Valacyclovir suppressive therapy reduces plasma and breast milk HIV-1 RNA levels during pregnancy and postpartum: a randomized trial

Abstract

Background: The effect of herpes simplex virus type 2 (HSV-2) suppression on human immunodeficiency virus type 1 (HIV-1) RNA in the context of prevention of mother-to-child transmission (PMTCT) interventions is unknown.

Methods: Between April 2008 and August 2010, we conducted a randomized, double-blind trial of twice daily 500 mg valacyclovir or placebo beginning at 34 weeks gestation in 148 HIV-1/HSV-2 coinfected pregnant Kenyan women ineligible for highly active antiretroviral therapy (CD4 > 250 cells/mm(3)). Women received zidovudine and single dose nevirapine for PMTCT and were followed until 12 months postpartum.

Results: Mean baseline plasma HIV-1 RNA was 3.88 log(10) copies/mL. Mean plasma HIV-1 was lower during pregnancy (-.56 log(10) copies/mL; 95% confidence interval [CI], -.77 to -.34) and after 6 weeks postpartum (-.51 log(10) copies/mL; 95% CI, -.73 to -.30) in the valacyclovir arm than the placebo arm. Valacyclovir reduced breast milk HIV-1 RNA detection at 6 and 14 weeks postpartum compared with placebo (30% lower, P = .04; 46% lower, P = .01, respectively), but not after 14 weeks. Cervical HIV-1 RNA detection was similar between arms (P = .91).

Conclusions: Valacyclovir significantly decreased early breast milk and plasma HIV-1 RNA among women receiving PMTCT.

Clinical trials registration: NCT00530777.

Figures

Figure 1.

Screening, enrollment, and follow-up of study participants. Women from the Mathare North City Council Clinic and women referred from 5 neighboring clinics were screened for eligibility between 28 and 32 weeks gestation. Analyses were separated by the pregnancy and postpartum periods due to several women delivering prior to 38 weeks gestation and not having follow-up visits during pregnancy. *Reasons women did not meet inclusion criteria (not mutually exclusive) included: age 3 (n = 67), eligible for HAART (n = 70), planned to deliver/reside outside of Nairobi (n = 24).

Figure 2.

Effect of valacyclovir on change in cervical human immunodeficiency virus type 1 (HIV-1) RNA and genital herpes simplex virus (HSV) DNA shedding status at 38 weeks gestation. A, Change in cervical HIV-1 shedding, by treatment arm. B, Change in genital HSV shedding, by treatment arm. Change in HIV-1 RNA and HSV DNA is for the period between the 34th and 38th week of gestation and was calculated as shedding at follow-up minus shedding at enrollment. Changes in shedding were assigned a value on an ordinal scale and compared between arms using Wilcoxon rank-sum tests. HIV-1 and HSV shedding were defined as having HIV-1 RNA or HSV DNA copies/mL above the lower limit of detection of the assay, respectively. Women with virus detected at 38 weeks gestation but not at 34 weeks gestation were classified in the group “start shedding”; women with virus detected at 34 weeks gestation but not at 38 weeks gestation were classified in the group “stop shedding.” Data exclude 1 valacyclovir due to missing swabs at 38 weeks gestation.

Figure 3.

The effect of valacyclovir on postpartum plasma (A) and breast milk (B) human immunodeficiency virus type 1 (HIV-1) RNA levels. Curves represent locally weighted smoothed curves of plasma and breast milk HIV-1 RNA levels over time, by treatment arm.

Figure 4.

The effect of valacyclovir on breast milk human immunodeficiency virus type 1 (HIV-1) RNA detection. χ2 tests were used to compare breast milk HIV-1 RNA detection between study arms. Error bars represent interquartile ranges, by treatment arm. Abbreviation: RR, relative risk.

Figure 5.

Infant human immunodeficiency virus type 1 (HIV-1) transmission, by treatment arm. Time of infant infection was defined as the midpoint between the first positive and the last negative HIV-1 DNA test. The effect of valacyclovir on HIV-1 was evaluated using Cox proportional hazards regression. Abbreviations: CI, confidence interval; HR, hazard ratio.