Quality and quantity of antenatal HIV counselling in a PMTCT programme in Mombasa, Kenya

A landmark randomised trial of male circumcision (MC) in Orange Farm, South Africa recently showed a large and significant reduction in risk of HIV infection, reporting MC effectiveness of 61% (95% CI: 34%-77%). Additionally, two further randomised trials of MC in Kisumu, Kenya and Rakai, Uganda were recently stopped early to report 53% and 48% effectiveness, respectively. Since MC may protect against both HIV and certain sexually transmitted infections (STI), which are themselves cofactors of HIV infection, an important question is the extent to which this estimated effectiveness against HIV is mediated by the protective effect of circumcision against STI. The answer lies in the trial data if the appropriate statistical analyses can be identified to estimate the separate efficacies against HIV and STI, which combine to determine overall effectiveness.

Focusing on the MC trial in Kisumu, we used a stochastic prevention trial simulator (1) to determine whether statistical analyses can validly estimate efficacy, (2) to determine whether MC efficacy against STI alone can produce large effectiveness against HIV and (3) to estimate the fraction of all HIV infections prevented that are attributable to efficacy against STI when both efficacies combine.

Valid estimation of separate efficacies against HIV and STI as well as MC effectiveness is feasible with available STI and HIV trial data, under Kisumu trial conditions. Under our parameter assumptions, high overall effectiveness of MC against HIV was observed only with a high MC efficacy against HIV and was not possible on the basis of MC efficacy against STI alone. The fraction of all HIV infections prevented which were attributable to MC efficacy against STI was small, except when efficacy of MC specifically against HIV was very low. In the three MC trials which reported between 48% and 61% effectiveness (combining STI and HIV efficacies), the fraction of HIV infections prevented in circumcised males which were attributable to STI was unlikely to be more than 10% to 20%.

Estimation of efficacy, attributable fraction and effectiveness leads to improved understanding of trial results, gives trial results greater external validity and is essential to determine the broader public health impact of circumcision to men and women.

To determine whether herpes simplex virus type 2 (HSV-2) infection was associated with risk of intrapartum human immunodeficiency virus type 1 (HIV-1) transmission and to define correlates of HSV-2 infection among HIV-1-seropositive pregnant women.

We performed a nested case control study within a perinatal cohort in Nairobi, Kenya. Herpes simplex virus type 2 serostatus and the presence of genital ulcers were ascertained at 32 weeks of gestation. Maternal cervical and plasma HIV-1 RNA and cervical HSV DNA were measured at delivery.

One hundred fifty-two (87%) of 175 HIV-1-infected mothers were HSV-2-seropositive. Among the 152 HSV-2-seropositive women, nine (6%) had genital ulcers at 32 weeks of gestation, and 13 (9%) were shedding HSV in cervical secretions. Genital ulcers were associated with increased plasma HIV-1 RNA levels (P=.02) and an increased risk of intrapartum HIV-1 transmission (16% of transmitters versus 3% of nontransmitters had ulcers; P = .003), an association which was maintained in multivariable analysis adjusting for plasma HIV-1 RNA levels (P=.04). We found a borderline association for higher plasma HIV-1 RNA among women shedding HSV (P=.07) and no association between cervical HSV shedding and either cervical HIV-1 RNA levels or intrapartum HIV-1 transmission (P=.4 and P=.5, [corrected] respectively).

Herpes simplex virus type 2 is the leading cause of genital ulcers among women in sub-Saharan Africa and was highly prevalent in this cohort of pregnant women receiving prophylactic zidovudine. After adjusting for plasma HIV-1 RNA levels, genital ulcers were associated with increased risk of intrapartum HIV-1 transmission. These data suggest that management of HSV-2 during pregnancy may enhance mother-to-child HIV-1 prevention efforts. LEVEL OF EVIDENCE: II.

To understand the changing impact of herpes simplex 2 (HSV-2) and other sexually transmitted infections (STIs) on HIV incidence over time in four sub-Saharan African cities, using simulation models.

An individual-based stochastic model was fitted to demographic, behavioural and epidemiological data from cross-sectional population-based surveys in four African cities (Kisumu, Kenya; Ndola, Zambia; Yaounde, Cameroon; and Cotonou, Benin) in 1997. To estimate the proportion of new HIV infections attributable to HSV-2 and other STIs over time, HIV incidence in the fitted model was compared with that in model scenarios in which the cofactor effect of the STIs on HIV susceptibility and infectivity were removed 5, 10, 15, 20 and 25 years into the simulated HIV epidemics.

The proportion of incident HIV attributable to HSV-2 infection (the model estimated population attributable fraction (PAF(M))) increased with maturity of the HIV epidemic. In the different cities, the PAF(M) was 8-31% 5 years into the epidemic, but rose to 35-48% 15 years after the introduction of HIV. In contrast, the proportion of incident HIV attributable to chancroid decreased over time with strongest effects five years after HIV introduction, falling to no effect 15 years after. Sensitivity analyses showed that, in the model, recurrent HSV-2 ulcers had more of an impact on HIV incidence than did primary HSV-2 ulcers, and that the effect of HSV-2 on HIV infectivity may be more important for HIV spread than the effect on HIV susceptibility, assuming that HSV-2 has similar cofactor effects on HIV susceptibility and infectivity. The overall impact of other curable STIs on HIV spread (syphilis, gonorrhoea and chlamydia) remained relatively constant over time.

Although HSV-2 appears to have a limited impact on HIV incidence in the early stages of sub-Saharan African HIV epidemics when the epidemic is concentrated in core groups, it has an increasingly large impact as the epidemic progresses. In generalised HIV epidemics where control programmes for curable STIs are already in place, interventions against HSV-2 may have a key role in HIV prevention.