*Vaccine and Infectious Diseases Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington; and †Departments of Global Health and Medicine, University of Washington, Seattle, Washington.
Correspondence: Ruanne V. Barnabas, MBChB, DPhil, Vaccine and Infectious Diseases Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109. E-mail: email@example.com.
Received for publication January 20, 2009, and accepted February 16, 2009.
The legendary Sphinx is said to have asked all who sought to enter Thebes “Which creature in the morning goes on 4 legs, at midday on 2, and in the evening upon 3?,” devouring those who could not solve the riddle.1 The HIV pandemic poses the reverse riddle: How many “legs” propel spread of an HIV epidemic in each of its phases from early to late? In this issue of Sexually Transmitted Diseases, the findings of a multicenter, prospective observational cohort study exploring the effect of sexually transmitted diseases (STDs) and other reproductive tract infections (RTIs) on HIV acquisition in Africa are reported and they again confront us with this deadly HIV riddle.2
We have begun to appreciate that as HIV epidemics evolve from nascent, through concentrated, to mature or generalized phases, changes in key factors must guide the design and iterative refinement of HIV prevention strategy. For example, initially the risk of encountering an HIV-infected partner increases as HIV prevalence grows. Gradually the subpopulation distribution of infection shifts from being concentrated primarily among “core groups,” characterized by high risk behaviors, to include more stable partnerships involving people with lower risk behaviors.3 With growing HIV prevalence, the impact of factors affecting HIV viral load and infectiousness (e.g., coinfections such as herpes simplex virus type 2 [HSV-2]), and interventions such as antiretroviral therapy (ART) are likely to become increasingly important determinants of epidemic trajectory.4 Eventually, in late phase epidemics, the pool of susceptible individuals shrinks as those at biologic risk are exhausted and as lower risk behaviors are increasingly adopted with expanded access to HIV prevention information and services. Finally, as a reflection of these behavioral trends and the reciprocal effects of HIV infection on HSV-2 infection, in generalized epidemics, if STD services have been widely available, bacterial STD rates fall and HSV-2 prevalence rises, making this infection an increasingly important cause of genital ulcers and risk factor for HIV transmission.5
It is now clear that multicomponent, phase-specific packages of interventions, tailored to the population being served, are essential to control the HIV pandemic.6 But what is the role of STD or RTI treatment in the package for each phase and population? And how do we know which phase we are dealing with in the first place?
Unfortunately, evidence to answer the first question is, itself, limited in part by the riddle of epidemic phases. Observational data from numerous, well-designed studies conducted across 4 continents have consistently demonstrated at least a 2- to 5-fold increased risk of HIV acquisition associated with other STDs.7 Yet only 1 of 7 randomized controlled trials (RTCs) of STD treatment for HIV prevention has demonstrated efficacy. This RCT was conducted in Mwanza, Tanzania (1991-1995) in a concentrated epidemic. HIV incidence was reduced by 38% with improved syndromic management of curable STDs or RTIs.8 The other 6 trials9–14 that showed no reduction in HIV incidence were implemented in generalized epidemics, but 410–12,14 did not include HSV-2 therapy, a clear mismatch between epidemic phase and the intervention being tested. Indeed, stochastic modeling of the results of the first 3 RCTs indicates that earlier epidemic phase in Mwanza and phase-related reductions in behavioral risk in the Ugandan trial populations in Rakai and Masaka were the key factors in the divergent results.15 Furthermore, these models highlight the substantial fall in population attributable fraction (PAF) for curable STDs both over time within trial sites, and in comparing the earlier phase epidemic in Mwanza (PAF 65%) and the later phase epidemic in Rakai (PAF 20%), with a concomitant increase in the importance of HSV-2 infection.16 The 2 remaining RCTs evaluated a more phase-appropriate approach, HSV-2 suppressive therapy.9,13 Lack of efficacy in these HSV-2 trials raises the fundamental question of whether the underlying hypothesis or the specific intervention is flawed.17 Extensive epidemiologic data make the former unlikely.18–20 But critical questions have emerged about the mechanisms through which HSV-2 augments HIV risk. Frequent, asymptomatic HSV-2 recurrences21 and/or the recruitment and persistence of HIV receptor positive target cells may play central roles yet may not respond to standard acyclovir regimens.22–24 Ongoing studies are exploring acyclovir pharmacokinetics, dose and adherence requirements for HSV-2 suppressive therapy to achieve HIV prevention.
Accurately assessing epidemic phase is equally important. A prevalence-based framework has been used by WHO (WHO framework is defined as follows: Nascent/low: <5% in all defined subpopulations (e.g., SW, IDU, MSM); concentrated: >5% in at least 1 defined subpopulation and <1% in urban pregnant women; generalized: >1% in pregnant women) but this approach requires data on 1 or more subpopulations and provides little ability to compare phase across populations or over time. An alternative when population-specific incidence data are available, is the incidence-to-prevalence (I:P) ratio, which permits temporal and population comparisons. Higher I:P ratios are seen in earlier phase epidemics because a greater proportion of HIV infections are newly acquired in these settings. For example, the I:P ratio in the concentrated epidemic of the Mwanza trial was 4 to 6 times those in the generalized epidemics of the RCTs in Uganda and Zimbabwe, and the ratios from the Ugandan and Zimbabwean sites in the study published in this issue are similar to those from the RCTs in each of these countries (Table 1). It is noteworthy that the I:P ratios from the 2 Zimbabwe sites suggest a similar, generalized epidemic despite the marked difference in incidence and prevalence, which characterize the force and volume of infection, rather than the subpopulation distribution.
How does this new study help us solve the riddle? van de Wijgert et al enrolled 4439 HIV uninfected women attending family planning clinics in Zimbabwe and Uganda and followed them every 3 months for an average of 23 months, with good retention. Despite HIV risk reduction counseling, provision of male condoms and screening and treatment for curable STDs or RTIs, HIV incidence did not decline. During the 2 year follow-up, HSV-2 incidence doubled in Uganda; gonorrhea, chlamydia, and syphilis incidence remained stable; and the incidence of RTIs treated at diagnosis (trichomoniasis, and yeasts in both sites; bacterial vaginosis (BV) in Zimbabwe) decreased significantly. HSV-2 seropositivity at baseline (Hazard ratio [HR] = 3.69; 95% CI: 2.45-5.55), incident HSV-2 (HR = 5.35; 3.06-9.36), incident gonorrhea (HR = 5.46; 3.41-8.75), and altered vaginal flora (BV HR = 2.12; 1.50-3.01 and intermediate flora HR = 2.02; 1.39-2.95) were all independently associated with HIV acquisition after controlling for demographic and behavioral cofactors and other STDs or RTIs. Consistent with the phase of these epidemics, of the RTIs evaluated, almost 60% of incident HIV infections were attributable to HSV-2 infection, followed by BV or intermediate flora (population attributable risk percent [PAR%] 29%). Less than 10% of new HIV infections were attributable to curable STDs.
This study suggests that, as an HIV prevention intervention, STD treatment must be phase specific. In mature epidemics such as in Uganda and Zimbabwe, common, persistent, or recurrent infections such as HSV-2 and BV, may be more important than bacterial STDs in the synergistic spread of HIV. HSV-2 serologic testing was done after study completion, precluding the provision of suppressive therapy for seropositive individuals. In this study, only 23 Ugandan participants presented with herpetic lesions on examination and received treatment and no participants were treated in Zimbabwe (van de Wijgert, personal communication). Hence, HSV-2 infections were essentially untreated, despite having the largest PAR. Even if the majority of HSV-2 seropositive study subjects had received suppressive therapy, recent RCT data suggest that the investigators would have observed little change in HIV incidence with standard regimens.9,13 It is also noteworthy that HSV-2 seroincidence more than doubled in the Uganda cohort (from 6.5/100 woman-years during the first year of follow-up to 14.4/100 woman-years in the second year) in the absence of changes in laboratory assay or methods, perhaps reflecting changes in HSV-2 incidence in the community. Such changes would be consistent with the reciprocal increases in HSV-2 and HIV infections seen in late phase HIV epidemics.
BV has also been associated with increased risk of HIV infection.25 In this study, BV treatment was routinely provided upon diagnosis, and BV incidence declined significantly in the Zimbabwe cohort, but did not impact HIV incidence. BV is an important synergist RTI to explore further, but the high frequency of recurrence or persistence months after therapy26–29 and our limited understanding of the mechanisms underlying HIV risk may present challenges analogous to those for HSV-2 suppression.
The study also highlights the challenges of STD control. The incidence of infections diagnosed and treated immediately (trichomoniasis, BV, and yeasts) decreased between the first and second year of follow-up at both country sites and these decreases were statistically significant for all 3 infections, except for BV in Uganda. Notably, no change in incidence was seen for those infections that required a follow-up visit for treatment, i.e., gonorrhea, chlamydia, and syphilis. As the authors discuss, another challenging aspect was that few partners came to the clinic for treatment.
Finally, in late phase epidemics such as those in this study, treating STDs/RTIs in HIV-infected individuals may be especially important. This study looked only at susceptible women, leaving many questions about STD/RTI epidemiology among this critical population. High prevalence of STDs and other RTIs can also be expected among HIV-infected individuals, which may increase HIV infectiousness, and, consequently transmission probability. Preventing and treating infections among this group may have benefits for HIV prevention at the population level.
HIV epidemics, like human beings, move differently in different phases of their lives. Solving the riddle of phase-specific HIV prevention strategies is essential to effective control of the HIV pandemic.
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