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Reduction of HIV-1 drug resistance after intrapartum single-dose nevirapine, Commentary
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The Lancet Nov 2007
Shahin Lockman a and James Alasdair McIntyre b
a. Brigham and Women's Hospital, Harvard School of Public Health, Boston, MA 02115, USA
b. Department of Obstetrics and Gynecology, University of the Witwatersrand, Chris Hani Baragwanath Hospital, Johannesburg, South Africa
Few issues in mother-to-child HIV-1 transmission have sparked as much controversy as intrapartum single-dose nevirapine. This drug is 40% efficacious in the prevention of such transmission,1 easy to use, safe, and cheap, which are all especially important in the developing world, where half a million children are infected annually by this route. But, by 2006, only 11% of HIV-infected women in sub-Saharan Africa were receiving antiretroviral drugs to prevent transmission to their children.2 The obstacles there include limited antenatal care: only two-thirds of pregnant women have at least one antenatal visit with a nurse or doctor, and under half have four or more.3 However, single-dose nevirapine programmes can be effectively implemented in these settings.4
After single-dose nevirapine, 19-75% of women5,6 and 33-87% of the minority of infants who become infected7,8 develop virus that is resistant to non-nucleoside reverse-transcriptase inhibitors (NNRTIs). Combination of other antiretrovirals with single-dose nevirapine somewhat attenuates the emergence of nevirapine resistance (figure). The TOPS study from South Africa showed that addition of intrapartum plus 4-7 days of maternal postpartum zidovudine/lamivudine significantly reduced detectable nevirapine resistance (from 57% to 9-13%) in women who did not receive any antenatal antiretrovirals.11
NNRTIs are a component of first-line antiretroviral regimens throughout the world. Resistance that arises after single-dose nevirapine can compromise response to subsequent maternal treatment with nevirapine-based antiretrovirals,19,20 although the problem is less in women who start antiretrovirals 6 or more months after taking single-dose nevirapine.20,21 Maternal combination prophylaxis regimens are also more effective at preventing vertical transmission than is single-dose nevirapine alone, and some practitioners therefore believe the latter should not be used at all-even though it may be the only feasible intervention in many areas.
In today's Lancet, Benjamin Chi and colleagues present new and encouraging data from Zambia to show that addition of one intrapartum dose of tenofovir/emtricitabine to short-course zidovudine plus single-dose nevirapine significantly reduced the prevalence of detectable nevirapine-resistant maternal virus at 6 weeks' postpartum.15 In the subgroup of women with sequences available for analysis at 6 weeks' postpartum, 30% of 138 women in the control group compared with 14% of 147 women in the intervention group harboured nevirapine-resistant virus. Importantly, mutations associated with resistance to tenofovir or emtricitabine were not detected at any time.
In Chi and colleagues' study, only women with less advanced HIV-1 disease (who did not qualify for combination antiretrovirals) were eligible to enter. Also, 81% of participants also took short-course zidovudine (for a median of about 37 days) before single-dose nevirapine (in either group). Both these factors might have reduced the median maternal HIV-1 RNA levels at delivery. Because higher HIV-1 RNA at delivery has been associated with greater risk for selection of resistance after single-dose nevirapine,4 the relative risk of developing nevirapine resistance might be different in settings in which women do not have access to or present too late in pregnancy to receive antenatal antiretrovirals (as recommended by WHO22 and used by Chi).
Chi and colleagues classified maternal samples with HIV-1 RNA levels below 2000 copies per mL (not genotyped due to low yield) as harbouring no resistance in the primary analysis, rather than omitting them from the analysis altogether as would generally be done. The analysis as done could lead to underestimation of the prevalence of resistance, particularly in the intervention group at 2 weeks, in view of the transient suppression of viral load that was associated with being on tenofovir/emtricitabine. The secondary analysis which omitted samples that were not genotyped might be more valid.
We also need to learn about the incidence of nevirapine resistance in infants who become HIV-1 infected despite the addition of tenofovir/emtricitabine to zidovudine and single-dose nevirapine. Since Chi and colleagues' study was conceived, new data20,21 have somewhat allayed concerns about the clinical implications of maternal nevirapine resistance after single-dose nevirapine, but resistance in HIV-infected infants may have more dire implications for subsequent paediatric response to nevirapine-based treatment.20 Additionally, although the clinical implications of minority resistant variant populations are unknown, future studies of the presence of such variants after the addition of single-dose tenofovir/emtricitabine will be important, particularly to assess for resistance to emtricitabine. It would be of concern if the use of single doses of both tenofovir/emtricitabine and nevirapine resulted in large proportions of patients developing even low-level resistance to both emtricitabine and nevirapine, which might affect subsequent response to treatment with these commonly used classes of drugs. Finally, although it is unlikely that one dose of tenofovir given to a mother and newborn infant is associated with important toxic effects in infants (including adverse effects on bone development), the safety of in-utero exposure to tenofovir is being examined.
The question today is under what circumstances single-dose tenofovir/emtricitabine should be used as part of a regimen to prevent mother-to-child transmission of HIV, in view of Chi and colleagues' data. Combination three-drug prophylaxis might in the future be increasingly available to all pregnant HIV-1-infected women regardless of CD4+ cell count, which would make single-dose nevirapine obsolete. Currently, however, most women either do not receive any intervention at all, or take only single-dose nevirapine. Chi's results cannot necessarily be extrapolated to women who take only nevirapine without antenatal zidovudine, for the reasons noted above. However, WHO recommends that women with less advanced HIV (who comprise the majority of HIV-infected pregnant women) be given short-course zidovudine with single-dose nevirapine (with a 7-day gtailh of zidovudine plus lamivudine).22 Chi's results do provide strong evidence that addition of single-dose tenofovir/emtricitabine to short-course zidovudine and single-dose nevirapine in women with higher CD4+ cell counts is a new, effective, and feasible approach to reducing maternal nevirapine resistance, and one that should be seriously considered for implementation.
We declare that we have no conflict of interest.
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