Time to Move On: More Questions About Single-Dose Nevirapine
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, Côte 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."
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.
Polly Clayden is with HIV i-Base. This article originally appeared in: HIV Treatment Bulletin, Volume 5, Number 9/10, Oct/Nov 2004.
This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.