In our study, twice daily 500 mg valacyclovir reduced plasma HIV-1 RNA levels by 0.54 log10 copies/mL during pregnancy and by 0.51 log10 copies/mL after 6 weeks postpartum among pregnant Kenyan women ineligible for HAART and receiving ZDV plus sdNVP prophylaxis for PMTCT. The proportion and levels of HIV-1 RNA in breast milk were also lower at 6 and 14 weeks postpartum among women randomized to valacyclovir but were similar between the two arms at 2 weeks postpartum after maternal sdNVP administered at the time of delivery. At 12 months, 7.0% of infants were infected with HIV-1; there were no differences in HIV-1 transmission between arms.
Previous studies have estimated the risk of HIV-1 infection through breastfeeding to be 1%–2% per month in the absence of postnatal antiretroviral prophylaxis [32
]. The significant reduction in breast milk HIV-1 RNA we observed prior to 6 months corresponds to a period when infants were at risk of postnatal MTCT. By 5–6 months the cumulative risk of postnatal infection is estimated to be 8%–10% with a ZDV plus sdNVP regimen and 3%–5% with extended infant NVP or maternal HAART [34
]. In addition, cumulative exposure to HIV-1 RNA in breast milk was shown to be a more important predictor of breast milk transmission than duration of feeding [37
]. Thus, if HSV-2 suppressive therapy can reduce breast milk HIV-1 RNA, it may provide an additional intervention to decrease HIV-1 transmission via breastfeeding.
We also observed a ~0.5 log10
copies/mL reduction in plasma HIV-1 RNA levels both during and after pregnancy, consistent with previous studies of HSV-2 suppression among men and nonpregnant women [12
]. Women in the valacyclovir arm continued to benefit from suppressive therapy, despite the effect of ZDV on HIV-1 RNA levels during pregnancy. It is possible that the additional viral suppression during pregnancy was due to synergy between ZDV and valacyclovir. However, although in vitro studies suggest that acyclovir may potentiate the action of ZDV [38
], an in vivo study did not support these findings [40
]. During the postpartum period the effect of suppressive therapy on HIV-1 RNA continued and was sustained for 12 months after the effect of sdNVP on plasma and breast milk HIV-1 RNA waned.
Our study had some limitations. We were unable to evaluate the effect of valacyclovir on MTCT or on change in HIV-1 RNA among women who were eligible for HAART. We were also underpowered to detect an association between valacyclovir and breast milk HIV-1 RNA levels or detection at 6 and 12 months postpartum due to small numbers of women who were able to express breast milk at these visits.
The reduction in plasma HIV-1 RNA levels we observed with valacyclovir suppressive therapy may provide some protection against in utero, intrapartum, or postnatal MTCT; however, our study was not designed to evaluate the effect of valacyclovir on MTCT. In order to detect a 2-fold difference in transmission between study arms, assuming a transmission rate of 7% in the placebo arm, we would need to enroll nearly 1400 mother-infant pairs. Although a 0.25 log10
copies/mL reduction in plasma HIV-1 RNA levels did not correspond to a decreased risk of heterosexual HIV-1 transmission, we observed a viral load effect twice as large, and a 0.4 log10
lower HIV-1 RNA level in breast milk and plasma has previously been associated with lower risk of postnatal MTCT [37
]. The impact of a reduction in plasma HIV-1 RNA levels on MTCT may differ from the impact on heterosexual transmission due to prolonged exposure to HIV-1 containing bodily fluids during pregnancy, labor and delivery, and breastfeeding. Additional research is needed to determine the effect of valacyclovir on postnatal and peripartum HIV-1 transmission through breast milk.
We also found that women randomized to valacyclovir had a lower risk of genital HSV DNA shedding, consistent with previous studies [41
]. In contrast, we did not detect a significant association between valacyclovir and cervical HIV-1 RNA levels or shedding, which is consistent with results from a cohort receiving HAART reported by Ouedraogo et al [43
] and an antiretroviral-naive cohort reported by Delany et al [17
] but in conflict with 3 other randomized trials conducted in antiretroviral-naive cohorts [12
]. One potential explanation for the lack of association in our study is that a high proportion (>40%) of women in our cohort were not shedding HIV-1 in cervical secretions and had low baseline cervical HIV-1 RNA levels after initiation of ZDV, which reduces cervical HIV-1 RNA levels by ~1 log10
copies/mL after 1 week of ZDV treatment [44
]. Other potential explanations include short duration of valacyclovir suppression, use of cervical swabs rather than cervicovaginal lavages, and hormonal changes associated with pregnancy.
Valacyclovir has many features that make it an appealing intervention. It is commercially available in generic form, has a good safety profile during and after pregnancy, and could be used as an intervention to reduce infant exposure to HIV-1 during breastfeeding. Furthermore, HSV-2 suppressive therapy can be safely used without inducing HIV-1 resistance, as has been shown in cohorts receiving acyclovir or valacyclovir [45
]. Our study demonstrates that valacyclovir significantly reduces plasma and breast milk HIV-1 RNA and the risk of genital HSV DNA shedding during pregnancy and can be easily administered within the existing PMTCT infrastructure. In addition, the effect of valacyclovir was sustained after PMTCT antiretroviral effects had waned, which may also lower the risk of early breast milk HIV-1 transmission. Valacyclovir suppressive therapy, in conjunction with PMTCT antiretrovirals, should be further evaluated in a larger trial as a combination intervention for reducing MTCT and improving maternal health.