A small Kenyan study has contributed new information to the complex body of evidence that is helping researchers identify new strategies for the prevention of mother-to-child transmission of HIV (PMTCT). The study suggests that a widely used prophylactic antiretroviral regimen, AZT (zidovudine, Retrovir) plus a single dose of nevirapine (Viramune), may be more likely to cause nevirapine resistance than a three-drug regimen being evaluated for its potential to reduce HIV transmission during breastfeeding.
The resistance findings came out of a randomised PMTCT study that had the primary objective of comparing HIV levels in the breast milk of two groups of HIV-positive women with baseline CD4 cell counts of 200 to 500 cells/ mm3.
One group was prescribed 300 mg of ZDV twice daily for the last six weeks of pregnancy plus a single 200-mg dose of nevirapine during labour. (Newborns also received a single dose of nevirapine [2mg/kg].)
The other group was prescribed a twice-daily regimen of 300 mg AZT, 200 mg nevirapine, and 150 mg 3TC (lamivudine, Epivir) for the last six weeks of pregnancy and first six months post-partum.
The resistance substudy was based on analyses of plasma samples collected three months after treatment ended – three months postpartum for the AZT/single dose nevirapine group (N=23) and nine months postpartum for the nevirapine/AZT/3TC group (N=17). Twenty-seven samples were suitable for viral load testing: sixteen from the AZT/single dose nevirapine group, and eleven from the nevirapine/AZT/3TC group.
Three-quarters of women (12/16) in the AZT/single dose nevirapine group had either the K103N mutation or the Y181C mutation or both, compared to 18% (2/18) in the triple treatment arm group, a statistically significant difference (p = 0.006). These rates translated into 13.5 times higher odds of resistance in the AZT/single dose nevirapine group, according to univariate logistic regression analysis (p=0.007). Further analyses led investigators to conclude that viral load level, CD4 count, and viral subtype were not confounding factors.
Nevirapine is one of the most effective antiretrovirals for preventing mother-to-child transmission of HIV, but a major challenge associated with the use of nevirapine is that it lingers in the body longer than other antiretrovirals after the discontinuation of treatment, resulting in a high risk of resistance. (Without additional drugs helping to suppress viral replication, HIV can more easily mutate to become resistant to the single drug that it encounters.) Nevirapine resistance is signaled by the emergence of the K103N and Y181C mutations, which diminish over time in some people but persist in others. In short, women who use nevirapine-containing PMTCT regimens run the risk of developing K103N- and Y181C-mediated nevirapine resistance, and thus limiting their future treatment options.
The Kenyan study underscored this concern by demonstrating that resistance persisted at six months and twelve months post-treatment in a large proportion of cases, according to allele-specific PCR testing. Two of the five women with K103N mutations still had those mutations at twelve months post-treatment. Y181C mutations persisted at twelve months post-treatment in eight of nine women in the AZT/single dose nevirapine group, and also persisted at six months post-treatment in one of two women in the triple drug treatment group.
The authors propose that the two regimens they investigated may cause different degrees of risk for resistance because nevirapine/AZT/3TC lowers HIV viral load levels much more than AZT/single dose nevirapine. “As a result, the levels of replicating virus during the period when drug levels wane immediately after treatment cessation is lower with [nevirapine/AZT/3TC],” they state.
A further consequence of using the triple-drug regimen, they add, is that 3TC stays in the body for longer than AZT, reducing the amount of time after treatment cessation when NVP remains as the only active drug.
The strategy of using a 3TC “tail” at the end of a period of treatment with the AZT/single dose nevirapine regimen to reduce nevirapine resistance has been explored by other researchers, and there is clear evidence that doing so reduces the risk of resistance. The authors note that “it is unknown whether the addition of a ‘tail’ concurrent with treatment cessation of AZT/single dose nevirapine would make the prevalence of resistance in the two regimens studied here more similar.”
Even so, the study findings are notable for what they contribute to ongoing efforts to improve PMTCT regimens. A key question is whether regimens taken during breastfeeding further reduce postpartum HIV transmission; if so, understanding the benefits and drawbacks of those regimens is crucial.
“The data presented here should be considered as a benefit of [antiretroviral prophylaxis during breastfeeding] when balancing the safety, efficacy, and feasibility of different strategies currently being tested to reduce breastfeeding transmission,” the authors conclude.
The World Health Organization is currently undertaking an evidence review that will guide revisions to its PMTCT recommendations, with one outcome expected to be an updated approach to reducing HIV transmission through breastfeeding. The new recommendations are scheduled for December 2009 publication.
Lehman DA et al. Lower risk of resistance after short-course HAART compared with zidovudine/single-dose nevirapine used for prevention of HIV-1 mother-to-child transmission. J Acquir Immune Defic Syndr 51: 522–529, 2009.