Antiretroviral treatment lowers rates of HIV transmission in heterosexual couples in Africa

Antiretroviral treatment is associated with a lower risk of heterosexual HIV transmission in African serodiscordant couples, according to findings from Uganda, Rwanda and Zambia, presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections.

This reduction in risk has been detected despite evidence presented in the same session showing that treatment does not consistently eliminate HIV in semen.

In 2000, Quinn et al. published one of the earliest studies to show that heterosexual HIV transmission is less common at lower plasma viral loads. This finding was based on data from heterosexual couples in Rakai (a rural district of south-west Uganda) who were not on antiretroviral treatment (ART). It was unclear whether the same would hold true for those whose viral loads have been lowered as a result of ART.

In this new study, also based on stable, mixed-status heterosexual couples in Rakai, Steven Reynolds of NIAID and the Johns Hopkins School of Medicine has shown that sexual transmission is greatly reduced in those who are on ART.

Starting in June 2004, free antiretroviral treatment was offered to members of the Rakai Community Cohort whose CD4 cell count was below 250 cells/mm³, or who had symptoms of advanced HIV disease (WHO stage IV). Serodiscordant couples in the cohort were surveyed annually to determine HIV incidence in the uninfected partner. Using questionnaires, information was also gathered on HIV risk factors, such as number of partners, condom use and ulcerative sexually transmitted infections. All HIV-positive participants also received basic HIV care and ongoing risk-reduction counselling.

Between 2004 and 2007, a total of 205 serodiscordant couples were identified and enrolled. HIV treatment was started by the HIV-positive partner in 20 of these couples (twelve men and eight women), according to standard treatment-eligibility guidelines. The median duration of follow-up was 1.5 years for couples not taking HIV treatment and 1.1 years for those taking ART.

In couples not taking ART, a total of 34 HIV transmissions were recorded during the total of 396.4 person-years of follow-up – an HIV incidence of 8.6 per 100 person-years (95% confidence interval [CI], 5.9-12.0). There were no instances of HIV transmission during the 24.6 person-years of follow-up of couples whose HIV-positive partner was on treatment.

Before the start of HIV treatment, the median viral load in the HIV-infected partners was 54,927 copies/ml. After six months of HIV treatment, 15 of 19 individuals (79%) had a viral load below 400 copies/ml and 19 of 20 (95%) achieved at least one viral-load measurement below this level during the first 18 months of HIV treatment. Adherence levels, based on pill count, exceeded 90% in 55% of those on ART, and was less than 70% in only 10%.

There were no significant differences in age, circumcision prevalence, self-reported condom use or sexual risk behaviour, number of extramarital partners or genital ulcerative disease in the couples on and not on ART. (Rates of non-use of condoms was high, at 64% to 71%.) The only significant difference found was lower alcohol use in people on ART, possibly as a result of the counselling interventions.

Reynolds concluded that ART significantly reduced the rates of sexual transmission between HIV-discordant couples. He also noted that these conclusions are based on a relatively treatment-adherent population with relatively good resources for care, treatment and support – a situation that may not apply more widely. The other major study limitation was the short follow-up period of roughly a year on ART, and the small sample – limitations which were both addressed to some extent in the next presentation.

Patrick Sullivan of Emory University next presented similar data from larger cohorts in the cities of Lusaka and Kigali, the capitals (and largest cities) of Zambia and Rwanda respectively. A total of 2993 serodiscordant couples were followed up between 2002 and late 2008 in these two cities.

In these couples, the HIV-infected partner started antiretroviral therapy when their CD4 cell count was below 200 cells/mm³ or if they developed symptomatic HIV disease (WHO stages III and IV). Every three months, the HIV-negative partners were tested for the virus and received risk-reduction counselling. Information on sexual risk behaviour was collected at every screening visit. Vaginal smears were also used to check for the presence of sperm, and information was gathered on pregnancies.

The median duration of follow-up was 512 days, during which a total of 175 HIV infections were recorded. New infections were confirmed (by sequencing) as originating with the HIV-positive partner. Those that could not be confirmed (roughly 15%) were not considered in the analysis as their source was uncertain.

Of the confirmed within-couple transmissions, the overwhelming majority (171) occurred in couples where the HIV-infected partner was not taking HIV treatment. The remaining four infections occurred in couples during HIV treatment. This resulted in an HIV incidence rate, during antiretroviral therapy, of 0.7% per 100 couple-years, compared to an incidence of 3.4% per 100 couple-years when HIV treatment was not being taken – a fivefold risk reduction (relative risk = 0.21; 95% CI, 0.08-0.59).

Another, more conservative, estimate included two people who seroconverted in the three-month period after their partner began taking ART. Considering these two as 'infections while on ART' increased the count of on-ART infections to six, for an incidence rate of 1.0 per 100 couple-years, and a threefold reduction in risk (relative risk = 0.32; 95% CI, 0.14-0.73).

The investigators found comparable rates of pregnancy and self-reported condom use between the two groups, although sexual-risk-level assessment largely depended on self-reporting. To try to control for possible underreporting of risky sex, vaginal smears were also taken from female participants to test for the presence of semen. Semen was actually found in somewhat fewer women in on-ART couples (2.2% vs 3.1%), and combined indicators of risk were also somewhat lower in on-ART couples (19% vs 25%, p<.05 for both).

There were also significant differences between the two cities, with people in Kigali at half the risk of those in Lusaka. This was not explained, although it was consistent with several previous study findings. Viral-load measurements were also not routinely done and were not available for analysis; nor were adherence data.

In summary, Sullivan concluded that three- to fivefold lower rates of HIV transmission were seen in mixed-status heterosexual couples on ART in the capital cities of Rwanda and Zambia. However, both presenters also stressed that ART should not be considered a primary means of HIV prevention, but part of a combination approach to prevention. In addition, most HIV-positive persons in Africa are either not aware of their status, or are not on ART because they do not qualify (based on CD4 cell counts).

The reduction in risk of transmission seen in the Rwanda/Zambia study falls considerably short of the efficacy assumed for antiretroviral therapy in preventing transmission by a World Health Organization modelling exercise published in late 2008. That model projected a very substantial decline in HIV incidence if all people with HIV could be treated, assuming that treatment reduced the risk of transmission by 99%.

However, speaking at a CROI symposium on the global epidemic on Sunday, epidemiologist Christophe Fraser of Imperial College, London, noted that his own modelling, using the other assumptions contained in the WHO model, suggests that if the preventive efficacy of ART is even a little less than 99%, there is a much less substantial decline in HIV incidence, while an efficacy of 80% would result in a paradoxical increase in HIV incidence in the short term.

He called for multiple groups of epidemiologists to explore the issue of 'treatment as prevention' very carefully before policy is made, with a particular focus on determining whether all the assumptions in models are based on robust evidence.