Burkinabe women with HIV-1 and HSV-2 coinfections had significantly elevated genital and plasma HIV-1 viral loads due to HSV-2 reactivations, according to the findings of a randomised placebo-controlled trial published in the 15th July edition of the Journal of Infectious Diseases. The study suggests that HSV-2 suppression therapy might be a useful strategy for prevention of onward transmission in women not eligible for antiretroviral therapy.
HSV-2, the cause of genital herpes, is a common sexually transmitted infection (STI) worldwide with a prevalence of up to 70-90% in HIV-infected patients. There is epidemiological evidence that a correlation exists between HSV-2 infection and increased risk of HIV-1 acquisition. However, the exact nature and significance of this relationship is difficult to establish due to the high variability of HIV-1 and HSV-2 genital shedding within and between individuals.
An earlier clinical trial in Burkina Faso demonstrated that treatment of HSV-2 with valaciclovir resulted in a lower frequency and level of detectable HIV-1 RNA in genital secretions and plasma. This finding highlighted the potential of HSV-2 control as a tool for the prevention of HIV-1 infection.
The best HSV-2 control strategy will only be identified with the elucidation of the relative roles of clinical and sub-clinical HSV-2 activations in HIV-1 replication on the one hand, and the level and impact of HIV-mediated immunosuppression on HSV-2 reactivation on the other. This issue has been addressed by a team of Burkinabe, UK, and French investigators in a clinical trial.
The study site was the Centre Muraz in Bobo-Dioulasso, Burkina Faso. The study participants were high-risk women who had antibodies to both HIV-1 and HSV-2, no contraindication against valaciclovir, were not eligible for HSV-2 suppressive therapy nor antiretroviral therapy, nor had any AIDS-defining condition.
One hundred and forty eligible women were enrolled in a randomised placebo-controlled trial of therapy to suppress reactivation of HSV-2 infection. Patients were counselled and followed-up, episodes of genital ulcer disease (GUD) which necessitated unscheduled clinic visits were documented, and clinically confirmed ulcers were treated. GUD was treated with antibiotics and patients whose ulcers had not healed within a week received aciclovir.
Blood, urine samples, and genital samples were taken for various laboratory analyses including serological detection of STIs, CD4 cell counts, and pregnancy testing. During the baseline phase, six enriched cervico-vaginal lavage specimens were obtained over 12 weeks to detect and quantify the HIV-1 RNA and HSV-2 DNA loads.
One hundred and thirty-six women were available for analysis after four were excluded because of erroneous recruitment. There were 784 visits representing 96% of all potential visits. CD4 counts were moderately immuno-suppressed with a median CD4 count of 446 cells/mm3. However, 41.8% of the women had CD4 counts > 500 cells/mm3 and 58.2% had 200-500 cells/mm3.
Women in whom GUD was detected at least once were more likely to have genital HIV-1 RNA detected during ≥1 visit than women in whom GUD was not detected (risk ratio [RR], 1.23;95%confidence interval [CI], 1.09–1.37). Similarly, women with genital HSV-2 DNA during ≥1 clinic visit were more likely to have genital HIV-1 RNA detected at least once than women in whom genital HSV-2 DNA was not detected (RR, 1.17; 95% CI, 1.01–1.34).
The mean genital HIV-1 RNA loads for women with GUD detected during ≥1 visit and women with HSV-2 genital shedding detected during ≥ 1 visit were greater than that for women in whom genital HSV-2 DNA or GUD was never detected.
The plasma HIV-1 RNA load was increased among women for whom ≥1 visit revealed GUD or genital HSV-2 DNA, compared with women who did not experience GUD or HSV-2 genital shedding, respectively.
The association of HSV-2 reactivations to HIV-1 replication was stronger in patients with a higher CD4 cell count (i.e. > 500 cells/mm3). The contribution of HSV-2 to HIV-1 replication among women with CD4 cell count of ≤ 500 cells/mm3 was reduced since almost all women had detectable genital HIV-1 RNA.
In conclusion, both clinical and subclinical HSV-2 reactivations play a role in increasing the rate of HIV-1 replication, the investigators conclude. HSV-2 suppressive therapy is a promising tool for HIV control. The effect of early initiation of such therapy when the CD4 cell count is > 500 cells/mm3 deserves further investigation. The results of ongoing clinical trials to test this strategy will inform future HSV-2 control policies.
Nagot N et al. Roles of clinical and subclinical reactivated Herpes Simplex Virus type 2 Infection and human immunodeficiency virus type 1 (HIV-1)–induced immunosuppression on genital and plasma HIV-1 Levels. Journal of Infectious Diseases 198:241–249, 2008.