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Revisiting the Role of Single-Dose Nevirapine for Preventing Perinatal HIV Transmission

Single-dose nevirapine is a well-established strategy for preventing mother-to-child transmission (pMTCT) of HIV. This winter, however, media reports cited concerns at the National Institutes of Health about the first major study (the HIVNET 012 trial) to demonstrate the efficacy of nevirapine in resource-poor settings. To address the current and future role of nevirapine in pMTCT programs, AIDS Clinical Care convened a discussion with Dr. Mary Glenn Fowler, Chief, Maternal Child Transmission Team, Epidemiology Branch, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention; Dr. Shahin Lockman, Research Associate at the Harvard School of Public Health and Associate Physician in Medicine at Brigham and Women’s Hospital in Boston; and Dr. James McIntyre, Executive Director of the University of the Witwatersrand's Perinatal HIV Research Unit at the Chris Hani Baragwanath Hospital in Soweto, South Africa, and Principal Investigator of the CIPRA-SA research program. The discussion was moderated by Dr. Hoosen Coovadia, the Victor Daitz Chair in HIV/AIDS Research at the Nelson R. Mandela School of Medicine, University of KwaZulu-Natal.

Dr. Coovadia:
Let’s start by looking at the new controversy around the HIVNET 012 trial and try to separate fact from fiction.

Dr. Lockman:
I think the recent publicity surrounding HIVNET 012 has been a sad and unfortunate distraction from the real issue at hand — namely, how to deliver appropriate and effective pMTCT strategies where they are most needed. Most of the concerns raised about this trial (and reported in the popular press) have been related to the nature of documentation in the trial, but the Institute of Medicine panel and other reviewers have concluded that the study results are valid. Single-dose nevirapine remains an incredibly safe and effective pMTCT strategy. HIVNET 012 and a number of other studies have shown that most serious adverse events following nevirapine exposure are far more likely to be HIV-related than drug-related. The events that are potentially drug-related occur with equal frequency among nevirapine recipients and placebo recipients.

Dr. McIntyre:
Based on information from about 4500 mother-infant pairs who have received nevirapine in clinical trials — and the hundreds of thousands of women who have received it through access programs — we really have no indication of a need to be concerned about the drug’s safety or toxicity.

Dr. Coovadia:
I think all of us agree with both Dr. Lockman and Dr. McIntyre. Let’s move on then to the more basic question of how widely single-dose nevirapine is being used in sub-Saharan Africa. It obviously varies tremendously from region to region.

Dr. McIntyre:
pMTCT programs have very high coverage in some areas of sub-Saharan Africa, but in most places, fewer than 5% to 10% of women who need a pMTCT intervention actually get one.

Dr. Lockman:
Even with simple interventions like nevirapine, there are hurdles and barriers. For example, in a study in Zambia, women identified as HIV-infected were given single-dose nevirapine to take home, but, according to unpublished data, only 75% of the women who said they took the nevirapine actually had detectable levels of the drug in their blood. On the flip side, I see many notes of hope in Botswana. Since the national program became available there, the uptake of pMTCT interventions has increased from an estimated 10% or 15% to more than 50%. Some of that probably has to do with the institution of opt-out HIV testing, which has increased testing-acceptance rates from about 45% to 95% in most areas.

Dr. Coovadia:
Let’s move on then to the issue of resistance. How common is nevirapine resistance, and what factors appear to be associated with it?

Dr. Fowler:
Resistance occurs with nevirapine whether it’s used in a single dose or as part of combination therapy. The extent of resistance seen really varies with the type of probe used and the clade. With the usual probes, resistance has been seen in 13% to 60% of patients, but with ultra-fine probes, it appears that almost everyone is resistant early on. In terms of clades, the one indication we have of a real difference is from data that Sue Eshleman presented at the Retrovirus Conference this year: Using a standardized technique in a single laboratory, she found a higher rate of resistance with clade C versus D — and with clade D versus A. Other factors that might lead to higher rates of resistance include high viral loads, low CD4-cell counts, and higher doses of nevirapine. We also see higher rates of resistance in the first 2 weeks of treatment versus later on.

Dr. Lockman:
Resistance might also differ by compartment. In HPTN 023 in Zimbabwe, Lee and colleagues found that the rate of resistance mutations was higher in breast milk than in maternal plasma and that the type of mutation varied by compartment, which may be a function of different mutations evolving over time. For example, we’ve seen a transition from Y181C to K103N in the first few weeks after nevirapine. Other questions that are only now being looked at in more detail are the rate of archived drug resistance in cellular DNA and whether that archived resistance dissipates over time.

Dr. Coovadia:
What does nevirapine resistance mean for the subsequent treatment of a child or mother?

Dr. Fowler:
With effective pMTCT programs, we should be able to get the infection rate among infants down to <5%. For those infants who do end up infected, we can expect resistance rates, at least early on, of about 43%. Given the high mortality rate among these infants in the first 2 years, early treatment is important, and the preference would be non–NNRTI-based potent combination antiretroviral therapy. For the mothers, the implications of resistance and the long-term treatment options are less clear.

Dr. Lockman:
The main data we have so far for evaluating adult response to treatment after exposure to single-dose nevirapine are from Mark Lallemant’s group, where women in Thailand received short-course AZT and either single-dose nevirapine or placebo. Results from this study suggest that the likelihood of achieving a very low viral load on nevirapine-based therapy is reduced with prior receipt of single-dose nevirapine, but the ultimate clinical implications of this are unknown — particularly if patients start therapy many months or years after nevirapine exposure, when reversion to circulating wild-type virus has presumably occurred in those who had resistance early on. Most of us in the field feel that these data validate our concerns but have not been strong enough to change practice yet, either in terms of completely abandoning the use of single-dose nevirapine or in terms of switching women with previous nevirapine exposure to alternative regimens that might be associated with other problems, such as side effects, heat instability, or high cost. We hope to have more data on response to nevirapine-based therapy after nevirapine exposure later this year from Botswana, and other related studies elsewhere are planned or are underway.

Dr. Fowler:
Daniel Westreich has done some interesting statistical work, modeling survival in women who started potent combination antiretroviral therapy after receiving either single-dose nevirapine or potent combination antiretroviral therapy for pMTCT. What was striking was his conclusion: The long-term effects of nevirapine resistance appeared minor compared with the effects of less-than-universal access to potent combination antiretroviral therapy. It’s a reality check of the big picture.

Dr. Coovadia:
What about the other implications of nevirapine resistance, for example, on future pregnancies or sexual partners?

Dr. McIntyre:
Very few data are available on how nevirapine use affects a subsequent pregnancy. Our group has an ongoing study (presented by Neil Martinson at the Retrovirus Conference) that suggests higher transmission rates among women exposed to nevirapine in a previous pregnancy (10.3%) than in multiparous women receiving it for the first time (3.8%), but there is wide overlap of the confidence intervals, and the difference is not statistically significant. About half of the women had detectable resistance at 6 weeks, regardless of whether they had previous nevirapine exposure.

We also don’t have hard data on whether there’s an increased rate of transmission of resistant virus to sexual partners and whether it’s being spread into the HIV-positive community. We do know, though, that we’re generally seeing the K103N mutation, which is quite a fit virus, but even when one can detect K103N, the resistant virus is only a proportion of the total virus population. We don’t think it would be transmitted preferentially to sexual partners, but we don’t know for sure.

Dr. Coovadia:
What are some possible avenues for reducing nevirapine resistance, given what we know about it?

Dr. McIntyre:
Nevirapine has a long half-life and a very low genetic barrier to resistance: even after a single dose, it remains detectable in the bloodstream for up to 3 weeks, and the virus needs only one point mutation to become resistant. Evidence is accumulating that we can reduce this resistance by covering the tail — that is, using two drugs after single-dose nevirapine to cover the drug’s prolonged active phase. We presented preliminary data last year in Bangkok from a study that looked at covering the tail with 4 to 7 days of Combivir started in labor: We found 10% resistance rates (compared with 50% where there was no tail cover). We also have an expanded dataset on that now (with close to 200 women), and we do, in fact, see those results holding true. There’s also evidence on this approach from the DITRAME Plus study that François Dabis presented at the Retrovirus Conference this year on behalf of Chaix and colleagues. The difference in that study was that women received antenatal Combivir, as well as single-dose nevirapine and postpartum Combivir, so you would expect their viral loads to be lower at delivery. In a similar population in Côte d’Ivoire, Chaix and colleagues studied women who received antenatal AZT with a nevirapine boost. They saw the rate of nevirapine resistance drop substantially with a 3-day Combivir cover: from around 20% to 1%. The tradeoff was a 3TC resistance rate of around 8% or 9%.

All of these data suggest that we could avoid resistance after single-dose nevirapine by starting a simple cover in labor. This approach could be applied in settings where women are not delivering in the health sector or are not presenting for prolonged antenatal care, so it would allow us to preserve the efficacy of the nevirapine regimen while getting around the resistance issue. Of course, we still need more information on how long the tail cover should be and what it should consist of.

Dr. Fowler:
The data that stand in contrast to these — and the numbers in all the studies are relatively small — were presented by Lyons and colleagues at the 2004 Retrovirus Conference. They saw about 16% resistance after 5 days of postpartum Combivir to cover the tail.

Dr. McIntyre:
One difference between our study and that one, though, is that women in our study had received single-dose nevirapine, whereas those in the Lyons study had received nevirapine-containing multidrug therapy throughout their pregnancies. I’m not sure what the biological plausibility is here, but it does seem that there may be a difference in covering after a single dose of nevirapine compared with covering after a longer regimen containing nevirapine.

Dr. Lockman:
Another option for reducing resistance — as an alternative to covering the nevirapine tail — might be to use drugs other than nevirapine, such as single-dose tenofovir, that also have a long half-life but have a higher barrier to developing resistance.

Dr. Coovadia:
Is it possible that we might not need the maternal dose of nevirapine at all?

Dr. Lockman:
We looked at the necessity of the maternal nevirapine dose in the Mashi study in Botswana, where all of the infants received AZT and nevirapine and the mothers received short-course AZT with either placebo or nevirapine. We found — and this was reported by Roger Shapiro at this year’s Retrovirus Conference — that the two groups of mothers had similar transmission rates at 1 month: 3.7% in those who received placebo and 4.3% in those who received nevirapine. So in the setting of short-course AZT to mothers and infants, we feel pretty comfortable saying that if the infants get nevirapine, the mothers don’t necessarily have to. I don’t think we can say, though, whether the maternal dose is needed if you’re using nevirapine only and not including it with AZT.

Dr. Fowler:
We need to continue assessing this, but it’s important to keep in mind that there are theoretical reasons for the maternal dose of nevirapine. It covers the intrapartum period, which is a very high-risk period of exposure for the infant, and it might also lower the viral load in breast milk during the first several weeks after delivery.

Dr. Coovadia:
Do any of you expect that rollout programs will help outpace single-dose nevirapine in the next year or two — or do you expect that we’ll need some sort of short-course pMTCT intervention for many years to come?

Dr. McIntyre:
I’m sure that we’ll need another intervention. Rollout programs focus on providing antiretroviral therapy to people who need ongoing treatment. In our setting, about 20% of HIV-positive pregnant women will have CD4-cell counts low enough (<200 cells/mm³) to qualify for such treatment. The remaining 80% will still need an effective pMTCT strategy that is simple, safe, and easy to take. This will be a major challenge, even in areas where treatment rollout is going ahead.

Dr. Lockman:
Another challenge is that many women in Africa don’t deliver in traditional health facilities or receive antenatal care early in pregnancy. This makes it difficult to deliver antiretroviral therapy antepartum and again increases the current role for single-dose nevirapine.

Dr. Fowler:
Given that most women do show up for antenatal care several times in later pregnancy, one could look at innovative approaches to ensuring some degree of coverage both in the late prenatal period and peripartum. For example, Mark Lallemant’s findings from the Thai trial — and data from the DITRAME Plus trial from western Africa — that suggest a synergistic reduction in transmission with short-course AZT and single-dose nevirapine are quite exciting.

Dr. McIntyre:
I agree. Results from Africa and Asia suggest that dual therapy (with AZT and nevirapine, in particular) can reduce transmission rates to below 5% — or even 2% in women who are not breastfeeding. The challenge now is to figure out how to implement the most effective regimen possible while still protecting a baseline regimen for women who can’t gain access to longer treatment or who don’t present early enough to do so. In some areas, dual therapy could be implemented almost immediately, but in other areas, we’re still struggling to start even a simple nevirapine regimen.

Dr. Lockman:
And even if more complex regimens were available now, most would be nevirapine-based in sub-Saharan Africa, and that raises concerns about toxicity. When nevirapine is used for ongoing treatment, it can cause toxicities that do not occur when it’s used as a single dose — and that toxicity seems to occur at higher CD4-cell counts, although there are conflicting data on that. So I think that the outstanding research questions in this area — even if combination therapy does become available to all women — involve determining what the optimal regimen would be for women with CD4 counts >200 cells/mm³, whether these women are less likely to transmit HIV, and how much less likely they are to develop resistance. Short-course therapy might be effective in this group, but we really don’t know.

Dr. Fowler:
That’s a very important point. As we move ahead, we’ll need to keep weighing the risk of toxicity against the transmission-reduction benefit. At this point, short-course AZT with single-dose nevirapine, as well as Combivir (AZT/3TC), appear to reduce the risk of perinatal transmission to about 2%, which is similar to what we see with triple therapy among nonbreastfeeding women in the U.S. In resource-limited settings, the toxicity issues with use of triple drugs for pMTCT and the required monitoring might make the use of simpler, less toxic regimens much more feasible in program situations. I think that this will turn out to be extremely important and that the knee-jerk reaction, particularly in resource-rich settings, to say, "Oh, yes, we can just use potent combination antiretroviral therapy for every HIV-infected pregnant woman," really does need to have a reality check in resource-limited settings. Certainly, the subset of pregnant HIV-infected women who do meet criteria for treatment should receive potent combination antiretroviral therapy, but the majority of pregnant HIV-infected women do not require potent combination therapy for their own care; the antiretrovirals are being used for pMTCT.

Dr. McIntyre:
That’s very true, and you also have to balance this movement toward potent combination therapy against the scale of the project. In many southern African settings, 1 in 3 pregnant women is HIV-positive, and these women are not being seen by obstetricians and gynecologists. It’s challenging to think how we could administer and monitor potent combination antiretroviral therapy in all of these women without having doctors or even experienced nursing staff in many of these settings.

Dr. Coovadia:
In a PEPFAR program here at McCord Hospital, the cost of providing potent combination antiretroviral therapy is almost double if we use a doctor versus a trained nurse. So it’s a question of cost and other resources that might need to be put in place. And in every situation, we’ll need to evaluate whether potent combination antiretroviral therapy is appropriate for all pregnant women or only for those with CD4 counts <200 cell/mm³. My sense, or what I’m hearing, is that it’s highly unlikely that the majority of developing countries will be able to use potent combination antiretroviral therapy for all women, even though that’s what we support.

— Hoosen Coovadia, MD, Mary Glenn Fowler, MD, MPH, Shahin Lockman, MD, MSc, and James McIntyre, MD

Published in AIDS Clinical Care June 15, 2005

Citation(s):

Chaix ML et al. Genotypic resistance analysis in women who received intrapartum nevirapine associated to a short course of zidovudine to prevent perinatal HIV-1 transmission: The Ditrame Plus ANRS 1201/02 Study, Abidjan, Côte d'Ivoire. 11th Retrovirus Conference, San Francisco, Feb 2004. Abstract 657 .

Chaix ML et al. Addition of 3 days of ZDV+3TC postpartum to a short course of ZDV+3TC and single-dose NVP provides low rate of NVP resistance mutations and high efficacy in preventing peri-partum HIV-1 transmission: ANRS DITRAME Plus, Abidjan, Côte d’Ivoire. 12th Retrovirus Conference, Boston, Feb 2005. Abstract 72LB .

Eshleman SH et al. Comparison of nevirapine resistance in women with subtype C compared with subtypes A and D after single-dose NVP. 12th Retrovirus Conference, Boston, Feb 2005. Abstract 799 .

Institute of Medicine of the National Academies. Review of the HIVNET 012 perinatal HIV prevention study . Washington, DC: National Academies Press; 2005.

Jourdain G et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004 Jul 15; 351:229-40.

• Original article (Subscription may be required)
• Medline abstract (Free)

Lyons E et al. Emergence of genotypic resistance in HIV-1-infected pregnant women taking HAART to reduce mother-to-child transmission of HIV-1. 11th Retrovirus Conference, San Francisco, Feb 2004. Abstract 892 .

Lallemant M et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004 Jul 15; 351:217-28.

• Original article (Subscription may be required)
• Medline abstract (Free)

Lee E. Breast milk shedding of drug-resistant subtype C HIV-1 and among women receiving single-dose nevirapine. 10th Retrovirus Conference, Boston, Feb 2003. Abstract 96 .

Martinson N et al. Effectiveness of single-dose nevirapine in a second pregnancy. 12th Retrovirus Conference, Boston, Feb 2005. Abstract 103 .

McIntyre J et al. Addition of short course Combivir (CBV) to single dose viramune (sdNVP) for prevention of mother to child transmission (MTCT) of HIV-1 can significantly decrease the subsequent development of maternal NNRTI-resistant virus. XV International AIDS Conference, Bangkok, Jul 2004. Abstract LbOrB09 .

Shapiro R et al. Maternal single-dose nevirapine may not be needed to reduce mother-to-child HIV transmission in the setting of maternal and infant zidovudine and infant single-dose nevirapine: Results of a randomized clinical trial in Botswana. 12th Retrovirus Conference, Boston, Feb 2005. Abstract 74LB .

Westreich D et al. Nevirapine resistance and survival of women receiving HAART subsequent to prevention of mother-to-child transmission: A population-based stochastic model. 12th Retrovirus Conference, Boston, Feb 2005. Abstract 73LB .