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Population-based interventions for reducing sexually transmitted infections, including HIV infection

RHL Commentary by Schulz KF

1. EVIDENCE SUMMARY

The Cochrane Reviewers conclude that limited evidence from randomized controlled trials indicates that Sexually transmitted infection (STI) control serves as an effective HIV prevention strategy. Evidence from a cluster randomized controlled trial in Mwanza, United Republic of Tanzania, suggests that control of sexually transmitted infections (STIs) is an effective strategy for the prevention of HIV under certain conditions (1). In particular, in an environment characterized by an emerging HIV epidemic, where STI treatment services were poor and where STIs were highly prevalent, improved STI treatment services were shown to reduce HIV transmission by about 40%. In other words, treatment of STIs can prevent HIV transmission, but these results may be specific to the types of conditions surrounding this trial in Mwanza.

Two other trials indicate no evidence for substantial benefit from STI treatment of all community members. In the cluster randomized trial in Rakai, Uganda, the reviewers found no evidence of substantial reductions in HIV transmission following mass treatment of all community members for STIs (2). The addition of a new trial in Masaka, Uganda (3) to the existing evidence supports the data from Rakai.

Evidence from all three trials suggests that STI control interventions reduce the prevalence and incidence of STIs and reproductive tract infections such as bacterial vaginosis. Indeed, all three trials displayed reduced levels of syphilis in the intervention communities.

The Cochrane reviewers used a comprehensive search strategy. They searched the trial registers of the Cochrane Infectious Diseases Group and Cochrane Collaborative Review Group on HIV Infections and AIDS. Furthermore, they searched the Cochrane Controlled Trials Register, MEDLINE and EMBASE. Two reviewers independently applied the inclusion criteria to potential studies, with any disagreements resolved by discussion.

I believe that they found all the trials pertaining to their search criteria. They seem to have used, however, a rather simplified analysis of the methodological quality of the trials.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

STIs, including HIV, are extremely common in many developing countries, particularly in sub-Saharan Africa. As the Cochrane reviewers note, WHO estimates that in 1999, 340 million new cases of syphilis, gonorrhoea, chlamydial infection, and trichomoniasis occurred; according to the latest WHO report (4) these numbers have continued to increase. Moreover, the reviewers note that UNAIDS estimates that by 2003 over 95% of the 40 million people infected with HIV lived in developing countries(5). In some areas of Africa (e.g. Botswana), between 40% and 50% of women attending antenatal care clinics are HIV-positive (6). Surveys in more general populations in Kisumu, Kenya, and Ndola, Zambia, (which do not represent the high extremes of those areas) also report relatively high HIV prevalence rates of 30% and 32%, respectively, in women of reproductive age (7). In other areas of Africa, however, the HIV prevalence rates are lower in women of reproductive age, but are still quite high. For example, in Yaoundé, Cameroon, the HIV prevalence rate in women of reproductive age is 8% (7).

Clearly, HIV in particular and STIs in general represent a mammoth public health problem in the developing world, especially in sub-Saharan Africa. Moreover, all indications suggest that STI, including HIV, are both an urban and rural problem that affect poor and affluent sections of Africa (6).

2.2. Applicability of the results

The results of this Cochrane Review are directly relevant to under-resourced settings because the pertinent randomized trials were actually conducted in resource-poor settings of Africa. Thus, these results can be easily extrapolated to other under-resourced settings, particularly in Africa. The Mwanza intervention would most likely succeed in areas in which especially treatable genital ulcer diseases (such as chancroid and syphilis) are relatively highly prevalent and HIV levels are relatively low. However, if the prevalence of treatable STIs is extremely low, an intervention addressing STIs would likely have limited benefit.

Some conclude that the results from the Mwanza randomized trial and the Rakai randomized trial contradict each other. It is argued that the data are inconclusive and that STI control interventions may not prevent HIV transmission. On the contrary, the results of the two trials are complementary. As discussed by the key investigators in the two trials, (8), their results were consistent and complementary because, first, the stages of the HIV-1 epidemics were quite different - Rakai being a mature epidemic and Mwanza being in the early, formative stage. Second, 45% of the genital ulcers in Rakai were related to HSV-2 whereas less than 10% of the ulcers in Mwanza could be attributable to HSV-2. Third, despite mass treatment in Rakai, substantial STI prevalence occurred throughout each 10-month follow-up period until the next mass treatment. In Mwanza, the improved case-management services were continuously available. Finally, in Rakai only 10% of new HIV-1 infections were attributable to STI symptoms or treatable STIs whereas in Mwanza, 43% of new HIV-1 infections among men in the comparison group could be attributed to symptomatic STIs or new episodes of syphilis. In the intervention group in Mwanza, the population attributable fraction dropped to 11%.

Thus, the different trial results between Mwanza and Rakai may reflect important differences in the two settings, as well as differences in the interventions. While all the four factors discussed above probably play a role, the differences in the prevalence rates of treatable and untreatable genital ulcer diseases are particularly notable. In the heterosexual HIV epidemics in Africa, treatable genital ulcer diseases in men, notably chancroid and syphilis, probably play a major facilitating role. That those treatable genital ulcer diseases were more prevalent in Mwanza meant that Mwanza was more susceptible to meaningful impacts from an STI intervention. I do not find the Mwanza and Rakai trials results to be contradictory. Indeed, the improved STI treatment in the Mwanza trial remains the only intervention that has been proven through a randomized trial to be effective in reducing HIV-1 incidence among adults in the general population in Africa (8).

2.3. Implementation of the intervention

The randomized trial in Mwanza, United Republic of Tanzania, found the intervention to be beneficial in reducing HIV incidence. That intervention comprised a set of four activities: training health workers in syndromic STI case management as recommended by WHO; providing inexpensive but effective drugs; making regular supervisory visits to health facilities; and conducting village campaigns to improve treatment-seeking behaviour. The Mwanza intervention was designed to be sustainable and affordable. Indeed, the investigators implemented an intervention that was pragmatic and adapted to circumstances in sub-Saharan Africa. The costs were not exorbitant and the provision of syndromic case management fitted into the cultural and educational milieu. That the investigators were able successfully to implement this intervention in Tanzania validates its feasibility for other parts of sub-Saharan Africa.

Conversely, the intervention used in Rakai, Uganda, involving repeated rounds of mass treatment for STIs, would not be as feasible. Operational implementation difficulties, excessive costs of the drugs, and the potential for development of resistant organisms all limit the feasibility of this mass treatment option. Had this project been effective, those concerns may have been surmountable. However, the mass treatment arm was found to be ineffective, at least in the rather high HIV prevalence environment that characterizes Rakai. Hence, the question of feasibility of that intervention is rendered irrelevant. Similarly, the question of feasibility for the intervention tested in Masaka is rendered irrelevant due to its null findings.

Success with the Mwanza intervention will depend on training health workers in the syndromic case management of STIs, having sufficient health facilities to provide treatment and maintaining adequate supplies of effective STI therapy. The training of health workers in syndromic case management is critical, but syndromic treatment should not be introduced without determining the key STIs in the population to be covered by the services. Thus, syndromic case management depends upon determining the prevalence of STIs and then training health workers in the implementation of the syndromic approach. Presumably, additional STI control will improve case-management services, screening, or periodic presumptive treatment of STIs, but those approaches, particularly case management based on laboratory results, may not be feasible in many under-resourced settings. The caveat again, however, is that the reduction in HIV transmission from STI control may be limited to settings characterized by an emerging HIV epidemic, where STI treatment services are inadequate, and where STIs are highly prevalent.

3. RESEARCH

Other authors have thoroughly dealt with potential additional research topics (8). I believe the potentially most fertile research topics are the following:

• Determination of how the treatment-seeking behaviour of STI patients can be improved.
• Development of better treatment approaches for the management of herpetic lesions.
• Conduct of a randomized trial in sex workers to study the effectiveness of an intervention that includes provision of presumptive STI treatment in the prevention of HIV (9).

The above studies should be conducted in under-resourced settings.

References

• Grosskurth H, Mosha F, Todd J, Mwijarbui E, Klokke A, Senkoro K, Mayaud P, Changalucha J, Nicoll A, ka-Gina G, Newell J, Mugeye K, Mabey D, Hayes R. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomized controlled trial. The Lancet 1995;346:530-536.
• Wawer MJ, Sewankambo NK, Serwadda D, Quinn TC, Paxton LA, Kiwanuka N, Wabwire-Mangen F, Li C, Lutalo T, Nalugoda F, Gaydos CA, Moulton LH, Meehan MO, Ahmed S. The Rakai Project Study Group and Gray RH. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. The Lancet 1999;353(9152):525-535.
• Kamali A, Quigley M, et al. Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: a community randomised trial. The Lancet 2003;361:645-652.
• Global prevalence and incidence of selected curable sexually transmitted infections. Overview and estimates. World Health Organization;Geneva, Switzerland, WHO 2001.
• UNAIDS. AIDS in Africa: AIDS epidemic update. Geneva, Switzerland. UNAIDS;2003.
• UNAIDS. AIDS in Africa: Country by country. Geneva, Switzerland. UNAIDS;2000.
• Glynn JR, Buve A, Carael M, Musonda RM, Kahindo M, Macauley I, et al. Factors influencing the difference in HIV prevalence between antenatal clinic and general population in sub-Saharan Africa. AIDS 2001;15:1717-1725.
• Grosskurth H, Gray R, Hayes R, Mabey D, Wawer M. Control of sexually transmitted diseases for HIV-1 prevention: understanding the implications of the Mwanza and Rakai trials. The Lancet 2000;355:1981-1987.
• Kaul R, Kimani J, Nagelkerke NJ, Fonck K, Ngugi EN, Keli F, MacDonald KS, Maclean IW, Bwayo JJ, Temmerman M, Ronald AR, Moses S. Kibera HIV Study Group. JAMA 2004;291(21):2555-2562.

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This document should be cited as: Schulz KF. Population-based interventions for reducing sexually transmitted infections, including HIV infection: RHL commentary (last revised: 24 June 2004). The WHO Reproductive Health Library; Geneva: World Health Organization.

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