Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2

Abstract

Background: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1.

Methods: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses.

Results: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed.

Conclusions: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Figure 1. Enrollment and Follow-up of Participants

Data are shown for the intention-to-treat cohort, from which the modified intention-to-treat analysis was derived. Seropositivity for HSV-2 at enrollment was determined with the use of the HerpesSelect-2 immunoassay (Focus Technologies) at the site laboratory (a cutoff index value for seropositivity of >3.4 was used to improve specificity [see Laboratory Procedures in the Supplementary Appendix]); inclusion in the primary analysis was based on positive results of Western blotting for HSV-2 performed at the University of Washington (see the Supplementary Appendix). The numbers for follow-up visits include only participants who attended scheduled visits; in the case of partners not infected with HIV-1, visits with HIV-1 tests up to and including the first visit in which a positive HIV-1 test result was recorded were included. The total study populations include all participants who were expected to attend visits (in the case of partners not infected with HIV-1, this included visits up to and including the first visit in which a positive HIV-1 test result was recorded) and reflect a staged close-out of the sites after 12 months. During the follow-up period, three participants who were seropositive for HIV-1 were given a drug kit that was incorrect for their randomization group; the follow-up time for their HIV-1–uninfected partner was censored at that point.

Figure 2. End Points with Respect to Transmission of HIV-1, According to the Study Group, in the Modified Intention-to-Treat and the Intention-to-Treat Populations

The 132 seroconversions to HIV-1 excluded 19 in partners who, during confirmatory testing, were found to be seronegative for HIV-1 (i.e., negative for HIV-1 antibodies) but who were infected with HIV-1 (i.e., positive for HIV-1 RNA) at study enrollment and were infected therefore with HIV-1 before their HIV-1–infected partner received acyclovir or placebo. Determination of linkage for transmission pairs was based on viral sequencing in the partner who was originally infected with HIV-1 and that person's partner who underwent seroconversion to HIV-1; linkage data were reviewed by an expert adjudication committee. The modified intention-to-treat analysis excluded HIV-1 transmissions among male partners who underwent seroconversion when their HIV-1–infected female partners were pregnant and not taking the study drug as specified by the protocol (two in the acyclovir group and four in the placebo group).

Figure 3. Kaplan-Meier Curves for the Modified Intention-to-Treat Analysis

The cumulative probability of genetically linked transmission of HIV-1 is shown for the two study groups.

Figure 4. HIV-1 Seroconversion Events, Overall and within Subgroups

The intention-to-treat analysis included all HIV-1 transmissions; the modified intention-to-treat analysis included only genetically linked HIV-1 transmissions. Subgroup analyses were performed on the modified intention-to-treat data set. P values are for the effect of acyclovir overall and in subgroup analyses. Hazard ratios less than 1.0 are consistent with a protective effect of acyclovir.

Figure 5. Plasma HIV-1 RNA Levels in Participants Infected with HIV-1, According to Study Group

The values represent the mean plasma viral load during the 24-month follow-up period. Enrollment values were adjusted for a difference of 0.12 log₁₀ copies per milliliter in the average plasma HIV-1 RNA level that arose from validating the HIV-1 RNA measurements in the two laboratories that performed the viral load measurements at enrollment and follow-up.