
will have access to the most effective drug regimens possible.
Ultimately, our goal must be for all pregnant women throughout
the world to have access to the same drug therapy that is
currently available in the United States and other developed
nations. In the face of the worst pandemic of infectious
disease in history, anything less than a full effort to save
the lives of the next generation is a tragic avoidance of
our fundamental responsibility.
www.pedaids.org |
Comments by Global Strategies
for HIV Prevention on Nevirapine Resistance
The Resistance Issue
The issue of resistance to nevirapine and its impact on subsequent
use in HIV infected women has been debated. Several important
facts need to be considered.
1. Nevirapine resistance occurs even with single-dose nevirapine
given to mothers. This resistance is transient and there is no
evidence that it prevents the effectiveness of nevirapine in subsequent
pregnancies. Health care workers have known about nevirapine resistance
for over five years and have taken this into consideration in making
recommendations for PMTCT.
2. All drugs used to treat HIV infection result in resistance.
HIV rapidly mutates and resistance is inevitable. The use of combination
antiretroviral drugs, which controls viral replication, reduces
but does not eliminate the possibility of resistance. It is not
logical to withhold nevirapine to save the life of an infant based
on theoretical concerns regarding subsequent responses to therapy.
Resistance can develop whether nevirapine is used for PMTCT or
for treatment of HIV infection.
3. WHO, UNAIDS and other international and national health organizations
recommend combination drug therapy to treat HIV-infected adults
who meet certain criteria for initiation of treatment. Several
low-cost regimens include nevirapine as recommended therapy in
resource poor countries. Resistance to nevirapine can occur with
any of the recommended regimens for treatment of HIV-infected individuals.
4. The "threat of resistance" arguments are backwards. The greatest
threat for the development of widespread nevirapine resistance
is not from its use as single-dose nevirapine for PMTCT in several
hundreds of thousands of pregnant women. Rather widespread nevirapine
resistance is more likely to result from its use with combination
drugs to treat millions of HIV-infected individuals worldwide and
could jeopardize its use for PMTCT.
5. Withholding nevirapine, on the theoretical basis of blunting
a subsequent response if used in combination therapy to treat HIV
infection, would result in HIV infection and subsequent death of
hundreds of thousands of infants for whom no other options are
available. In contrast, over 17 antiretroviral drugs are available
which can be used in various combinations to treat HIV infection
if resistance occurs. In most resource poor countries the only
option for preventing HIV-infected babies is single-dose nevirapine.
Conclusion
So what is behind the recent publication of information that has
been known for over 4 years by the FDA, the international AIDS
community, WHO, UNAIDS and the scientific community? Basically,
the media report deceptively presents itself as new information.
Importantly, however, the clinical research and scientific community
have gone far beyond the 1999 HIVNET 012 report and have conducted
multiple additional studies to confirm both the effectiveness and
safety of nevirapine used either as a single dose for PMTCT or
in combination with other antiretroviral drugs. Many of these studies
are completed and confirm the safety and effectiveness of single-dose
nevirapine and its much greater effectiveness when used with other
antiretroviral agents to reduce HIV transmission by over 90%. The
media report fails to acknowledge these advances.
It is absolutely essential that PMTCT programs move forward quickly
to save the lives of infants from fatal HIV infection. Once an
opportunity is missed to prevent HIV infection, one cannot go back
and eradicate an already established and ultimately fatal infection.
We all want to treat with the best combination antiretroviral drugs
available to prevent as many infections of babies as possible.
We also want to optimally treat the mother's HIV infection.
But as we move toward that goal, single dose nevirapine may be
the only option for resource poor countries until more effective
therapy becomes available.
www.globalstrategies.org
The Rolls-Royce and the
Túk-Túk
By Gregg Gonsalves
Over a year ago, sharing a cab on the way to the airport after
a meeting at the NIH (National Institutes of Health), I had a conversation
with two AIDS researchers about the Good Clinical Practice (GCP)
guidelines for conducting clinical research. As soon as I got home
I looked up the guidelines and was struck by the fact that, while
these were supposed to be "universal" guidelines, they were obviously
drawn up with the resource-rich world in mind. It seemed unlikely
that the authors had asked anyone in Africa, Asia, Latin America,
or the Caribbean what they thought about these standards. I also
recall hearing what these researchers thought were the "right" and "wrong" lessons
to be learned from the HIVNET 012 trial (this was several years
ago, shortly after questions about the study were first raised).
The "wrong lesson" to learn from HIVNET 012 is that it was a poorly
executed trial with too many data irregularities, and that we need
to "crack down" on trial sites in Africa and elsewhere until they
can conform to the same standards found at a Hopkins or Harvard
site.
The "right lesson" would be that HIVNET 012 was a pivotal trial
that has saved thousands of babies from becoming HIV infected.
While there were certainly irregularities in data reporting and
recording, shouldn't the GCP guidelines pay more attention to the
realities of doing clinical research in developing countries? And,
if so, then shouldn't they be revised?
As a person with HIV, I want clinical trials to reflect the realities
of how medications are used in the real world. While there is a
role for high-tech clinical research, there is also a crying need
for public health-based research that looks at interventions in
settings where they will actually be used. This is exactly what
HIVNET 012 did. I have no problem with the FDA setting GCP standards
(or evaluating generics for use in other countries for that matter),
but I do have a problem with taking a unilateralist approach to
the development of such guidelines — in other words, the FDA
shouldn't simply hand down commandments from on high that determine
what is good and what is useless research.
We need a collaborative process with significant input from researchers,
regulators, and community in the developing world to help craft
a revised set of GCP guidelines that can help produce desperately
needed answers to some of the most crucial clinical questions.
Simply satisfying a bureaucrat in Rockville who can't see beyond
the checklist on his desk is not sufficient. While many of the
components of the GCP guidelines are indeed essential for the conduct
of quality clinical research everywhere and anywhere, there are
still plenty of historical accretions that are included simply
because, "that's the way we've always done it in the U.S., so that's
how to do it everywhere else in the world."
The data discrepancies in the HIVNET 012 study never placed the
basic conclusions of the trial into doubt and they never put any
woman or child in jeopardy. What the current campaign to discredit
the study may do is make it difficult to ever conduct similar public
health-based research in the future, which would be a terrible
disservice to people with AIDS or other diseases who need answers
to questions about the real-world use of drugs and other medical
interventions. Dr. Fishbein's crusade against the study makes him
look less and less like a heroic whistleblower and more and more
like an inflexible bureaucrat with little interest in exploring
the complexities of clinical research outside of settings where
he has his experience.
Women and their children living with HIV/AIDS need better and
more interventions to treat HIV infection and prevent transmission.
They also need to minimize the risk of developing drug resistance;
to treat both mother and infant; and to protect the child while
breast-feeding — and these interventions must be evaluated
in the settings where they will be eventually be used.
The NIH, FDA and other agencies concerned with the conduct of
research need to convene a discussion about revising the GCP guidelines
soon — the world is much bigger than when these guidelines
were first produced, and the sites in which studies are taking
place are far different than what most regulators in the United
States are used to. If we don't take this reality check, then obtaining
key answers about how to treat and prevent HIV infection in the
developing world will be put on hold until research sites in these
countries finally attain the same infrastructure, resources and
staffing found in Boston, New York, or Los Angeles. We don't need
to wait that long; we can't afford to.
© 2005 Gay Men's Health Crisis
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