In this study, the incidence of HIV infection declined significantly with the scale-up of a combination strategy for HIV prevention, which provides empirical evidence that HIV control efforts can have a substantial population-level effect. The declines in the incidence of HIV infection were probably a result of the scale-up of ART use and male circumcision, although reduced sexual activity in late adolescence may also have contributed. HIV incidence declined to a lesser degree among women than among men, which suggests that the combination of the direct effects of male circumcision and the indirect effects of ART use among women differentially benefited men. Additional efforts are needed to avert new infections in women, such as a further scale-up of ART use among men and the potential introduction of new interventions for primary prevention (e.g., preexposure prophylaxis, or PrEP).

Previously, we found that community levels of male circumcision and of ART use among women at modest coverage levels were associated with a lower community incidence of HIV infection among men than the incidence before these interventions.22 In another study in rural South Africa, higher rates of ART coverage were associated with a lower risk of individual-level acquisition of HIV infection, but that study did not assess temporal declines in incidence of HIV infection or male circumcision coverage.10 Our finding of a 42% reduction in the incidence of HIV infection to 0.66 cases per 100 person-years, relative to the incidence in the period before the scale-up, is substantial, but the incidence is still well above the incidence rate of 0.1 cases per 100 person-years, which is an estimated threshold for the elimination of HIV infection.6,23

From 2009 to 2016, the percentage of HIV-positive persons with viral-load suppression increased by 44%, which suggests that HIV viral-load suppression associated with ART use probably reduced HIV exposure to uninfected, opposite-sex partners, an assumption that is consistent with the findings from other studies.12,13,24-26 By 2016, among HIV-positive persons, the percentage of participants who had viral-load suppression was 75%, which met one of the 2020 goals of the joint United Nations Program on HIV and AIDS (UNAIDS) 90-90-90 initiative, an initiative that modeling suggests could end the HIV epidemic by 2030.27 Our results show that ambitious ART scale-up goals can be achieved. Similar results for viral-load suppression (71% of HIV-positive persons) have been reported in Botswana, although beneficial effects on HIV incidence rates in Botswana have not yet been reported.28,29

Male circumcision coverage increased steadily over time and reached 59% by 2016 but remained below the UNAIDS target of 80% coverage.30 Scale-up of ART and male circumcision were highly correlated (Figure 2D), so it is difficult to disaggregate their effects. Nevertheless, we attempted to address this issue empirically by assessing HIV incidence trends separately among men and women and among uncircumcised and circumcised men. Previous mathematical modeling studies have suggested that there are substantial, long-term, indirect effects of male circumcision on the incidence of HIV infection both among female partners and among uncircumcised men; however, these indirect benefits are unlikely to be realized until at least a decade after the prevalence of HIV declines as a result of the direct effects of male circumcision.31 Therefore, the significant reductions in the incidence of HIV infection among women and among uncircumcised men that were observed in this study probably result from the population-level effect on HIV incidence of the increase in ART coverage over time. The sharpest declines in HIV incidence were observed among circumcised men — nearly twice the decline that was observed among uncircumcised men — which is probably because circumcised men benefit from the direct protective effect of male circumcision as well as from the indirect effect of female partners who are using ART. In comparison, the declines in the incidence of HIV infection among women and among uncircumcised men were more moderate, probably because these persons benefit largely from the reduced exposure afforded by their infected partner’s use of ART. The percentage of persons who used ART was lower among HIV-positive men than among HIV-positive women, which would further attenuate benefits for women.31

Significant declines in the incidence of HIV infection were first observed in 2012, when ART coverage levels reached 36% and male circumcision coverage levels reached 43%. It would be tempting to conclude that these coverage levels represent threshold effects, but because interventions were scaled concurrently and the effect of interventions may be delayed, we cannot reliably make such inferences from these empirical data alone. The ability to define intervention thresholds would also depend on the proportion of infections that are introduced from outside the population of interest, a quantity that probably varies depending on geographic location.

We found reductions in sexual activity among both male and female adolescents 15 to 19 years of age. Previous studies conducted by the Rakai Health Sciences Program showed a decline in the incidence of HIV infection among 15-to-19-year-old girls that was associated with factors such as delayed sexual debut, which was coincident with an increased rate of enrollment in school.32 However, given the fact that this age group represents only a small fraction of all incident HIV infections and that there were limited behavioral changes in older age groups, the reduction in sexual activity among adolescents probably has a modest effect on population-level HIV incidence. No significant changes over time in condom use were observed in any age group, which is a sobering finding, given the many years of efforts to promote the use of condoms and to facilitate access to condoms.

This study has several limitations. First, ART coverage, male circumcision coverage, and sexual behaviors were reported by the participants and may be subject to social desirability and other biases. However, there are no clear indications that any biases changed over time, and participant-reported ART use has been validated with high specificity in this population.19 Second, viral-load testing was conducted on stored serum samples; such serum samples may be subject to RNA degradation over time, which could potentially result in an overestimation of viral-load suppression in the earlier surveys and an underestimation of the magnitude of viral-load suppression over time.33 Third, although the RCCS has relatively high participation rates as compared with other African population-based cohorts, there was substantial mobility among the participants, which reduced the rates of participation and follow-up.34,35 However, rates of participation among persons who were present in the community increased over time, and sensitivity analyses to assess potential selection bias did not change our inferences. Fourth, we cannot rule out the possibility that unmeasured secular trends or other potential confounders explain the declines in the incidence of HIV infection. However, this observational study showed a strong temporal association between the scale-up of a combination strategy for HIV prevention and population-level declines in the incidence of HIV infection, as well as greater reductions in HIV incidence with higher coverage of interventions.

An important consideration is whether our estimates of service coverage and HIV incidence results can be generalized. Demographic and behavioral data in the RCCS are largely consistent with surveys of demographic and health data in the region.36 The RCCS is also an open, population-based cohort with extensive migration in and out of the cohort, which probably minimized, but did not eliminate, potential Hawthorne effects (i.e., changes in behavior resulting from awareness of being observed) of repeat observations. The Rakai Health Sciences Program has conducted combination studies of HIV intervention and prevention, which may have increased ART and male circumcision coverage.37-39 All participants in the RCCS are offered HIV testing services, which results in high coverage (98% in 2015). Although conditions in Rakai may have been favorable for rapidly scaling ART use and male circumcision services, the effect of these interventions on population-level incidence of HIV infection should be generalizable. Indeed, data from the National AIDS Control Program of the Uganda Ministry of Health indicate that a dramatic scale-up of a combination strategy for HIV prevention was also occurring nationally: in 2016, ART coverage was 68% and male circumcision coverage was 54% (Wiersma S: personal communication).

In summary, data from this longitudinal cohort in Rakai, Uganda, showed a 42% decline in the incidence of HIV infection that was associated with the scale-up of a combination strategy for HIV prevention. This decline provides evidence that HIV control efforts can have a population-level effect. Differential declines in the incidence of HIV infection according to sex indicate a need to strengthen prevention efforts to benefit women, including improvement in ART coverage among men and consideration of newer, primary prevention interventions. Intensification of HIV prevention efforts for both women and men, including key underserved populations such as migrants, as well as long-term surveillance, are needed.