We found substantial regional differences in VL with SSA having about four times the VL levels found elsewhere. The highest VLs were seen in Southern and East Africa. Modeling the impact of the elevated VL in a representative population, Kisumu, Kenya, we demonstrated that the elevated VL in SSA could be a central driver of the massive HIV epidemics that erupted in this part of the world. The VL effect is particularly important driver of HIV transmission among the general population and may explain, in part, the general population HIV epidemics that uniquely characterize this region. The robustness of our results to multiple sensitivity and uncertainty analyses points to a potentially substantial role for this biological cofactor in shaping HIV epidemic trajectories in SSA and warrants further investigation.
The higher regional VL in SSA poses a question about the causes of such elevated VL levels. We suspect that the high burden of infectious diseases beyond HIV in SSA, particularly malaria, tuberculosis, HSV-2, helminthes and other tropical diseases [14
], may have caused to a large extent the higher VL in SSA. Mounting epidemiological and laboratory evidence suggests that these co-infections induce transient, but substantial increases in HIV-1 VL, due to enhanced HIV replication associated with the immune response (see SuppDC Section 2
for description of evidence). A recent systematic review and meta-analysis found that acute malaria increases HIV-1 VL by 0·67 log10
(95% CI: 0.15, 1.19), active tuberculosis by 0.40 log10
(95% CI: 0.13–0.67), and HSV-2 infection by 0·18 log10
(95% CI: 0.01, 0.34 ) [15
]. Furthermore, high levels of serum immune activation markers have been found in African populations compared to those in industrialized countries [16
], possibly reflecting extended exposure to a range of pathogens. Together, the comparatively high burden of infectious diseases in SSA, and the links among co-infections, immune activation and increased HIV replication, suggest that VL may be higher in this region than elsewhere, and that immune activation due to co-infections may be an important causal mechanism.
The first work to explore the impact on HIV epidemic trajectory of a co-infection that increases HIV-1 VL, for the case of malaria, suggested a small, but tangible effect in fuelling HIV spread [4
]. But the impact of a single co-infection on HIV transmission may be relatively limited, while the combined effects of multiple recurrent or persistent co-infections could potentially result in considerable population-level impact. The transient effect of one co-infection increasing VL may not be discernible at the population level, but the cumulative effect of multiple potentially overlapping co-infections on raising the VL, throughout the course of HIV infection, may be substantial as schematized in . Such effect would alter the natural history of HIV infection for the individual and consequently the epidemic trajectory for the community.
Figure 3 Potential role of co-infections in causing higher community HIV-1 plasma RNA viral load (VL). Schematic diagram of the potential role of the high co-infection disease burden in sub-Saharan Africa (SSA) in increasing mean HIV-1 VL (diagram not to scale). (more ...)
Another reason, in addition to co-infections, that may contribute to explaining the elevated mean VLs in SSA is virus subtype. Emerging data suggest that persons infected with HIV-1 subtype C infection, the dominant type in SSA particularly in Southern Africa, may maintain high VLs even after acute infection [19
Our approach assumes a log-linear relationship between HIV-1 VL and HIV per coital-act transmission probability, based primarily on empirical evidence from cohort studies of sero-discordant couples [10
]. These studies may under- or over-estimate the relationship between VL and risk of transmission due to selection bias such as the selection of more “resistant” couples in the recruitment of discordant partnerships with high-VL infected individuals. A linear relationship between VL and risk of transmission, assuming implicitly, for example, an intuitive concept for the establishment of the infection in terms of clonal expansion of a single infecting virion, would imply a stronger effect for the higher VL on transmission, and more differential epidemiologic impact as a consequence of the differences in community VL.
To our knowledge, the database we assembled in this study of summary measures of more than 70,000 VL measurements from cohorts representing every major region of the globe, is the most extensive ever analyzed to assess the regional VL differences and their impact on HIV transmission. However, there are limitations to these exploratory analyses. We used heterogeneous datasets from studies not designed to investigate this effect. Our hypothesis of higher community VL in SSA was examined using regional VL data measured on subjects recruited for different reasons (Table S3.1
). The recruitment strategies could, in principle, be a source of selection bias where the VL data were measured on subjects who may not necessarily represent the community of HIV-infected persons, and this may confound the assessment of the regional VL differences. Of note, however, this vast amount of VL data was collected from subjects who were recruited using diverse recruitment strategies. The diversity of the modes of recruitment suggests a minimal bias in recruitment of persons who are more likely to have higher (or lower) VL in one region as opposed to another.
The widest difference in VL between SSA and developed settings was observed in the CD4 ≥ 500 category (), a category that potentially could encompass samples including persons within acute infection. The observed differences in VL could accordingly reflect differences in the distribution of persons across HIV natural history stages. However, all except one of the VL studies in this analysis have targeted recruitment of HIV sero-prevalent subjects, suggesting minimal contribution of acute infection. Beyond acute infection, we stratified our analysis in four CD4 categories and this should implicitly, at least in part, correct for potential differences between the regions in the distribution of persons across HIV natural history stages.
Our ecological analysis did not control for VL assay type which could potentially affect the observed regional VL differences. While we were not able to control for VL assay, PCR-based assays were used in both North America and SSA. VL assays would have to provide consistently lower absolute VL readings in North America and Europe, and higher readings in SSA, for this difference in VL to be seen. Historically, the opposite trend has been observed; commercially available RNA tests are generally optimized to detect subtype B, which predominates in North America and Europe, and are frequently suboptimal in detecting HIV-1 subtypes found in other parts of the world [20
]. Furthermore, despite the heterogeneity of assays used within North America and Europe, mean VLs were similar. Another limitation of our database is the small number of VL cohorts from Asia and South America, where only a single country is represented from each region. Finally, pregnancy data were incomplete in five cohorts.
Nevertheless, our study provides a tantalizing “smoking gun”, suggesting both substantially higher VLs in SSA compared to other regions, and a potentially profound VL effect on HIV infectiousness and epidemic trajectory. This is despite conservative assumptions in the mathematical model for the magnitude of the heightened VL and the potential impact of co-infection-associated morbidities on sexual activity.
Several lines of evidence support our findings. The VL differences we found (~ 0.3 to 0.7 log10
) are similar to those observed earlier (0.7 log10
) in comparing a cohort of 49 Malawians to a cohort of 61 US and Swiss HIV-positive patients matched by CD4 count [21
]. Yet, existing evidence suggests that African descent among those residing in North America and Europe is associated with lower, not higher, VL [22
]. Therefore, it is likely that ecological factors, such as frequently recurrent or persistent co-infections and HIV-1 sub-type, rather than host biology factors, explain these regional VL differences. Recent data further indicate that individuals living in areas of high malaria prevalence have more than twice the odds of being HIV-positive than individuals living in areas with low malaria prevalence (odds ratio of 2.24, 95% CI 1.62–3.12 for men and 2.44, 95% CI 1.85–3.21 for women) [24
Additional lines of evidence support our thesis of higher HIV infectiousness per coital act in SSA compared to other regions. A recent systematic review and meta-analysis found HIV transmission probability per coital act in low-income countries (predominantly SSA countries) to be six times that in high-income settings [25
]. The VL regional differences identified here of 0.58 log10
implies that the per-coital transmission probability in SSA is only 1.68 times that in North America and Europe (SuppDC Table S4.2
); smaller than that observed in this meta-analysis [25
]. This suggests that other factors may also contribute to the higher HIV infectiousness in SSA. The recent landmark HPTN 52 clinical trial found four-fold higher HIV sero-conversion rate among the sero-discordant partnerships in the African sites compared to the non-African sites [8
], further supporting higher HIV infectiousness in SSA.
One of the truly remarkable research advances of the past two years was the demonstration of the very high efficacy of ART in reducing HIV transmission [8
]. This outcome attests to the critical role of VL in driving HIV epidemics. Observational studies and intervention trials designed specifically to elucidate the role of co-infections in HIV infectiousness and epidemic trajectory – such as the on-going trial evaluating the impact of helminthes treatment on HIV-1 VL in Kenya [27
] – are essential. They will determine whether aggressive prevention and treatment of selected, persistent or frequently recurrent, co-infections should be included in randomized controlled trials of combination HIV prevention packages, and in HIV prevention programs and policy recommendations. As we are learning from trials evaluating HSV-2 treatment for HIV prevention [28
], this may require development of new regimens that target the biological mechanisms underpinning these interactions.
A potential role for co-infections in the exceptionally fulminant spread of HIV in Africa is of great interest because these infections offer feasible intervention points with co-benefits that lie at the intersection of HIV prevention and other major health programs. Until we can assure immediate and sustained access to ART for all people diagnosed with HIV infection, complementary strategies will be essential. Addressing co-infections potentially may offer such a complementary strategy for the control of HIV in SSA.