HIV This Week

Powers KA, Poole C, Pettifor AR, Cohen MS. Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet 2008 Published online August 5, 2008 DOI:10.1016/S1473-3099(08)70156-7

Studies of cumulative HIV incidence suggest that cofactors such as genital ulcer disease, HIV disease stage, and male circumcision influence HIV transmission; however, the heterosexual infectivity of HIV-1 is commonly cited as a fixed value (approximately 0∙001, or one transmission per 1000 contacts). Powers et al sought to estimate transmission cofactor effects on the heterosexual infectivity of HIV-1 and to quantify the extent to which study methods have affected infectivity estimates. They undertook a systematic search (up to April 27, 2008) of PubMed, Web of Science, and relevant bibliographies to identify articles estimating the heterosexual infectivity of HIV-1. They used meta-regression and stratified random-effects meta-analysis to assess differences in infectivity associated with cofactors and study methods. Infectivity estimates were very heterogeneous, ranging from zero transmissions after more than 100 penile-vaginal contacts in some serodiscordant couples to one transmission for every 3∙1 episodes of heterosexual anal intercourse. Estimates were only weakly associated with study methods. Infectivity differences, expressed as number of transmissions per 1000 contacts, were 8·1 (95 % CI 0·4–15·8) when comparing uncircumcised to circumcised susceptible men, 6·0 (3·3–8·8) comparing susceptible individuals with and without genital ulcer disease, 1·9 (0·9–2·8) comparing late-stage to midstage index cases, and 2·5 (0·2–4·9) comparing early-stage to mid-stage index cases. A single value for the heterosexual infectivity of HIV-1 fails to reflect the variation associated with important cofactors. The commonly cited value of 0∙001 was estimated among stable couples with low prevalences of high-risk cofactors, and represents a lower bound. Cofactor effects are important to include in epidemic models, policy considerations, and prevention messages.

Editors’ note: The findings of this systematic analysis suggest that in many contexts, such as lack of male circumcision, presence of sexually transmitted infections, practice of anal sex, and early-stage or late-stage infection, heterosexual infectivity of HIV-1 might exceed the commonly cited value of one-in-a-thousand by more than an order of magnitude (i.e. more than one-in-a-hundred). Other cofactors, for which there are insufficient data but that clearly may play a role, such as viral load, viral subtype, and antiretroviral drug use, can further increase or decrease transmission probabilities. Since the overall probability of HIV transmission also depends on the probability of exposure to HIV in the first place, we need to work on the determinants of exposure as well as the co-factors for transmission.

Few longitudinal studies have described the interactions between reactivation of herpes simplex virus type 2 (HSV-2) infection (hereafter, "HSV-2 reactivation") and genital and systemic replication of human immunodeficiency virus type 1 (HIV-1). Women in Burkina Faso who were seropositive for both HIV-1 and HSV-2 were enrolled in a randomized placebo-controlled trial of therapy to suppress reactivation of HSV-2 infection (hereafter, "HSV suppressive therapy"). During the baseline phase, 6 enriched cervicovaginal lavage specimens were obtained over 12 weeks to detect and quantify the HIV-1 RNA and HSV-2 DNA loads. Women with genital ulcer disease (GUD) detected at least once were more likely than women in whom GUD was not detected (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.09-1.37) to have genital HIV-1 RNA detected during >or=1 visit. Similarly, women with genital HSV-2 DNA detected during >or=1 clinic visit were more likely than women in whom genital HSV-2 DNA was not detected (RR, 1.17; 95% CI, 1.01-1.34) to have genital HIV-1 RNA detected at least once . In addition, the mean genital HIV-1 RNA loads for women with GUD detected during >or=1 visit and women with HSV-2 genital shedding detected during >or=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 >or=1 visit revealed GUD (+0.25 log(10) copies/mL; 95% CI, -0.05-0.55) or genital HSV-2 DNA (+0.40 log(10) copies/mL; 95% CI, 0.15-0.66), compared with women who did not experience GUD or HSV-2 genital shedding, respectively. The association of HSV-2 reactivations on HIV-1 replication tended to be stronger in patients with a higher CD4(+) cell count (i.e., >500 cells/microL). The contribution of HSV-2 to HIV-1 replication among women with CD4(+) cell count of <or=500 cells/microL was reduced because almost all experienced HIV-1 genital shedding. Both clinical and subclinical HSV-2 reactivations play a role in increasing the rate of HIV-1 replication. HSV suppressive therapy is a promising tool for HIV control. Initiation of such therapy when the CD4(+) cell count is >500 cells/microL deserves further investigation.

Editors’ note: More than 70% of people living with HIV in high-income, middle-income, and low-income countries may be co-infected with herpes simplex virus type 2 (HSV-2). This study of 136 women who were moderately immunosuppressed but not on antiretroviral treatment and who contributed data from 784 study visits, demonstrates that both clinical (i.e. symptomatic with genital ulcers) and subclinical (i.e. no symptoms) HSV-2 reactivations contribute to HIV replication in the plasma and to genital HIV shedding. Because HSV-2 suppressive therapy has the potential to both prevent onward transmission and slow HIV disease progression, consideration may be given to offering it to people with known HIV–positive status who present with genital ulcer disease, to take until they become eligible for antiretroviral treatment, pending further studies.