Genital herpes has played a more important role than any other sexually transmitted infection in driving HIV prevalence in Africa

Abstract

Background: Extensive evidence from observational studies suggests a role for genital herpes in the HIV epidemic. A number of herpes vaccines are under development and several trials of the efficacy of HSV-2 treatment with acyclovir in reducing HIV acquisition, transmission, and disease progression have just reported their results or will report their results in the next year. The potential impact of these interventions requires a quantitative assessment of the magnitude of the synergy between HIV and HSV-2 at the population level.

Methods and findings: A deterministic compartmental model of HIV and HSV-2 dynamics and interactions was constructed. The nature of the epidemiologic synergy was explored qualitatively and quantitatively and compared to other sexually transmitted infections (STIs). The results suggest a more substantial role for HSV-2 in fueling HIV spread in sub-Saharan Africa than other STIs. We estimate that in settings of high HSV-2 prevalence, such as Kisumu, Kenya, more than a quarter of incident HIV infections may have been attributed directly to HSV-2. HSV-2 has also contributed considerably to the onward transmission of HIV by increasing the pool of HIV positive persons in the population and may explain one-third of the differential HIV prevalence among the cities of the Four City study. Conversely, we estimate that HIV had only a small net impact on HSV-2 prevalence.

Conclusions: HSV-2 role as a biological cofactor in HIV acquisition and transmission may have contributed substantially to HIV particularly by facilitating HIV spread among the low-risk population with stable long-term sexual partnerships. This finding suggests that prevention of HSV-2 infection through a prophylactic vaccine may be an effective intervention both in nascent epidemics with high HIV incidence in the high risk groups, and in established epidemics where a large portion of HIV transmission occurs in stable partnerships.

Figure 1. Time course of the HIV epidemic in Kisumu, Kenya.

Here assuming a susceptibility enhancement per-exposure cofactor of PEC_Acq = 4 (implying a RR = 2.1 [24]). The upper panel (A) shows HIV and HSV-2 prevalences in the presence of the two disease interaction compared to the prediction in the absence of interaction. The references for the data are discussed in Protocol S2. The middle and lower panels show the epidemiologic synergy measures of HIV and HSV-2 interaction. The middle panel (B) displays the fraction of all incident HIV infections that are directly caused by the enhanced susceptibility of HSV-2 seropositive persons to HIV acquisition (PAF_Sus), the fraction of all incident HIV infections that are directly caused by the enhanced HIV infectivity in dually infected persons (PAF_Inf), and the fraction of all incident HIV infections that are directly caused by HSV-2 biology whether due to enhanced susceptibility or enhanced infectivity (PAF_{Sus +Inf}). The lower panel (C) shows HIV and HSV-2 excess prevalences.

Figure 2. Time course of the HIV epidemic in Kisumu, Kenya.

As in Figure 1, but now assuming PEC_Acq = 9 (implying RR = 2.9 [23]).

Figure 3. HSV-2 and the findings of the Four City study .

HIV prevalence in 1997 in the four cities as predicted by the model for the scenarios of PEC_Acq = 4 and PEC_Acq = 9 compared to HIV prevalence as measured in the survey , versus HSV-2 prevalence in the four cities . The calculations were done using the same sexual behavior parameters as those in Kisumu. The figure estimates the magnitude of HSV-2 contribution to the differential HIV prevalence across the four cities.

Figure 4. HSV-2 role in different risk groups. Role of HSV-2 in fueling HIV spread per sexual activity group in the calculations of Figure 1 (A and C) and Figure 2 (B and D).

The upper panels A and B show the time course of HIV incidence per year attributed directly to HSV-2 in the low-risk population and in the high risk group. The lower panels C and D display the cumulative incidence of HIV infections since 1980 (actual number of infections) attributed directly to HSV-2 in the low-risk population and in the high risk group.

Figure 5. Epidemiologic synergy between HIV and HSV-2.

Measures of the impact on HIV of the epidemiologic synergy between the two infections in diverse HSV-2 settings. The PAF_Sus, PAF_Inf, PAF_{Sus +Inf}, and HIV excess prevalence as a function of HSV-2 prevalence. The HIV prevalence in absence of interaction is at 20%.

Figure 6. Schematic diagram of the role of HSV-2 in HIV epidemiology.

The upper panel (A) shows the HIV and HSV-2 groups of sustainable transmission (GST) in absence of interaction between the two diseases while the lower panel (B) shows the groups of sustainable transmission in presence of the epidemiological synergy. The high HSV-2 prevalence in sub-Saharan Africa has facilitated a substantial increase in the size of the HIV group of sustainable transmission to encompass a large fraction of the low-risk population.