By both consensus sequencing and the more sensitive OLA assay, the 3 arms of P1032 had similar low rates of NVP resistance after SD-NVP therapy, with resistance identified in 7.7% of women overall. Each arm had a rate significantly lower than that in the historical comparison group (1.8%, 7.1%, 5.3%, respectively, vs 30%). The finding that a short tail of highly active antiretroviral therapy was as effective as a longer tail suggests that early suppression of viral replication prevents the selection of resistant virus for the full duration of NVP exposure. No P1032 participant had resistance mutations detectable by consensus sequencing alone, in contrast to 13.4% of the comparison group, suggesting that the mutations in the P1032 participants were present in low frequency. It is likely that low-frequency mutations are archived at a low concentrations in long-lived cells and will decay relatively rapidly after NVP has cleared, making them less likely to compromise subsequent therapy with NVP.
We included didanosine rather than lamivudine in the tail, because didanosine is less likely to cause viral resistance when used with zidovudine to prevent MTCT of HIV infection [30
]. In addition, hepatitis B virus (HBV) infection is common in Thailand, with a prevalence of 10% [32
]. Because lamivudine has activity against HBV, its use will promote HBV resistance to lamivudine, and a rebound in HBV disease has been reported when lamivudine therapy is discontinued [33
Factors that increase the risk of developing NVP-resistant virus after SD-NVP include the virus subtype [36
], a higher plasma viral load [37
], and a higher plasma NVP concentration, which prolongs the duration of NVP exposure [6
]. Participants in the comparison group, who were enrolled 5 years before P1032, were younger and had a slightly lower median CD4 cell count and higher median viral load. However, the results were unchanged when adjusted for these covariates in a logistic regression model.
Resistance mutations cannot be identified in specimens with a very low viral load, which we considered to be free of resistance mutations. Thus, in a planned secondary analysis, we estimated the incidence of resistance among only those women with a detectable viral load at entry. Among these women, the rates of resistance increased somewhat in all arms, but the differences between the P1032 arms and the comparison group remained significant (). Thus, the lower viral load in the P1032 participants is unlikely to account for their lower incidence of viral resistance.
Compared with 4–7 days of zidovudine plus lamivudine [14
] or a single dose of tenofovir and emtricitabine [17
], the 3 regimens that we studied are more effective in reducing the risk of NVP resistance mutations as detected by consensus sequencing. Seven days of tenofovir and emtricitabine therapy also eliminated this risk [19
]. In a recent study in Thailand, with use of the OLA assay, a 30-day tail of zidovudine and didanosine resulted in an incidence of NVP resistance of 1.8%, similar to the incidence in our study [20
A limitation of the study is that it did not include a 7-day course of 2 nucleoside reverse-transcriptase inhibitors, as currently recommended by the World Health Organization. In the TOPS study, 3 and 7 days of zidovudine plus lamivudine resulted in a frequency of resistance of 13% and 9%, as shown by sequencing, whereas in P1032, no mutations were found by sequencing [14
]. However, in the TOPS study, women did not receive zidovudine before labor. The risk of resistance in women receiving prepartum zidovudine and intrapartum NVP with a 7-day course of 2 reverse-transcriptase inhibitors remains to be evaluated.
In conclusion, all 3 P1032 regimens were well tolerated and, using a sensitive assay, markedly reduced the incidence of NVP resistance to a similar degree. In choosing among these options, 7 days of highly active antiretroviral therapy has the advantage of a short duration of therapy, but the cost, potential for intolerance, and limited availability of lopinavir and ritonavir in some locations may be a disadvantage. On the other hand, 30 days of dual reverse-transcriptase inhibitor therapy has the advantage of simplicity and low cost, but the longer duration of therapy has the potential for poorer adherence.