A
preponderance of research has shown that the presence of sexually transmitted
infections (STIs) that cause genital ulcers facilitates the transmission and acquisition
of HIV. For example, herpes simplex virus type2 (HSV-2) -- the usual cause of
genital herpes - has been associated with a 2- to 3- fold increase in susceptibility
to HIV. It therefore makes sense that STI treatment should reduce HIV transmission,
and several epidemiological studies have suggested that this is the case.
Study
HPTN 039 was a placebo-controlled proof-of-concept trial designed to assess whether
HSV-2 suppression reduces the risk of HIV acquisition among heterosexual women
in Africa and men who have sex with men (MSM)
in North and South America (abstract 32).
The
study enrolled more than 3000 total participants: 1871 MSM from the U.S. and Peru,
and 1380 women from South Africa, Zambia, and Zimbabwe. At entry, all participants
were HIV negative, HSV-2 positive, and reported high-risk sexual behavior. They
were randomly assigned to receive 400 mg twice-daily oral acyclovir (Zovirax)
or placebo and were followed for 12-18 months.
Results
•
At study entry, 12% of the MSM and 26% of
the women reported clinically recognized genital herpes in the previous 3 months.
•
The median number of sexual partners in the
past 12 months was 10 for the MSM and 1 for the women, with 60% reporting a partner
of unknown HIV status.
•
Adherence to acyclovir by self-report and
pill count was excellent at > 90% of total drug taken, and fewer than 5% reported
having missed 6 or more doses in a row.
•
Genital ulcers were reduced by 35% in the
acyclovir arm based on self-report and exam findings.
•
HIV incidence, however, was not significantly
lower in the treated arm.
•
Looking at the men and women combined, the
overall HIV incidence rate was 3.9 cases per 100 person-years in the acyclovir
arm (75 infections) compared with 3.3 per 100 person-years in the placebo arm
(64 infections) (HR 1.16).
•
There were no significant differences by sex
(HR 0.9 for men, 1.5 for women), reported adherence (HR 1.6 for < 90% adherence,
1.0 for > 90% adherence), or history of genital ulcer disease (HR 1.4
with GUD, 1.1 without).
•
No serious adverse events attributed to the
study drug were observed.
Conclusion
"In
HPTN 039, with excellent retention and adherence to twice-daily study drug, daily
suppressive therapy with standard doses (400 mg twice daily) of acyclovir did
not reduce HIV acquisition among HSV-2 positive women and MSM," the investigators
concluded.
They added, however, that the incidence of genital ulcer disease
was reduced. "Thus, acyclovir (400 mg twice daily) suppresses HSV-2, but
does not prevent HIV acquisition."
Given the conflicting results of
this and past studies, they recommended that, "Further research is needed
to elucidate the disparity between extensive data on epidemiologic and biologic
interactions between HSV-2 and HIV and these trial results."
Lead
investigator Connie Celum of the University of Washington called the findings
"surprising and disappointing," given the promise of earlier acyclovir
trials showing a decrease in HIV levels in both the blood and the genital tract.
Better
Outcomes with Valacyclovir?
Acyclovir
Tablet
A
smaller study by the same research group, presented as a poster at the conference
(abstract 676), demonstrated promising results with the acyclovir pro-drug valacyclovir
(Valtrex).
In this randomized cross-over trial, 20 HIV positive Peruvian
women with HSV-2 were assigned to receive 500 mg twice-daily valacyclovir or placebo
for 8 weeks, then after a 2-week washout period, switched to the other regimen
for an additional 8 weeks. The women had a CD4 count above 200 cells/mm3 (median
372 cells/mm3) and were not on antiretroviral therapy.
HSV-2 in the genital
tract was detected on 4% of days on valacyclovir versus 22% of days on placebo.
In addition, HIV plasma viral load was significantly lower while taking valacyclovir.
Cervical HIV levels were significantly lower and was detected at fewer visits
while on valacyclovir versus placebo (54% vs 71%).
The researchers concluded
that, "Daily valacyclovir therapy (500 mg twice daily) for HSV-2 suppression
significantly reduced plasma and genital HIV-1 concentrations among HSV-2/HIV-1
coinfected women. Suppressive HSV-2 therapy has the potential to reduce HIV-1
infectiousness and the rate of disease progression; these outcomes are under evaluation
in ongoing clinical trials."
This trial supports results seen in previous
studies. However, plasma and genital HIV suppression has also been observed
in prior studies of acyclovir, so further research is needed to determine whether
valacyclovir works better than acyclovir, or whether it will meet the same fate
in large trials that look at actual HIV incidence rather than viral load.
2/12/08
References
C
Celum, A Wald, J Hughes, and others. HSV-2 Suppressive Therapy for Prevention
of HIV Acquisition: Results of HPTN 039. 15th Conference on Retroviruses and Opportunistic
Infections. Boston, MA. February 3-6, 2008. Abstract 32.
J Baeten, L Strick,
A Lucchetti, and others. Herpes Simplex Virus Suppressive Treatment Decreases
Plasma and Genital HIV-1 Viral Loads in HSV-2/HIV-1 Co-infected Women: A Randomized,
Placebo-controlled, Cross-over Trial. 15th Conference on Retroviruses and Opportunistic
Infections. Boston, MA. February 3-6, 2008. Abstract 676.
Treating
Genital Herpes with Acyclovir Fails to Lower Risk of HIV Infection 
A
preponderance of research has shown that the presence of sexually transmitted
infections (STIs) that cause genital ulcers facilitates the transmission and acquisition
of HIV. For example, herpes simplex virus type2 (HSV-2) -- the usual cause of
genital herpes - has been associated with a 2- to 3- fold increase in susceptibility
to HIV. It therefore makes sense that STI treatment should reduce HIV transmission,
and several epidemiological studies have suggested that this is the case.
Study
HPTN 039 was a placebo-controlled proof-of-concept trial designed to assess whether
HSV-2 suppression reduces the risk of HIV acquisition among heterosexual women
in Africa and 
Results
