Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials

Summary

Two randomised controlled trials of sexually transmitted disease (STD) treatment for the prevention of HIV-1 infection, in Mwanza, Tanzania, and Rakai, Uganda, unexpectedly produced contrasting results. A decrease in population HIV-1 incidence was associated with improved STD case management in Mwanza, but was not associated with STD mass treatment in Rakai. Some reductions in curable STDs were seen in both studies. These trials tested different interventions in different HIV-1 epidemic settings and used different evaluation methods; the divergent results may be complementary rather than contradictory. Possible explanations include: differences in stage of the HIV-1 epidemic, which can influence exposure to HIV-1 and the distribution of viral load in the infected population; potential differences in the prevalence of incurable STDs (such as genital herpes); perhaps greater importance of symptomatic than symptomless STDs for HIV-1 transmission; and possibly greater effectiveness of continuously available services than of intermittent mass treatment to control rapid STD reinfection. Implications of the trials for policy and future research agenda are discussed.

Introduction

The global burden of curable sexually transmitted diseases (STDs) is enormous, with an estimated total of more than 300 million new cases of syphilis, gonorrhoea, chlamydia, and trichomoniasis each year.¹ Because of their many serious complications and sequelae, particularly among women, STDs are one of the leading causes for the loss of healthy years of life. Even in the absence of HIV-1 infection, STDs account for a larger number of disability-adjusted life-years lost in women of childbearing age than any other group of diseases apart from maternity-related disorders.² Effective control of STDs was therefore a pressing global health priority even before their role as a cofactor in HIV-1 transmission was recognised.

During the past decade, overwhelming evidence has accumulated that some STDs enhance the transmission of HIV-1. Proving that STDs were indeed a cofactor was initially difficult, because HIV-1 and STDs share a mode of transmission, so associations seen in epidemiological studies may well have resulted from the confounding effect of risky sexual behaviour.³ Moreover, in cross-sectional studies, the time sequence of infections is difficult to establish. Longitudinal studies provided stronger evidence, and showed substantial relative risks for HIV-1 infection associated with various STDs.4, 5, 6, 7 Further evidence has come from studies showing that viral shedding in the genital tract of HIV-1-infected men and women is substantially increased if they have an STD, and that treatment of the STD decreases viral shedding.8, 9, 10

Towards the end of the 1980s, Pepin and colleagues¹¹ suggested that STD control could be used as an indirect strategy to reduce HIV-1 transmission. On the basis of this hypothesis, WHO promoted improved STD treatment services, together with behavioural risk reduction, as essential components of national AIDS control programmes,¹² and this strategy has since been adopted in many countries. However, the impact of this approach is difficult to predict because it depends on the size of the cofactor effect, the prevalence of STDs in HIV-1-discordant partners, the proportion of treatable compared with untreatable STDs, and the effectiveness of control measures in reducing STD prevalence, none of which are easy to estimate.

Two types of investigation have collected empirical evidence on the effectiveness of an STD control strategy for HIV-1 prevention: uncontrolled intervention studies among sex workers, and community-based randomised controlled trials in general populations. These studies were done in sub-Saharan Africa, the region most severely affected by the HIV-1 pandemic, and where high prevalences of treatable STDs have been recorded in many countries. In former Zaire and Côte d'Ivoire, the introduction of effective and accessible STD treatment services for sex workers, with condom promotion and provision, was followed by a substantial and significant reduction in STD and HIV-1 incidence.13, 14 The effects remained after adjusting for condom use in the analysis, but residual confounding cannot be excluded and it is therefore difficult to disaggregate the effects of STD treatment from those of condom use. A further study in a mining community in South Africa showed that monthly presumptive STD treatment of sex workers reduced the prevalence of STDs not only in this high risk group, but also in the surrounding population of miners.¹⁵ However, the effect on HIV-1 transmission was not measured directly in this study.