Ask the Experts - Risk of Resistance with Single-Dose Nevirapine?
As an OB/GYN, my question is, How can we in good conscience talk about single-dose nevirapine as "the answer" to perinatal transmission when using it (especially in developing countries) is likely to induce resistant mutants like K103N? In particular, what's going to happen if those resistant mutants are passed around to children, or partners?
Single therapy nevirapine usage is not the current recommended prophylactic regimen to use in pregnancy for HIV-1-infected women, or for that matter, in any HIV-infected individual, except in special circumstances. Your question most likely relates to the recently published HIVNET 012 study in sub-Saharan African patients, which demonstrated that a single dose of oral nevirapine given to the pregnant mother at the start of labor and to her newborn at 48-72 hours of age resulted in a 50% decrease in transmission, compared with short-course zidovudine. Clearly, the overriding worry about single-dose nevirapine therapy is the development of mutations associated with high-level resistance, such as K103N. It is for this reason that single therapy with nevirapine is not used for any extended period. Nevertheless, in the setting of single-dose therapy in the HIVNET 012 study, there is some preliminary info that resistance may develop even with one dose (B. Jackson, personal communication, 2000). However, this study was designed to prevent transmission in a setting where there is limited access to health care, including HIV care and antiretroviral regimens. In the setting of sub-Saharan Africa, the benefit of a 50% reduction in transmission greatly outweighs the risk of resistance.
In those parts of the developing world where antiretroviral therapy and prenatal care are available, there are other options for pregnant women. If zidovudine is given during pregnancy (po), intrapartum (IV) , and to the newborn (po), the rate of HIV transmission is reduced by two-thirds, from 28% to 8%. Furthermore, in the era of combination therapy, the transmission rate has been reduced to 4%. Guidelines for antiretroviral therapy recommend potent therapy for all women, regardless of their pregnancy status, if their CD4+ count is <500 cells/mm3 and their HIV RNA is >10,000 copies/mL. However, many HIV care providers treat all HIV-infected pregnant women with HAART, regardless of their HIV RNA or CD4+ count levels, both for the health of the woman herself and because studies to date have shown that, although women with higher HIV RNA levels transmit at a greater rate than those with lower levels, no HIV RNA threshold has been established below which transmission does not occur. Although two recent studies have demonstrated no transmission from women with HIV RNA <1,000 copies/mL, other studies have shown transmission even below these levels. However, these studies were before the advent of HAART, and some centers have observed no transmission since HAART has become available. There are several key factors in making a choice of therapy, if you are in a country where specialized HIV care and medications are available. First, it is essential that the pregnant women be diagnosed sufficiently early that treatment can be initiated for her and her newborn. Second, it is essential that she receive care in a setting where specialists in the care of HIV are available and that this care be given in a team approach; through this approach, maximal compliance will be achieved and the best care will be given to both the pregnant women and her newborn, especially in view of the complex therapies available and the toxicities that occur.
The 3-part regimen of zidovudine should form the basis of the antiretroviral regimen, combined with additional antiretroviral agents to construct a potent HAART regimen, and initiated during the second trimester. However, for the HIV-infected pregnant woman who does not present until shortly before delivery, there are several options that have been shown to reduce transmission in clinical trials, including single-dose nevirapine to mother and baby, and oral zidovudine plus lamivudine during labor and for 1 week to the newborn. Other possible options that may be efficacious, based on epidemiologic evaluations, include intravenous zidovudine intrapartum followed by 6 weeks of oral zidovudine to the newborn.
As an OB/GYN, my question is, How can we in good conscience talk about single-dose nevirapine as "the answer" to perinatal transmission when using it (especially in developing countries) is likely to induce resistant mutants like K103N? In particular, what's going to happen if those resistant mutants are passed around to children, or partners?
Single therapy nevirapine usage is not the current recommended prophylactic regimen to use in pregnancy for HIV-1-infected women, or for that matter, in any HIV-infected individual, except in special circumstances. Your question most likely relates to the recently published HIVNET 012 study in sub-Saharan African patients, which demonstrated that a single dose of oral nevirapine given to the pregnant mother at the start of labor and to her newborn at 48-72 hours of age resulted in a 50% decrease in transmission, compared with short-course zidovudine. Clearly, the overriding worry about single-dose nevirapine therapy is the development of mutations associated with high-level resistance, such as K103N. It is for this reason that single therapy with nevirapine is not used for any extended period. Nevertheless, in the setting of single-dose therapy in the HIVNET 012 study, there is some preliminary info that resistance may develop even with one dose (B. Jackson, personal communication, 2000). However, this study was designed to prevent transmission in a setting where there is limited access to health care, including HIV care and antiretroviral regimens. In the setting of sub-Saharan Africa, the benefit of a 50% reduction in transmission greatly outweighs the risk of resistance.
In those parts of the developing world where antiretroviral therapy and prenatal care are available, there are other options for pregnant women. If zidovudine is given during pregnancy (po), intrapartum (IV) , and to the newborn (po), the rate of HIV transmission is reduced by two-thirds, from 28% to 8%. Furthermore, in the era of combination therapy, the transmission rate has been reduced to 4%. Guidelines for antiretroviral therapy recommend potent therapy for all women, regardless of their pregnancy status, if their CD4+ count is <500 cells/mm3 and their HIV RNA is >10,000 copies/mL. However, many HIV care providers treat all HIV-infected pregnant women with HAART, regardless of their HIV RNA or CD4+ count levels, both for the health of the woman herself and because studies to date have shown that, although women with higher HIV RNA levels transmit at a greater rate than those with lower levels, no HIV RNA threshold has been established below which transmission does not occur. Although two recent studies have demonstrated no transmission from women with HIV RNA <1,000 copies/mL, other studies have shown transmission even below these levels. However, these studies were before the advent of HAART, and some centers have observed no transmission since HAART has become available. There are several key factors in making a choice of therapy, if you are in a country where specialized HIV care and medications are available. First, it is essential that the pregnant women be diagnosed sufficiently early that treatment can be initiated for her and her newborn. Second, it is essential that she receive care in a setting where specialists in the care of HIV are available and that this care be given in a team approach; through this approach, maximal compliance will be achieved and the best care will be given to both the pregnant women and her newborn, especially in view of the complex therapies available and the toxicities that occur.
The 3-part regimen of zidovudine should form the basis of the antiretroviral regimen, combined with additional antiretroviral agents to construct a potent HAART regimen, and initiated during the second trimester. However, for the HIV-infected pregnant woman who does not present until shortly before delivery, there are several options that have been shown to reduce transmission in clinical trials, including single-dose nevirapine to mother and baby, and oral zidovudine plus lamivudine during labor and for 1 week to the newborn. Other possible options that may be efficacious, based on epidemiologic evaluations, include intravenous zidovudine intrapartum followed by 6 weeks of oral zidovudine to the newborn.
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