October 21, 2010 — An international study led by Shahin Lockman, assistant professor in immunology and infectious diseases at HSPH and a physician at Brigham and Women’s Hospital in Boston, has found that women who took single-dose nevirapine in labor in the past and who need antiretroviral treatment for their own advanced HIV/AIDS should be treated with more effective treatment like ritonavir-boosted lopinavir-based regimens instead of the standard, cheaper nevirapine-containing ones.
The report is one of two studies and an accompanying editorial on antiretroviral treatment of postpartum HIV-infected mothers and their babies featuring HSPH researchers published in the October 14, 2010, New England Journal of Medicine. Both studies found evidence of the nevirapine-resistant HIV among women and infants with prior exposure to single-dose nevirapine, and the effectiveness of the more expensive treatment regimens.
Many of the women in developing nations who take single-dose nevirapine in labor to decrease the chances of their baby becoming infected are found to develop nevirapine-resistant virus. Nevirapine (or a related drug, efavirenz) is also almost always a component of antiretroviral treatment regimens in resource-limited settings for people whose HIV disease progresses to AIDS. Presence of drug-resistant virus in the body declines over time following single-dose nevirapine ingestion, but persists at low levels and may reduce the effectiveness of nevirapine if the woman later requires treatment for HIV or AIDS herself–particularly if she starts treatment within six months of taking single-dose nevirapine. However the outcomes are improved for women taking a nevirapine-based combination therapy if more than six months have passed after initially taking single-dose nevirapine. Click here to read study.
According to UNAIDS, approximately half of the 33 million people living with HIV worldwide are women of reproductive age. Among the 2.1 million HIV-infected children, virtually all were infected during pregnancy, delivery, or breastfeeding.
Women in Lockman’s study were enrolled at 10 African sites, including the Botswana-Harvard AIDS Institute Partnership research site and nine other locations in South Africa, Kenya, Zimbabwe, Zambia, Malawi, and Uganda. Other HSPH researchers participating in the study include Michael Hughes, director of the Center for Biostatistics in AIDS Research (CBAR) and professor of biostatistics, and Evelyn Zheng of the CBAR. The study was funded by the NIH’s National Institute of Allergy and Infectious Diseases and the National Research Center.
In this clinical trial known as the Optimal Combination Therapy after Nevirapine Exposure (OCTANE) study, Lockman and her colleagues gave either nevirapine plus two other drugs, or an alternative drug regimen (with lopinavir/ritonavir plus two drugs) to 241 African women who had taken one dose of nevirapine at least six months earlier. They found 26% of those who took nevirapine-containing drugs were unable to fight the virus or died, compared with 8% of those given ritonavir-boosted lopinavir. Women who failed treatment could switch to the other drug in the study.
The second study reported in the NEJM issue was led by Paul Palumbo of Dartmouth-Hitchcock Medical Center. It examined antiretroviral treatment in 164 HIV-positive African infants and toddlers, age 6 to 36 months, who had received nevirapine at birth. This National Institutes of Health (NIH) sponsored study, which included HSPH statisticians Jane Lindsey and Michael Hughes, also found resistance to nevirapine in 18 of 148 children (12%) and was predictive of treatment failure. The researchers also found that children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission did better on alternative antiretroviral treatments. Click here to read study.
The results of both studies, announced at scientific meetings last year, led the World Health Organization (WHO) in July 2010 to change its guidelines for treating HIV infection in certain women and children. The revised WHO guidelines recommend that HIV-infected women who take only single-dose nevirapine to prevent mother-to-child transmission should not be treated for their own infection with a drug regimen containing nevirapine within a year of taking single-dose nevirapine.
“We have an obligation to protect and improve the health of the hundreds of thousands of HIV-infected women who take antiretroviral drugs each year to prevent their babies from becoming infected with HIV,” said Lockman. “These mothers sacrifice to get tested for HIV despite the stigma and fear if they are found to be positive. Then they take nevirapine during labor to decrease HIV transmission to their babies, but what happens to the women later when they need treatment for their own HIV or AIDS? We must find ways to get these women access to more effective drugs during pregnancy or postpartum, so that drug resistance won’t hamper their own treatment.”
“These results illustrate that the Botswana-Harvard AIDS Institute Partnership research site in Gaborone, Botswana, and other sites in developing countries can work together toward a very important goal for treatment of HIV/AIDS in infected mothers,” said Max Essex, chair of the Harvard AIDS Initiative. “Lockman and colleagues deserve tremendous credit.”
NEJM carried an accompanying editorial by HSPH’s Marc Lallemant, research associate in immunology and infectious diseases, and Gonzague Jourdain, visiting scientist in immunology and infectious diseases, both of whom also are affiliated with the Institut de Recherche pour le développement, Marseille, and Chiang Mai University in Thailand. Lallemant and Jourdain said that while nevirapine has shortcomings, it remains a useful drug.
“The results of these two studies are remarkably coherent,” Lallemant said. “They confirm the short-term negative impact of single-dose nevirapine on subsequent nevirapine-based treatments and show that one way to get around it is to initiate therapy with lopinavir/ritonavir. But most importantly, they demonstrate that a majority of mothers and infants exposed to single-dose nevirapine do succeed with a subsequent nevirapine-based therapy.Identifying good responders based on resistance mutations tests would allow most women and infants to benefit from simple, inexpensive and potent nevirapine or efavirenz based treatments.” Click here to read editorial.
Single-dose nevirapine is a very potent drug for the prevention of HIV in children, Lallemant added. “It can select resistance mutations but there are many solutions to this problem,” he said. “The bottom line remains that the absolute priority is to prevent HIV infection in children in the first place, but resistance mutations to nevirapine can be avoided or managed.”
photo: Katrina Manson/Reuters
Drs. Roger Shapiro & Shahin Lockman: Partners in Research & Parenting (HAI Spotlight interview, Fall 2010)
NIH studies influence revision of WHO guidelines for treating HIV-infected women, infants (NIH press release, October 13, 2010)