The challenge of nevirapine resistance

Anthony Mwatha finds mothers and infants with some HIV subtypes show increased resistance to drug used to prevent perinatal transmission of HIV in developing countries
Dr. Deborah Donnell and Anthony Mwatha
Dr. Deborah Donnell of the HIV Prevention Trials Network and Anthony Mwatha of SCHARP study complications with the drug treatment that helps prevent mother-to-child HIV transmission. Photo by Dean Forbes

In 1999, news from Uganda made headlines around the world: An inexpensive drug prevents transmission of HIV, the virus that causes AIDS, from infected mothers to their infants during birth. Researchers found that a single $3 dose of nevirapine was 50 percent more effective that a short course of the anti-retroviral drug AZT in stopping perinatal transmission of HIV. Two hundred times more cost-effective than AZT, the treatment was a breakthrough for developing countries in which HIV transmission can occur in 25 percent to 50 percent of babies born to HIV-positive mothers.

However, a new study published in the Dec. 2 issue of the journal AIDS shows the same nevirapine regimen that prevents perinatal HIV transmission leads to drug resistance in a significant number of infants. Malawian infants with a subtype of HIV infection called subtype C, who received nevirapine and contracted HIV despite the treatment, developed resistance to the drug in 87 percent of cases.

The study was conducted by a group of researchers from Johns Hopkins University with help from statistical research associate Anthony Mwatha of the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) in the Hutchinson Center's Public Health Sciences Division.

Breakthrough treatment

The landmark HIVNET 012 study, published in 1999 in The Lancet, demonstrated that the single-dose nevirapine regimen was more effective than a short course of zidovudine (AZT) in preventing the transmission of HIV from mother to child. The trial was conducted a single study site in Uganda by a group that included several researchers from the Statistical Center for HIV/AIDS Research and Prevention (SCHARP), in the Hutchinson Center's Public Health Sciences Division. In the trial, expectant mothers received a single oral dose of nevirapine during labor, and infants receive one dose within 72 hours of birth. The breakthrough nevirapine regimen became the most commonly used treatment for preventing perinatal transmission of HIV in developing countries.

In 2001, a study showed that the single-dose nevirapine regimen was associated with selection of nevirapine-resistant HIV in 19 percent of women and 46 percent of infants in the original trial, most of whom were infected with HIV subtypes A and D.

Mwatha's new study detected an even higher rate of nevirapine resistance (87 percent) among Malawian infants with subtype C HIV infection who had received the single-dose nevirapine treatment. The increased incidence of nevirapine resistance found in infants with subtype C is consistent with another related study which showed that nevirapine resistance developed more frequently in Malawian mothers, all of whom had subtype C, than in the mother from the original trial with subtypes A and D.

The observation that both mothers and infants with subtype C have a greater incidence of nevirapine resistance than those with subtypes A or D (tested in the original Ugandan trial) suggests the possibility that subtype C may be more susceptible to developing drug resistance than other subtypes. Alternately, resistance viruses selected after single-dose nevirapine may persist longer in women and infants with subtype C, making them more readily detectable in the weeks following birth.

"It's not really known why one subtype would be more resistant than another," Mwatha said.

Mwatha, a native of Kenya, feels a special sense of responsibility to do something about the epidemic of HIV in his homeland. In sub-Saharan Africa there are roughly 30 million people living with HIV/AIDS. This is akin to populations of the states of Washington, Oregon, Idaho, Montana, Wyoming, Nevada, Utah, Colorado, Arizona and New Mexico combined. In 2005, more than 3 million people in sub-Saharan Africa were newly infected with HIV. Transmission of HIV from mother to child accounts for a significant portion of this staggering number of HIV infections.

"There is a big HIV problem in most of Africa, and so I think that's been one of the reasons I've wanted to do this work. I feel like I would like to contribute my skills in statistics in research because that's the only way we can come up with better ways of understanding the disease and preventing it" Mwatha said.

The nature of modern HIV treatments makes nevirapine-resistant HIV infections more difficult to treat. According to Mwatha, Africa is slowly starting to build an infrastructure to treat people using the same drugs that have long been used in the developed world. "Nevirapine would be one of the drugs that would be used in Africa to treat people as part of a 'cocktail'," said Mwatha, referring to a combination of three or more drugs from different classes that each attack HIV in a different way. Drug cocktails are also called anti-retroviral treatment (ART). However, if someone is resistant to even one of the drugs in a cocktail, the combination may be less effective in combating their infection. So if a mother or infant becomes nevirapine-resistant, they may not respond optimally to certain ART treatments that are just now becoming available in Africa.

Further study

It is also important to determine whether emergence of resistance after the single-dose treatment compromises use of the HIVNET 012 regimen in a subsequent pregnancy. New studies are examining how long nevirapine-resistant strains persist in women after the single-dose regimen, and clinical trials are underway to examine the relationship between emergence of nevirapine resistance in this setting and subsequent use of nevirapine for HIV prevention and treatment.

Mwatha and other SCHARP researchers are also examining HIV transmission though breast-feeding. In developed nations, mothers are counseled to feed their babies with a bottle to avoid this risk, but in many parts of Africa, this is not feasible due to the expense and a lack of potable water. Breast-feeding also offers health advantages to infants in resource limited settings.

"Another study, HPTN 046, is about to start, looking at the use of nevirapine to prevent HIV transmission during breast feeding," Mwatha said. "Nevirapine resistance is a big question in this study and so it will be closely monitored."

Since the initial results of HIVNET 012 were published, there has been an international effort in resource-limited settings to establish the infrastructure needed to provide single-dose nevirapine to as many HIV-infected women as possible. To date, more than 500,000 pregnant women have received the regimen. Because nevirapine resistance emerges after the single-dose treatment, it may not be the best option for curbing perinatal transmission in the future. Further data are needed to evaluate the clinical impact of nevirapine resistance after treatment with the regimen. If nevirapine in this setting is found to compromise use of the drug for subsequent treatment of HIV infection in women or children, or for prevention of HIV mother-to-child transmission in subsequent pregnancies, those concerns might outweigh the significant advantages of the regimen, including its safety, simplicity and low cost.

Deborah Donnell, deputy director of the HIV Prevention Trials Network statistical center based at SCHARP, said the fact that ART is unavailable to most infected individuals in Africa means problems of nevirapine resistance do not outweigh the known benefits of preventing infection in the newborn. "It is not yet known how significant nevirapine resistance is in settings where ART treatment is not yet available," Donnell said. "For the moment, single-dose nevirapine is a proven, effective strategy for prevention of transmission to infants in these countries, whereas [ART] treatment still remains beyond the reach of the majority of these women today." Thus, nevirapine resistance will become a bigger issue in Africa only when the drug cocktails that contain it become more widely available.

Mwatha agreed, adding that there is still much to be done to prevent the spread of HIV in his homeland. "Given the situation we are in, I think [nevirapine] is still the best way to prevent mother to child transmission of HIV," Mwatha said. "I believe there is more we can do, and hopefully over time we will see more being done and more drugs will be available to better prevent transmission."

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