The incidence of drug resistance associated with single-dose nevirapine, a drug used to prevent mother-to-child transmission of HIV-1, may be substantially higher than previously thought and of particular risk for those infected with HIV-1 subtype C, according to three new studies published in the July 1 issue of The Journal of Infectious Diseases, now available online.
A single dose of nevirapine given to an HIV-infected pregnant woman during delivery, and another given to her newborn, can cut the rate of mother-to-child HIV transmission in half. The relative simplicity and affordability of single-dose nevirapine have made it the drug of choice for prevention of mother-to-child transmission in many developing countries.
This new research expands understanding of the risks of drug resistance associated with single-dose nevirapine, but as noted by all three research groups, the clinical implications for patients are not yet clear. More research will be needed to determine whether nevirapine used to prevent mother-to-child transmission affects the chances of successful treatment later with nonnucleoside reverse transcriptase inhibitors, the class of drug to which nevirapine belongs.
Two of the studies analyzed the incidence of nevirapine-associated resistance using laboratory tests more sensitive than standard genotypic assays. In the first, researchers led by Jeffrey A. Johnson, PhD, of the Centers for Disease Control and Prevention, used a new, very sensitive technique to detect resistance mutations in samples of HIV-1 obtained from 50 South African women before and after treatment with single-dose nevirapine. Using a less-sensitive conventional technique called sequence analysis, researchers had previously estimated that viral resistance to nevirapine emerged in approximately 40 percent of women after receiving the single-dose therapy. In contrast, Dr. Johnson and colleagues concluded that resistance emerges in at least 65 percent of women after use of single-dose nevirapine. This finding indicates that more than one-third of the resistance that emerges from this intervention is undetected by conventional laboratory tests.
In the second study, a group headed by Susan H. Eshleman, MD, PhD, of Johns Hopkins University, analyzed HIV samples from nine mothers and five infants in Uganda who had received single-dose nevirapine. The researchers used standard sequencing techniques and, like the first group of researchers, two more-sensitive assays. The more-sensitive assays detected resistance mutations a year or more after use of single-dose nevirapine, whereas the conventional assay could not detect resistance at one or two years. Taken together, these two studies indicate that resistance after the single-dose therapy occurs more frequently and may persist longer in the circulation than previously thought.
The third study, also led by Dr. Eshleman, asked whether the rate of nevirapine resistance differs according to HIV-1 subtype. The researchers examined the rate of nevirapine resistance after single-dose therapy in 65 women in Malawi infected with subtype C, the most common subtype in many developing countries where single-dose nevirapine is used, as compared with that of 241 women in Uganda infected with subtypes A or D. (In the United States, B is the predominant subtype.) Women in each subtype group had similar demographic characteristics. The frequency of mutations associated with nonnucleoside reverse transcriptase inhibitors was significantly higher in women with subtype C virus (69 percent) than in those with subtype A (19 percent) or subtype D (36 percent).
In an accompanying editorial, Scott M. Hammer, MD, of Columbia University, emphasized that these three studies raise questions for additional research, including whether the presence of nevirapine-associated resistance mutations in women and children compromises the subsequent treatment of their HIV infection, or the subsequent use of single-dose nevirapine in a second pregnancy. As an alternative approach to single-dose nevirapine, Dr. Hammer noted, combination therapies can reduce rates of newborn HIV infection while reducing the risk of resistance in the mother, but are more expensive and may require more health care infrastructure.
"As with any new medical intervention," Dr. Hammer said, "there are inevitable tradeoffs with single-dose nevirapine. Although no major safety issues have arisen in mothers or infants taking this therapy, the emergence of drug resistance has created an increasing challenge to the scientific and public health communities."