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Nevirapine - godsend or a drug from hell?
Dr Haroon Saloojee
Save our Babies
Dr Haroon Saloojee, a paediatrician at Wits University, and member of Save
our Babies, a health professionals' organisation closely aligned to the
Treatment Action Campaign, provides insight into the use of nevirapine in
preventing mother to child transmission of HIV, touching on some of the
controversy surrounding this drug in South Africa.
A simple drug, with a somewhat difficult to remember name, has over the past
six months captured the headlines in the South African and international media.
Nevirapine has been at the centre of a court case and a major political debacle
with all the intrigues and more twists than a Jeffrey Archer novel - South
African health professionals and AIDS activist jointly lobbying their
government, protesting in the streets and finally taking the matter to court; a
high court judge ordering government to make the drug available at health
centres; a provincial premier brawling with his provincial health minister about
extending drug coverage; an ANC premier publicly debating with the national
health minister; and Nelson Mandela chastising the government about its
inactivity on the issue.
Scientists and non-scientists (e.g., politicians, church leaders, trade
unionists) alike have all entered into the fray arguing the merits of the drug,
its benefits, toxicities and resistance patterns. It's been condemned as
"the drug from hell' by AIDS dissident David Rasnick while heralded as a
"godsend" by many health professionals. Amidst all the rhetoric, the
larger scientific and lay communities have had few opportunities to decipher the
real value of the drug except through public slanging matches played out in the
courts, parliament and in the media.
The human immunodeficiency virus (HIV) uses the enzyme reverse transcriptase
to incorporate its own genetic material into host cells, which then allows it
reproduce freely. Nevirapine, one of a class of drugs known as non-nucleoside
reverse transcriptase inhibitors, prevents this enzyme from functioning. This
results in a reduced amount of virus in the body and an increase in the CD4 cell
(T cell) count, improving the host's immune function, and thereby reducing the
risk of new and opportunistic infections, and death.
Nevirapine has been widely used in adults as one of a combination of drugs to
treat established HIV infection. It has a special role in the prevention of
mother to child transmission of HIV, as it is effective when given alone as a
single dose to the mother at the beginning of labour and one dose administered
to the baby within 72 hours of birth. Nevirapine given to HIV-positive pregnant
women rapidly crosses the placenta into the fetus with its effects lasting
through the first week of life. The timing of its delivery to the mother during
labour is important as up to two-thirds of infants born with HIV are infected in
the birth canal.
Clinical trials have confirmed the efficacy of nevirapine in preventing
mother-to-child transmission (MTCT) of HIV. In the absence of interventions, 20%
of infants born to women infected with HIV acquire infection from their mother
at or before delivery. A further 15% are infected through breast feeding. The
Ugandan HIVNET 012 study involving 626 women showed that nevirapine was able to
reduce MTCT, with only 8.1% of infants exposed to nevirapine acquiring HIV at
birth.[1] Almost all the babies were breast fed, resulting in ongoing exposure
to HIV. At 14 weeks, the rate of HIV infection was 13%, while at 12 months the
transmission rate was 15.7% confirming that the reduction in the risk of
transmission associated with nevirapine prophylaxis persists for at least the
first year of life, despite the ongoing risk posed by breast feeding.[2]
In the South African Intrapartum Nevirapine Trial (SAINT), 1306 mother/infant
pairs were randomised to either nevirapine during labour and post-delivery, or
multiple doses of AZT/3TC during labour and for one week after delivery to
mother and baby. In both treatment arms, about 40% of infants were breast-fed.
Eight weeks after birth, there was no significant difference observed between
the rate of HIV infection or death across the two treatment arms, with a rate of
14.3% in the simpler nevirapine arm and 12.5% in the more involved and expensive
dual therapy arm.[3] No trials are available comparing nevirapine with placebo.
For pregnant women already receiving highly active antiretroviral therapy, there
appears to be no additional advantage of adding nevirapine to an existing
regimen.[4]
Evidence of drug resistance among women given nevirapine monotherapy during
labour has raised concerns about this intervention. In addition, viral subtype
may affect the development of resistance to nevirapine, with women infected with
HIV subtype D at higher risk of developing resistance to nevirapine.[5] Drug
resistant mutations are usually naturally occurring variants that are present at
low frequency before the use of antiretroviral drugs and which are then selected
and expanded when nevirapine is introduced. However, resistance does not impact
on the efficacy of the treatment to prevent MTCT, and resistant mutations wane
over 12-24 months. Resistance to antimicrobials is not unique to HIV and a
recent study,[6] reaffirmed the WHO's view that concerns over drug resistance
should not delay the widespread use of nevirapine for preventing MTCT.
Opponents of nevirapine cite toxicity as an important limitation for its use
in MTCT prevention. Long-term use of nevirapine in adults has resulted in
significant side effects including life-threatening liver toxicity and skin
reactions. Similar adverse events have been reported in health care workers
taking nevirapine in combination with other antiretroviral drugs for
post-exposure prophylaxis after occupational exposure to HIV. However, in the
SAINT study where single doses were given to mother and infant, none of these
adverse events were noted, with the commonest, but infrequent, side effect being
a mild, self-limiting skin rash.
The low cost of nevirapine (US$2) and simplicity of administration offers
great advantage over more expensive MCTC prevention treatments, particularly for
low-income countries where women generally attend antenatal clinics irregularly
or late during pregnancy, and where many deliveries occur in home settings.
Further, the manufacturer has offered the drug to some governments at no cost.
The cost effectiveness of nevirapine and of MTCT strategies has been well
described in the South African setting, with all studies on the subject
consistently showing overwhelming cost benefit for prevention measures.
Nevirapine is a minor component of the costs of a total MCTC package. Annually,
it would cost the South African government (if it decided not to accept the free
offer) about 6 million rand (US$0.5 million) to provide the drug to all eligible
mothers and infants. A total MTCT package would cost about R 150 million (less
than 1% of the health budget), with testing (R15 million), counselling (R60
million) and replacement infant feeding (R70 million) costs being the major
contributors.[7] It is estimated that by providing the nevirapine package, the
health ministry would save about R360 million annually, by preventing about 31
000 children getting HIV and thus saving on the medical cost of treating the
disease (excluding the provision of long-term antiretroviral treatment).[8]
Operational capacity to implement nevirapine already exists in many health
care facilities; and most health professionals believe it is ethically and
morally unacceptable for government policy to preclude them from providing
nevirapine in the best interests of their patients. There is little
justification either for restricting access to pilot sites. In settings that do
not yet have the capacity for implementation, alternative approaches that are
less resource-intensive, could be considered. For example - while not ideal - in
high prevalence areas, the provision of nevirapine to all pregnant women without
HIV testing may be ethically justifiable as an alternate to not intervening at
all.[9]
In conclusion, current research confirms the benefits of nevirapine for
preventing MTCT of HIV. Nevirapine is cost-effective, safe, and has few
significant side effects. Drug resistance is a transient phenomenon. The
benefits of nevirapine appear to be maintained even in the presence of continued
breast feeding The potential value of nevirapine used for longer periods in
breast feeding populations needs to be researched as it may further reduce the
risk of mother-to-child transmission, particularly if combined with early
weaning. The challenge now is to translate these research findings into policy
and practice in South African and other resource poor settings.
Reference List
1. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C et al.
Intrapartum and neonatal single-dose nevirapine compared with zidovudine for
prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET
012 randomised trial. Lancet 1999;354:795-802.
2. Owor M. The one year safety and efficacy data of the HIVNET 012 trial. 2001.
XIII International AIDS conference, Durban, South Africa, 9-14 July 2000.
3. Moodley, D. The SAINT Trial: Nevirapine (NVP) versus Zidovudine (ZDV) +
Lamivudine (3TC) in prevention of peripartum transmission. 2001. XIII
International AIDS conference, Durban, South Africa, 9-14 July 2000.
4. Brocklehurst P,.Volmink J. Antiretrovirals for reducing the risk of
mother-to-child transmission of HIV infection (Cochrane Review).
Cochrane.Database.Syst.Rev. 2002;CD003510.
5. Eshleman SH, Becker-Pergola G, Deseyve M, Guay LA, Mracna M, Fleming T et al.
Impact of human immunodeficiency virus type 1 (hiv-1) subtype on women receiving
single-dose nevirapine prophylaxis to prevent hiv-1 vertical transmission (hiv
network for prevention trials 012 study). J.Infect.Dis. 2001;184:914-7.
6. Stringer JS, Sinkala M, Rouse DJ, Goldenberg RL, Vermund SH. Effect of
nevirapine toxicity on choice of perinatal HIV prevention strategies.
Am.J.Public Health 2002;92:365-6.
7. Geffen, N. Cost and Cost-Effectiveness of Mother-to-Child Transmission
Prevention of HIV. 2000. Briefing Paper for the Treatment Action Campaign.
8. Skordis, J and Nattrass, N. What is Affordable: The Political Economy of
Policy on the Transmission of HIV/AIDS from Mother to Child in South Africa.
2001. Paper presented to the AIDS in Context Conference, University of the
Witwatersrand, April 2001.
9. Hankins C. Preventing mother-to-child transmission of HIV in developing
countries: recent developments and ethical implications. Reprod.Health Matters.
2000;8:87-92.
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