Acyclovir
Reduces HIV Viral Load in People with Genital Herpes, but Not Risk
for HIV Transmission
By
Liz Highleyman
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 associated
with 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 southern Africa (Gaborone
in Botswana; Gugulethu, Orange Farm, and Soweto in South Africa;
and Kitwe, Lusaka, and Ndola in Zambia) and 7 sites in East Africa
(Eldoret, Kisumu, Nairobi, and Thika in 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 400 mg twice
daily, or else placebo. The primary end-point was transmission
of HIV to the partner who was not initially infected.
Results
 |
A
total of 132 new HIV seroconversions occurred after randomization,
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 acyclovir group 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 acyclovir group 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 was 73% 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 were observed.
|
|
92%
of HIV positive partners and 84% of HIV negative partners
remained in the study for 24 months, and acyclovir adherence
was 96%. |
|
High-risk
sexual practices reported by participants decreased significantly
during follow-up. |
Based on these findings, the investigators concluded, "Daily
acyclovir therapy did not reduce the risk of transmission of HIV-1,
despite a reduction in plasma HIV-1 RNA of 0.25 log10 copies[/mL]
and a 73% reduction in the occurrence of genital ulcers due to
HSV-2."
"[T]he lack of efficacy of HSV-2 suppressive therapy in preventing
the transmission of HIV-1 among participants in this study does
not appear to have been caused by poor activity of acyclovir against
HSV-2 or by poor adherence to treatment, as assessed by monthly
pill counts and 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 course of more than 20 years suggest that genital HSV-2
infection increases the infectiousness of persons with HIV-1 infection...Moreover,
in 5 placebo-controlled, randomized trials, plasma HIV-1 RNA levels
were reduced by 0.25 to 0.5 log10 copies[/mL] when persons who
were infected with both HIV-1 and HSV-2 but were not receiving
antiretroviral therapy received standard doses of HSV-2 suppressive
agents (valacyclovir at a dose of 500 mg twice 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 transmission
of HIV-1 in our study suggests that a greater reduction in HIV-1
levels is needed to reduce the risk of transmission," the
researchers stated -- adding support to the concept of early ART
as a potential prevention strategy.
University of Washington, Seattle, WA; Fred Hutchinson Cancer
Research Center, Seattle, WA; Bill and Melinda Gates Foundation,
Seattle, WA; University of Nairobi and Kenyatta National Hospital,
Nairobi, Kenya; Kenya Medical Research Institute, Nairobi, Kenya;
Moi University, Eldoret, Kenya; University of California at San
Francisco, San Francisco, CA; Makerere University, Kampala, Uganda;
University of Manitoba, Winnipeg, Canada; Botswana-Harvard Partnership,
Gaborone, Botswana; Harvard School of Public Health, Boston, MA;
Indiana University, Indianapolis, IN; University of the Witwatersrand,
Johannesburg, South Africa; University of Cape Town, Cape Town,
South Africa; Kilimanjaro Christian Medical Centre, Moshi, Tanzania;
London School of Hygiene and Tropical Medicine, London, UK; Rwanda-Zambia
HIV Research Group and Emory University Schools of Medicine and
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].
