Boston, MA -- Delaying the use of nevirapine-containing antiretroviral therapy (ART) for at least six months after labor may improve treatment outcomes among HIV-infected women in developing countries who took nevirapine during labor to prevent their babies from becoming infected, suggests a new study in The New England Journal of Medicine. The findings could potentially change treatment approaches for millions of mothers infected with the AIDS virus. The study appears in the January 11, 2007, issue of the journal.
Nevirapine, given once during labor, either alone or in combination with a short course of zidovudine (AZT) or other antiretroviral medications, significantly reduces the chances that a pregnant woman will pass HIV to her child. A single dose of nevirapine during labor is frequently all that is accessible to pregnant women in resource-limited settings where more complicated and expensive, multidrug treatments may not be available.
The use of single-dose nevirapine has successfully reduced mother-to-infant transmission of HIV, but has also created a terrible dilemma for physicians and patients. Research has shown that 20 to 69 percent of women who take a single dose of nevirapine during labor subsequently develop resistance to the drug -- a situation that may undermine the patients" ability to respond later to nevirapine-containing ART when they may need the treatment to save their lives. Nevirapine is the cornerstone of three-drug ART in most regions of the world. Drug resistance develops as well in a range of the minority of infants who become HIV infected, despite the use of single-dose nevirapine.
Now, a team of researchers led by Shahin Lockman, Assistant Professor in the Department of Immunology and Infectious Diseases at Harvard School of Public Health (HSPH) and at Brigham and Women's Hospital, and Max Essex, chair of the HSPH AIDS Initiative, has conducted a study that suggests a potential solution to this problem. The results may help women who already received a single dose of nevirapine during labor and those who have not yet given birth.
Working within a randomized clinical trial established by the Botswana-HSPH AIDS Initiative Partnership for HIV Research and Education, the team conducted a prospective observational study that included 218 postpartum, HIV-infected women who had received a single dose of nevirapine during labor, in addition to a short course of AZT during pregnancy. Sixty women started nevirapine-based ART within six months of giving birth, and the remaining women began the regimen after that time had passed.
Of the 60 women who started nevirapine-based ART within six months of giving birth, 24 had received a single dose of nevirapine during labor, while 36 had received a placebo. (All of the women in the study were given zidovudine from 34 weeks into their pregnancies through delivery; similar to nevirapine, zidovudine reduces HIV transmission from mother to child.) Of the women in this group who received a single dose of nevirapine during labor, 41.7 percent subsequently experienced treatment failure, or "virologic failure," within a half a year of starting ART -- compared to zero percent among the women in this group who had received placebo during delivery. Similar differences were found at follow-up visits one and two years after ART had started.
In contrast, there were no statistically significant differences in failure rates within the women who delayed ART for six months -- regardless of whether they had received a single dose of nevirapine during labor or not. This group (and additional women who have joined the study since) continues to be followed to ensure that no differences emerge as the women receive treatment over a longer period of time, said Dr. Lockman.
She added that these findings may be explained by the fact that the amount of nevirapine-resistant HIV in the body decreases as time passes from the time of exposure to single-dose nevirapine during labor.
Said Dr. Essex, "These results translate into very clear policy for how to treat AIDS in new mothers who received nevirapine to protect their infants. If you can wait six months to administer nevirapine-based ART, do so. If not, treat only with combinations of drugs that do not contain nevirapine or nevirapine-related drugs. Implementing this policy can improve the health of women who need AIDS treatment."
Treatment response was also measured among 30 infants in the study who received nevirapine-based ART. More than three-quarters of the 15 infants who were exposed to single dose nevirapine as newborns did not respond adequately to the triple-drug treatment (compared with 9.1 percent of the 15 infants without prior nevirapine exposure). While these results raise concerns regarding the use of nevirapine-based ART for infants following single-dose nevirapine exposure, said Dr. Lockman, the group of infants studied was small, and additional data among infants is needed.
Summarized Dr. Lockman, "Women who need combination ART for their own health during pregnancy should absolutely receive combination ART whenever possible. However, single-dose nevirapine remains important in preventing mother-to-child transmission of HIV in many locales where it is still the only intervention available. This study provides some important guidance and measured reassurance regarding the timing and effectiveness of nevirapine-based antiretroviral treatment for the many women with AIDS who previously received single-dose nevirapine in labor."
This NEJM paper is the third in a series recently published by the Botswana-HSPH AIDS Initiative Partnership to address the theme of saving infants and their mothers from HIV/AIDS in Southern Africa, a region of the world that suffers from the worst HIV/AIDS epidemic. See below for full citations.
The NEJM study was supported by the National Institute of Child Health and Human Development and the Fogarty International Center, both at the National Institutes of Health, by the Botswana Ministry of Health (which provided antiretroviral treatment medications and laboratory monitoring for women and infants receiving ART), by UNICEF, by Boehringer Ingelheim (which provided the single doses of nevirapine and placebo for the parent Mashi Study), and by GlaxoSmithKline (which provided zidovudine prophylaxis for the parent Mashi Study).
Lockman et al., (2007) Response to Nevirapine-Based Antiretroviral Therapy After Single-Dose Nevirapine, New England Journal of Medicine, January 11.
A complete list of the study's authors and their affiliations:
Shahin Lockman, M.D., M.S., Roger L. Shapiro, M.D., M.P.H., Laura M. Smeaton, M.S., Carolyn Wester, M.D., Ibou Thior, M.D., M.S., Lisa Stevens, M.D., Fatima Chand M.S., Joseph Makhema, M.B.ChB., M.R.C.P., Claire Moffat, M.B.ChB., M.P.H., Aida Asmelash M.D., M.P.H., Patrick Ndase, M.B.ChB., M.P.H., Peter Arimi, M.B.ChB., Erik van Widenfelt, B.S., Loeto Mazhani, M.D., Vladimir Novitsky, M.D., Ph.D., Stephen Lagakos, Ph.D., and Max Essex, D.V.M., Ph.D
From the Division of Infectious Diseases, Brigham and Women's Hospital (S. Lockman), the Departments of Immunology and Infectious Diseases (S. Lockman, R.L.S., C.W., I.T., L.S., J.M., V.N., M.E.), and Biostatistics (L.M.S., S. Lagakos), Harvard School of Public Health, the Infectious Disease Unit, Brigham and Women's Hospital (S. Lockman), the Division of Infectious Diseases, Beth Israel Deaconess Medical Center (R.L.S.)-- all in Boston; Botswana - Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education, (S. Lockman, R.L.S., C.W., I.T., L.S., F.C., J.M., C.M., A.A., P.N., P.A., E.V.W., V.N., M.E.), and the Botswana Ministry of Health (L.M.)- both in Gaborone.
Also see:
"Maternal Single-Dose Nevirapine Versus Placebo as Part of an Antiretrovial Strategy to Prevent Mother-to-Child HIV Transmission in Bostwana" Shapiro et al. (AIDS 2006; 20:1281-1288)
"Breastfeeding Plus Infant Zidovudine Prophylaxis for 6 Months vs Formula Feeding Plus Infant Zidovudine for 1 Month to Reduce Mother-to-Child HIV Transmission in Botswana: A Randomized Trial: The Mashi Study" Thior et al. (JAMA 2006; 296: 794-805)
Journal
New England Journal of Medicine