is defined as the fraction of the cumulative incident HIV infections since 1980 that are due to transmissions from index partners in their ν stage, relative to the total cumulative incident infections since 1980, at any given time in the epidemic.
In the early phase of the epidemic, the acute stage was responsible for almost half of HIV infections, but the contribution declined steadily as the epidemic evolved to a minimum of 8% earlier this decade. In contrast, the late-stage contribution was at 15% in 1980, but increased rapidly in the early 1990s as the high-risk population that acquired the infection in the 1980s progressed to late stage. The latent stage, however, maintained a contribution of about 50% most of the time after starting at 39%. Cumulatively from 1980 to 2007, 17, 51, and 32% of the infections were due to the acute, latent, and late stages, while by the endemic equilibrium around the year 2050, with 13, 52, and 35% were due to the three stages respectively. We found this pattern to hold within each risk group though the higher the risk the more pronounced is the impact of acute infection early in the epidemic.
Our predictions for Yaoundé, which indicate a similar pattern to that of Kisumu are shown in Fig. 2. The acute stage nevertheless played a substantially larger role consistent with the epidemic being more concentrated in the high-risk groups as opposed to Kisumu. Cumulatively from 1980 to 2007, 25, 44, and 31% of the infections were due to the acute, latent, and late stages, while by the endemic equilibrium around the year 2080, 18, 46, and 36% were due to the three stages respectively. It must be stressed here that the different roles of the stages in Kisumu as compared with Yaoundé are not behind the differences in HIV seroprevalence between the two cities. Other factors such as male circumcision and genital herpes may explain a large part of the gap in prevalence .
The large contribution of acute infection in both settings early in the epidemic is due to the relatively large fraction of the infected population that is in the acute stage; the higher infectivity of this population which is strongly amplified by the high risk of the index and receiving partners, and the large susceptible population where most potentially infectious contacts end up as susceptible people. The fractions of the HIV-infected population that are in each of the HIV stages in Kisumu and Yaoundé are displayed in Fig. 3. The time variation of the populations in the acute and advanced stages explains in part the large contribution of the acute stage early in the epidemic and the acceleration of the advanced stage contribution as the epidemic matured.
We performed two kinds of sensitivity and uncertainty analyses to assess the robustness of our predictions first to alternative assumptions in the model structure and second to the uncertainty in the behavioral and HIV progression parameters used to parameterize the model [Supporting information available from author on request.]. We found that our predictions are largely invariable both to the structural changes in the model and to the assumed variations in the behavioral and progression parameters.
The above results highlight how the roles of acute and late stages highly depend on the epidemic phase and level of sexual risk behavior in the groups where HIV is spreading, and that no HIV stage dominated the infectious spread in sub-Saharan Africa where the infection has been spreading generally in both the high-risk groups as well as the general population. Yet, the latent stage appears to be the largest driver of the epidemic in sub-Saharan Africa as a consequence of the prolonged duration of this stage that, despite the lower infectivity per act, will contribute to the majority of exposures, simply because of the longer duration. This result indicates the importance of assessing the determinants of transmission probability and levels of viral load in this stage, including the role of HIV coinfections [9,10] as well as the role of acute infection in dictating the virologic set point a few months following the seroconversion .
We found that the HIV stage dynamics is largely determined by the timing between HIV transmissions across sexual partnerships. When new partnerships are formed rapidly, that is, the higher is the sexual risk behavior, the role of the acute stage is more pronounced, as the index partner is more likely to transmit the infection to more partners and partners of partners, although still being in the short-acute stage. Accordingly, the acute stage contributed substantially more to the epidemic in Yaoundé compared with Kisumu, as the epidemic expansion was more concentrated in the high-risk groups [30,31].
Even though the contribution of acute infection is small in a mature epidemic, its contribution in stable partnerships formed before seroconversion of the index partner, and with the susceptible partner being monogamous, is still substantial at 40% . Nevertheless, the population characterized by such partnerships is only part of the population in which HIV is spreading. Acute infection transmissions in the low-risk population face ‘dead-ends’ as it is much less likely that index cases will form new partnerships during the short-acute stage.
Our results indicate that acute infection can still fuel a large fraction of HIV infections in epidemics concentrated in high-risk groups such as during the early phase of the epidemics in Kisumu and Yaoundé. This result corroborates the findings of the impact of acute infection in studies conducted in high-risk groups [33–35]. This also highlights how designing HIV interventions that aim to target the role of each of the stages strongly depends on the nature of the risk groups where the intervention is to be implemented. The dependence on the level of risk behavior may explain the varying clustering of acute infection individuals based on the mode of transmission, whether intravenous drug use (IDU) or homosexual or heterosexual contacts, that has been seen in HIV molecular epidemiology studies .
Our calculations assume a reduction in sexual activity in the late stage, in terms of reduction in coital frequency, by 30% based on the observed reduction in coital frequency in the Rakai study  (Table 1). It is possible that in addition to a reduction in coitus, late-stage infected people may also reduce their risk of exposure through changes in their sexual partnership formation structure in view of the increased presence of comorbidities in this stage. Such reduction would reduce the contribution of the late-stage infection and increase that of the acute and latent stages.
The predictions presented here assume a distribution from onset of infection to AIDS and death in sub-Saharan Africa according to the direct measurements of the Masaka cohort . Recent evidence suggests that the progression from infection to AIDS and death depends on the HIV-1 virus subtype where, for example, infection by subtype D leads to faster progression than infection with subtype A [36,37]. Such differences in progression rates can affect our predictions where a faster progression to AIDS may reduce the contribution of the latent stage as it is more likely to shorten the duration of this stage than those of the acute and advanced stages [Supporting information available from author on request.].
Our results suggests the importance of long-term follow-up for HIV CTL vaccine trials  as a beneficial impact of the vaccine only in the first 2 years post-infection may not be sufficient to capture the effectiveness of the vaccine as an intervention tool. This would also help clarify the role of acute infection in dictating the level of viral load in the latent stage. The large contribution of the latent stage alludes that interventions that target the determinants of viremia in this stage , such as HIV coinfections [7,8], may be beneficial in controlling HIV transmissions. The relatively large contribution of the late stage in mature epidemics, such as in sub-Saharan Africa, signifies that HAART may indeed be helpful in reducing HIV spread particularly if administered earlier than is the current practice. Detailed studies of the impact and effectiveness of these interventions might be of utility for prioritizing prevention strategies.
In conclusion, the lack of dominance of any stage in the epidemic hints that it is unlikely a single intervention measure targeting a specific HIV stage would be very effective against HIV. Only synergistic interventions, tailored to the nature and phase of the epidemic in a given community, can effectively curtail HIV spread. The sizable contribution of each of the stages suggests that intervention measures that reduce HIV acquisition and transmission irrespective of HIV stage, such as male circumcision  or possibly HSV-2 suppressive therapy , may provide effective tools in controlling HIV spread.
We thank Drs Steven M. Goodreau and Susan Cassels for valuable discussions. This publication resulted from the research supported by the University of Washington Center for AIDS Research (CFAR), an NIH-funded program (P30 AI 27757).
There are no conflicts of interest.
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