Does genital herpes affect HIV viral load during early HIV infection?

Genital herpes virus (HSV-2) infection does not affect blood plasma HIV viral load during acute or early HIV infection, according to a retrospective longitudinal cohort analysis from the United States, published in the May 1^st issue of the Journal of Infectious Diseases. The investigators suggest that it is unlikely that HSV-2 serostatus influences HIV disease progression during primary HIV-1 infection in white gay men, but since their study contradicts findings in heterosexual men and women in Africa, and the exact mechanisms by which HSV-2 influences HIV viral load are still unclear, further research is necessary.

Several studies have previously suggested that HSV-2 infection may increase blood plasma HIV viral load by up to 1 log, and that treating HSV-2 with antiviral drugs such as aciclovir can reduce HIV viral load.

Consequently, investigators from the University of California, San Diego (UCSD), speculated that HSV-2 might be a modifiable cofactor that influences the establishment of a higher viral load set point during early HIV infection. They therefore conducted a longitudinal study to investigate the effect of HSV-2 serostatus on the dynamics of HIV during acute and early HIV infection in their primary HIV infection cohort, which is part of the Acute Infection and Early Disease Research Program (AIEDRP).

Participants in the study were recruited between June 1996 and June 2005. Acute HIV infection was defined by detectable HIV viral load in the absence of antibody, with subsequently documented seroconversion. Early HIV infection was defined by a positive antibody test preceded by a documented negative test in the past 12 months, or a negative result using a detuned (STARHS) assay.

All participants were antiretroviral naive at enrolment and during follow-up, and were excluded if they were being treated with any type of HSV-2–specific antiviral therapy.

Out of 309 eligible participants, twelve women were excluded from the final analysis because the female sample size was too small to adjust for possible confounding by gender. In addition, three men who had low positive HSV-2 antibody titers and subsequent indeterminate HSV-2 Western blot results were also excluded from the study. Of the 294 remaining participants, more than 90% reported sex with men as their primary HIV risk factor.

A total of 122 participants (41.5%) were coinfected with HSV-2 at baseline: 85 (28.9%) had acute HIV infection and 209 (71.1%) had early HIV infection.

In bivariate analyses, baseline viral loads did not differ significantly between individuals who were HSV-2–seropositive or –seronegative, for those with either acute (p=0.42) or early (p=0.50) infection.

In multivariate analysis, controlling for age and disease stage at entry, HSV-2–seropositive status was associated with a 0.16 log¹⁰lower baseline viral load, but this was not statistically significant (p=0.21).

During the one-year study period, four individuals required prophylactic HSV-2 therapy and were excluded from further analysis.

Of the 85 men who entered the study with acute infection, the median follow-up times (before initiating HAART) were similar, at 76 days, for both HSV-2–seropositive and –seronegative individuals, and there were no significant differences in mean viral loads between HSV-2–seropositive and –seronegative individuals throughout the period of follow-up.

Similarly, of the 209 men who entered the study with early infection, no significant differences were seen in mean viral loads between HSV-2–seropositive and –seronegative individuals. In addition, the estimated median time to antiretroviral therapy was longer, at 331 days in the HSV-2–seropositive individuals, compared with 208 days in HSV-2–seronegative individuals.

The investigators note that their findings “are in contrast to those of a previous study that included 219 subjects with primary HIV-1 infection from Rakai, Uganda,” which found a strong correlation between HSV-2 and HIV viral load (Serwadda, 2003). However, they note that “there are important differences — such as sex, ethnicity, nutritional status, additional coinfections, and HIV-1 subtype — that distinguished our study from the Rakai cohort study.”

In particular, they say, “our study population was composed primarily of healthy white men who have sex with men. In African countries, the coexistence of endemic diseases such as malaria and tuberculosis is relatively common and may have contributed to the observed higher HIV-1 loads.” They add that “it is also unknown to what extent differences in HIV-1 clades linked to dissimilar genetic background could have contributed to the differences observed between our study and the ones conducted in Africa.”

They do note, however, that their study had several limitations, including not measuring HSV-2 genital shedding, which they concede “could be more likely to influence HIV-1 dynamics than latent HSV-2 infection as assessed by HSV-2–positive serostatus”. They also note that they “did not differentiate recently acquired (within 1 year of HSV-2 acquisition) from chronic HSV-2 serostatus.”

The investigators conclude that “HSV-2 serostatus showed no influence on the dynamics of plasma HIV-1 loads during acute or early HIV-1 infection; therefore, it is unlikely that HSV-2 serostatus influences HIV-1 disease progression during primary HIV-1 infection in men.” They suggest that further prospective studies are necessary to investigate “whether (1) discordant results with prior studies are related to differences in HIV-1 clades or genetic background and (2) subjects who have concurrent HSV-2 genital shedding or recently acquired HSV-2 infection may experience a stronger influence on the initial set-point level of HIV load during primary infection.”

In an accompanying editorial, Lawrence Corey of the University of Washington, Seattle, notes that reason for the discrepancies between the results of this study and previous studies “remains to be determined. We do know that the major reservoir for HIV in early infection is in the gastrointestinal tract,” he writes. “As such, other areas in which the virus is found and compartmentalized may not play a significantly discernible role in upregulating T cell replication and dissemination until this reservoir is ‘burnt out.’”.

“What is clear,” he concludes, “is that the complex biological interactions between these two unrelated pathogens that can occupy the same ecological ‘space’ but pursue their chronicity by different mechanisms continues to intrigue physician scientists and yet dismays the public health efforts to control these viral STDs.”