Genital herpes may raise HIV transmissibility

SAN FRANCISCO -- Physicians have long shrugged off genital herpes as basically a trivial infection, when in fact there is persuasive evidence that herpes simplex virus type 2 is a major force driving the AIDS epidemic, Dr. Lawrence Corey said at the annual meeting of the Infectious Diseases Society of America.

Not only do persons infected with herpes simplex virus type 2 (HSV-2) have up to a fivefold increased risk of acquiring HIV, it's now clear that coinfection with HIV-1 and HSV-2 increases HIV transmissibility and accelerates the course of HIV disease, Dr. Corey said in the annual John F. Enders Distinguished Lecture in Medical Virology. Further, coinfection leads to a marked upregulation of HIV replication peripherally, and HSV-2 shedding facilitates HIV shedding on mucosal surfaces.

The two viruses are "the odd couple" in terms of their dissimilar particle size, genome size, latency and replication sites, and adaptation to humans. But they interact synergistically: HSV-2 boosts HIV's infectivity, while HIV alters the natural history of HSV-2, resulting in more frequent HSV reactivation than in HIV-negative individuals, explained Dr. Corey, professor of medicine and of laboratory medicine at the University of Washington, Seattle, and head of the infectious diseases division at the Fred Hutchison Cancer Research Center in Seattle.

New data from the landmark HIV epidemiologic study in the Rakai district of rural Uganda demonstrate that an HIV-negative and HSV-2-seropositive individual whose sexual partner is HIV infected has a fivefold greater risk per sexual contact of acquiring HIV, compared with an HSV-2-seronegative partner.

The HSV-2-positive partner of an HIV-infected individual in the Rakai having a low viral load had an HIV acquisition rate as high as that of an HSV-2-seronegative person whose partner had an extremely high HIV viral load.

These African findings are consistent with the results of a 27-study metaanalysis by Dr. Anna Wald, also of the University of Washington. She found that the relative risk of being HIV-infected was increased 2.1-fold in HSV-2-positive subjects in the cohort studies and 4.2-fold in the cross-sectional studies.

These epidemiologic data are supported by a plausible biologic mechanism. The polymerase chain reaction revolution has shown that reactivation of genital HSV-2 occurs much more frequently than previously recognized in culture studies. In immunocompetent adults, HSV-2-seropositive women shed virus on 35% of days, men on 25%. Seventy-five percent of shedding episodes are subclinical.

These asymptomatic shedding episodes are associated with microscopic lesions. The initial infiltrating cells in these herpetic lesions are activated CD4 cells capable of being infected both by HSV-2 and HIV-1.

Clinically, HSV-2 infections need to be treated with greater respect for their role in HIV acquisition, transmission, and replication.

"All HIV-infected persons should have a specific HSV serology test. All HSV-2/HIV coinfected persons should be evaluated for antiviral therapy for HSV-2. Most, in my opinion, should be placed on daily therapy because of the high shedding rate. I think it's especially important for those who aren't controlling viremia and those who are sexually active," Dr. Corey said.

He went on to declare that the time has come for a clinical trial testing the hypothesis that HSV-2 suppression via daily acyclovir will reduce HIV acquisition in high-risk populations. Acyclovir at 400 mg twice daily has been shown to reduce HSV-2 shedding in immunocompetent individuals by more than 90%.

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