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Acyclovir Reduces HIV Viral Load in People with Genital Herpes, but Not Risk for HIV Transmission

Suppressing herpes simplex with daily acyclovir did not reduce the likelihood of HIV transmission among discordant heterosexual couples in Africa, even though it was associated with lower plasma HIV viral load and fewer genital ulcers, according to a study in the January 20, 2010 advance online edition of the New England Journal of Medicine.

The Partners in Prevention HSV/HIV Transmission Study Team designed a trial to determine whether acyclovir might help reduce the risk of HIV transmission in a high-prevalence setting.

People with HIV-1 are commonly coinfected with herpes simplex virus 2 (HSV-2), the usually cause of genital herpes, the investigators noted as background. HSV-2 is often reactivated as immune function declines, and prior research indicates that active herpes is associatedwith increased plasma and genital levels of HIV.

Researchers therefore hypothesized that by lowering HIV viral load and minimizing genital ulcers that provide a route for disease transmission, herpes treatment such as acyclovir might reduce HIV transmission.

The Partners in Prevention study included 3408 HIV serodiscordant (1 positive, 1 negative) heterosexual couples enrolled between November 2004 and April 2007 at 7 sites in southernAfrica (Gaborone in Botswana; Gugulethu, Orange Farm, and Sowetoin South Africa; and Kitwe, Lusaka, and Ndola in Zambia) and7 sites in East Africa (Eldoret, Kisumu, Nairobi, and Thikain Kenya; Kigali in Rwanda; Moshi in Tanzania; and Kampala in Uganda).

In 68% of the couples, the woman was the HIV positive partner, and all HIV positive partners were also infected with HSV-2. They had a relatively high median baseline CD4 count of 462 cells/mm³ (all > 250 cells/mm³) and were not yet taking antiretroviral therapy.

Participants were randomly assigned (1:1) to receive suppressive therapy for HSV-2 using oral acyclovir at a dose of 400mg twice daily, or else placebo. The primaryend-point was transmission of HIV to the partner who was not initially infected.

Results

• A total of 132 new HIV seroconversions occurred afterrandomization, for an overall incidence of 2.7 per 100 person-years.
• 84 of these seroconversions were verified by genetic sequencing to be transmissions within a couple and were included in the analysis (6 others were excluded because they occurred while off acyclovir due to pregnancy or medication error).
• In an intent-to-treat analysis, 41 verified seroconversions occurred in the acyclovirgroup compared with 43 in the placebo group, not a statistically significant difference (hazard ratio 0.92; P = 0.69).
• In a secondary analysis of all transmissions, 67 occurred in the acyclovirgroup compared with 64 in the placebo group (hazard ratio 0.99; P = 0.97).
• Daily acyclovir was associated with a 0.25 log₁₀ copies/mL decrease in mean plasma HIV RNA, a significant difference (P < 0.001).
• The occurrence of HSV-2 genital ulcers was73% lower in the acyclovir group compared with the placebo group, also a significant difference (risk ratio 0.27; P < 0.001).
• There were no significant differences in the treatment effect according to sex of the HIV positive partner, circumcision status of HIV negative male partners, baseline plasma HIV RNA, presence or absence of symptomatic genital ulcer disease in the HIV positive partner prior to enrollment, or extent of treatment adherence.
• However, HIV negative partners who were HSV-2 positive were more likely to become HIV infected than those who were HSV-2 negative(hazard ratio 2.02).
• No serious adverse events related to acyclovir wereobserved.
• 92% of HIV positive partners and 84% ofHIV negative partners remained in the study for24 months, and acyclovir adherence was 96%.
• High-risk sexual practices reported by participants decreasedsignificantly during follow-up.

Based on these findings, the investigators concluded, "Daily acyclovir therapy did not reduce the riskof transmission of HIV-1, despite a reduction in plasma HIV-1RNA of 0.25 log₁₀ copies[/mL] and a 73% reductionin the occurrence of genital ulcers due to HSV-2."

"[T]he lack of efficacy ofHSV-2 suppressive therapy in preventing the transmission ofHIV-1 among participants in this study does not appear to havebeen caused by poor activity of acyclovir against HSV-2 or bypoor adherence to treatment, as assessed by monthly pill countsand by serum acyclovir testing in a subgroup of participants," they added in their discussion.

Though these findings confirm those of other studies of acyclovir and HIV transmission, the lack of efficacy is not well understood, given that "[e]pidemiologic and laboratory data accumulated over the courseof more than 20 years suggest that genital HSV-2 infection increasesthe infectiousness of persons with HIV-1 infection...Moreover, in 5placebo-controlled, randomized trials, plasma HIV-1 RNA levelswere reduced by 0.25 to 0.5 log₁₀ copies[/mL] whenpersons who were infected with both HIV-1 and HSV-2 but werenot receiving antiretroviral therapy received standard dosesof HSV-2 suppressive agents (valacyclovir at a dose of 500 mgtwice daily or acyclovir at a dose of 400 to 800 mg twice daily)for 1 to 3 months."

A possible explanation, provided by a study reported last year, is that inflammatory and immune cells susceptible to HIV infection persist in the genital mucosa of people with herpes simplex, despite acyclovir treatment.

"The lack of efficacy of acyclovir in reducing the transmissionof HIV-1 in our study suggests that a greater reduction in HIV-1levels is needed to reduce the risk of transmission," the researchers stated -- adding support to the concept of early ART as a potential prevention strategy.

Universityof Washington, Seattle, WA; FredHutchinson Cancer Research Center, Seattle, WA; Bill and Melinda Gates Foundation, Seattle, WA; Universityof Nairobi and Kenyatta National Hospital, Nairobi, Kenya; Kenya Medical ResearchInstitute, Nairobi, Kenya; Moi University, Eldoret, Kenya; University of California at San Francisco, San Francisco, CA; Makerere University,Kampala, Uganda; Universityof Manitoba, Winnipeg, Canada; Botswana-HarvardPartnership, Gaborone, Botswana; Harvard School of Public Health, Boston, MA; IndianaUniversity, Indianapolis, IN; University of the Witwatersrand, Johannesburg, South Africa; University of CapeTown, Cape Town, South Africa; KilimanjaroChristian Medical Centre, Moshi, Tanzania; London Schoolof Hygiene and Tropical Medicine, London, UK; Rwanda-ZambiaHIV Research Group and Emory University Schools of Medicineand Public Health, Atlanta, GA.

1/22/10

Reference

C Celum, A Wald, JR Lingappa, and other (Partners in Prevention HSV/HIV Transmission Study Team). Acyclovir and Transmission of HIV-1 from Persons Infected with HIV-1 and HSV-2. New England Journal of Medicine (Free full text). January 20, 2010 [Epub ahead of print].