Heterogeneity in susceptibility and/or transmissibility was recognized during the early phases of the HIV epidemic, when it was found that transmission in heterosexual partnerships was not solely dependent on the number of sex acts[18
]. Strikingly, the risk of male-to-female HIV transmission in a discordant heterosexual partnership was as high as 10% for <10 unprotected contacts, but increased to only 23% after at least 2000 unprotected contacts[18
]. While these studies could not differentiate between heterogeneity in infectiousness and in host susceptibility, it is plausible that the effect was at least partly due to the latter, given that several genetic, immune and infectious correlates of altered susceptibility have since been identified[10
]. Further evidence for heterogeneity in host susceptibility is provided by the observation that some individuals appear to be relatively resistant[24
]. However, it is difficult to measure this heterogeneity precisely: since individuals can only acquire HIV once, estimation of individual risks becomes extremely difficult. In theory, heterogeneity in host susceptibility could be estimated from the distribution of time to infection in cohorts of equally exposed HIV uninfected individuals, but such cohorts are not available. High-risk sex worker cohorts provide limited insights, albeit valuable ones[24
], since most of these women had already been heavily exposed to HIV prior to enrollment in the cohort, presumably with infection of the most susceptible women. These difficulties in accurately measuring heterogeneity in host susceptibility may explain why the phenomenon has largely been overlooked.
We hypothesize that the decline in per-act acquisition of HIV observed over time in high-risk Kenyan sex workers[9
], independent of behavior change, may have been partly related to heterogeneity in susceptibility within the cohort. This decline occurred during a period when HIV prevalence in high-risk men was stable, making it unlikely that it was related to changing HIV prevalence in male clients, and was prior to significant roll out of antiretroviral therapy in the region[9
]. Altered patterns of sex worker client contact, particularly the establishment of “regular clients”, may impact STI and HIV prevalence[25
], but this effect will be blunted by the fact that regular clients of sex workers in the cohort report high numbers of concurrent partners (Kaul R, unpublished data). Additional factors are likely to have contributed to this decline, including a reduction in the prevalence of bacterial (transient) sexually transmitted infections, phase of the HIV epidemic, and other factors not included our model. Indeed, such factors may partly explain why the reductions in population prevalence in our model were more gradual than the empirical data gathered from Kenya antenatal clinics (as demonstrated in ).
Nonetheless, heterogeneity in susceptibility may have a significant impact on our ability to model future epidemic spread, as well as to interpret surveillance data. As an example, a high number of transmission events are attributed to individuals with very early HIV infection, so that this phase of infection may contribute disproportionately to HIV transmission[26
]. This phenomenon may relate to high HIV levels in genital secretions during this stage of infection[29
], but heterogeneity in the susceptibility of their uninfected partners may be another contributor, since many of these uninfected partners will be exposed to HIV for the first time by their acutely-infected partner. Available data cannot distinguish these two mechanisms. A study comparing the risk of seroconversion of steady partners of new seroconverters with that of new partners of people with established HIV infection should be able to clarify this.
Heterogeneity in host HIV susceptibility might also have more practical implications for prevention trials. HIV incidence within high-risk participants has been lower than expected in the context of trials testing STI prophylaxis/therapy[30
] and pre-exposure prophylaxis[32
], often despite prior studies to determine “predicted” incidence, and this has been a significant setback in some cases. While it has been assumed that the reduced HIV incidence was a direct result of behavior modification and trial-associated prevention activities[30
], it is also possible that early HIV acquisition by more susceptible hosts may have been followed by incidence declines within the remaining, less susceptible participants.
While there is good evidence that heterogeneity in susceptibility exists, we have little information on how it is distributed in the population. In our model we chose 4 discrete levels of susceptibility, although in reality a continuous distribution seems more realistic. In fact, 4 was the highest number of levels that we could fit in view of the dearth of data, although 3 levels yielded similar patterns (data not shown). This simple model demonstrates, at least qualitatively, that heterogeneity in HIV susceptibility may lead to epidemic overshoot. This overshoot is most pronounced in highly exposed populations, such as female sex workers.
In summary, we propose that the phenomenon of heterogeneity in HIV susceptibility may have contributed to the observed declines in HIV incidence and prevalence, both in highly-exposed “core transmitter” cohorts such as female sex workers, and in endemic countries. Heterogeneity in susceptibility is by no means the only contributor to these declines, and there is compelling evidence that at least part of the population HIV prevalence declines in many parts of Africa was caused by changes in risk behavior[2
]. However, our model demonstrates that some of this decline may have occurred without behavioral change, confounding our ability to attribute HIV epidemic shifts to specific interventions.