Syndromic management of sexually-transmitted infections and behaviour change interventions on transmission of HIV-1 in rural Uganda: A community randomised trial

A. Kamali*, M. Quigley, J. Nakiyingi, J. Kinsman, J. Kengeya-Kayondo, R. Gopal, A. Ojwiya, P. Hughes, L. M. Carpenter, J. Whitworth

*Corresponding author for this work

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Abstract

Background: Treatment of sexually-transmitted infections (STIs) and behavioural interventions are the main methods to prevent HIV in developing countries. We aimed to assess the effect of these interventions on incidence of HIV-1 and other sexually-transmitted infections. Methods: We randomly allocated all adults living in 18 communities in rural Uganda to receive behavioural interventions alone (group A), behavioural and STI interventions (group B), or routine government health services and community development activities (group C). The primary outcome was HIV-1 incidence. Secondary outcomes were incidence of herpes simplex virus type 2 (HSV2) and active syphilis and prevalence of gonorrhoea, chlamydia, reported genital ulcers, reported genital discharge, and markers of behavioural change. Analysis was per protocol. Findings: Compared with group C, the incidence rate ratio of HIV-1 was 0.94 (0.60-1.45, p=0.72) in group A and 1.00 (0.63-1.58, p=0.98) in group B, and the prevalence ratio of use of condoms with last casual partner was 1.12 (95% CI 0.99-1.25) in group A and 1.27 (1.02-1.56) in group B. Incidence of HSV2 was lower in group A than in group C (incidence rate ratio 0.65, 0.53-0.80) and incidence of active syphilis for high rapid plasma reagent test titre and prevalence of gonorrhoea were both lower in group B than in group C (active syphilis incidence rate ratio, 0.52, 0.27-0.98; gonorrhoea prevalence ratio, 0.25, 0.10-0.64). Interpretation: The interventions we used were insufficient to reduce HIV-1 incidence in rural Uganda, where secular changes are occurring. More effective STI and behavioural interventions need to be developed for HIV control in mature epidemics.

Original languageEnglish
Pages (from-to)645-652
Number of pages8
JournalThe Lancet
Volume361
Issue number9358
DOIs
Publication statusPublished - 22 Feb 2003

Bibliographical note

Funding Information:
In this community-randomised trial in rural south-western Uganda, behavioural and STI interventions were associated with an increase in condom use with the last casual partner—a proxy measure for consistent condom use in high-risk encounters, and substantial reductions in incidence of active syphilis and prevalence of gonorrhoea. There was also evidence in group A of reduced incidence of HSV2—a proxy measure of unprotected sexual contact, and increased recognition of symptoms of STIs in group B. These effects were not translated into any measurable reduction in HIV-1 incidence over a median follow-up of 3·6 years. Our findings could have several possible explanations. We have no reason to believe that the interventions were not adequately delivered: there were high levels of behavioural intervention activity producing credible coverage and the content of the intervention was of high quality, appropriate, and retained by the target population. 12,20,21 Activities in the control group could have masked any intervention effects, or intervention activities could have spilled over into the control group. However, we do not think that the activities in the control group would have been effective HIV-1 interventions. We kept contamination of interventions to a minimum by situating the study communities as far apart as possible geographically; scrutiny of the STI treatment registers in group B showed very few attenders from other study communities. More plausibly, the interventions could have been insufficiently applied for this setting, where a reduction in HIV-1 transmission is already occurring. 22 During the trial we noted substantial secular changes towards safer sexual behaviour in the whole study population, unrelated to our interventions, either in response to the HIV-1 epidemic itself or to HIV-specific health education from governmental and non-governmental sources and in the media (private local radio stations and newspapers). These secular changes could also have been associated with our own distribution of condoms and provision of voluntary counselling and testing for HIV-1, which could have had a diluting effect on the effectiveness of the interventions. The increase in reported safer sexual behaviour could also have been partly due to bias caused by people reporting what they think is the right answer. Our study might have been underpowered and therefore did not detect a smaller than expected effect. The observed HIV-1 incidence was lower than that expected, and was only half the rate in the Rakai 4 and Mwanza 3 studies. The observed coefficient of variation (0·32 based on HIV prevalence) was higher than expected. To achieve the same power to detect a 50% reduction in HIV-1 incidence with this coefficient of variation, about 11 communities would have been needed in each group instead of six. It is noteworthy that we included people aged 13 years and older, whereas Mwanza 3 and Rakai 4 included only those aged 15–54 years and 15–59 years, respectively. Individuals aged 13–14 years constituted 16% of our HIV-1 negative cohort and were less sexually active. However, the CIs around our adjusted results exclude a 42% reduction in HIV-1 incidence, as reported in Mwanza. 3 Also, the relative risks cluster close to 1, giving no hint of even a small effect. The unexpectedly wide variation in HIV-1 prevalence in communities at baseline was partly addressed by adjustment for baseline HIV-1 prevalence. We would advise stratifying or matching on initial HIV-1 prevalence rather than on other surrogate measures of incidence in future trials. Despite the poor matching, the study groups were comparable at baseline and we achieved good follow up of the study population. This trial used STI syndromic management as in the Mwanza trial in a population with a mature HIV-1 epidemic as in Rakai. Our results for HIV-1 were more consistent with those of the Rakai trial, suggesting that the type of intervention is not the key difference between the results of the various trials; the characteristics of the study population are probably more important. It could be that, as with the Rakai population, the population attributable fraction of new cases of HIV-1 due to STIs was lower than that in the Mwanza trial and such an association could have been compounded by the importance of HSV2 as a cause of genital ulcers. As in the Rakai study, HSV2 was a much more common infection than syphilis. Since no effective treatment for HSV2 was provided, the likely effect of the STI intervention is further reduced. The finding of a significant reduction in HSV2 incidence in group A (behavioural intervention alone) yet no effect in group B (the same behavioural intervention plus STI intervention) is difficult to explain. The behavioural intervention could have been applied differently in the two groups, although data monitoring of the activities suggests otherwise. Alternatively, the behavioural intervention could have been successful in both groups but the STI intervention increased incidence of HSV2, perhaps through an effect of ciprofloxacin or doxycycline on modulation of cytokines and innate immunity to viral infection. 23,24 Another explanation is that the findings were due to chance in view of the many significance tests done. The behavioural intervention was based on information, education, and communication, and was focused on the whole adult population. The methodological difficulties of measuring the effect of behavioural interventions on sexual behaviour should not be underestimated. 25 Although the absolute rates of reported behaviour should be treated with caution—for example 30% of respondents who reported having used a condom at baseline said they had never used a condom at round 2—the trends over time and the comparisons between groups are, we believe, reliable. Behavioural interventions are clearly important for controlling the spread of HIV-1 since the pandemic is determined by sexual behaviour. Interventions similar to those used in this trial could work in other regions with a rising incidence of HIV-1 and less health education available, such as Mbeya in Tanzania. 26 Additionally, behavioural interventions using other approaches, or focusing on specific subpopulations should be assessed. However, it is especially difficult to identify or access high-risk groups in rural African communities with mature epidemics. That STIs can facilitate transmission of HIV-1 is now well accepted. Promotion of interventions against STIs must continue to be accorded priority, both for their effect on STIs, and their potential effect on HIV-1. Ways to maximise the effect of syndromic treatment of STIs need exploration. Treatment algorithms should be appropriate for the local patterns of causes and antibiotic sensitivities. Adding specific treatment for HSV2 also needs to be assessed. In some circumstances, a combination of mass treatment and syndromic treatment for STIs might be more effective than either approach alone. 27 Contributors A Kamali was the project leader from December, 1997, to the end of the trial, contributed to analysis and interpretation of the data, and took the lead in drafting the report. M Quigley took the lead in analysis of data and contributed to its interpretation. J Nakiyingi contributed to data analysis and implementation of the study. J Kinsman was responsible for the behavioural intervention and contributed to data analysis and interpretation. J Kengeya-Kayondo was project leader from December, 1995, to December, 1997, and contributed to study design and implementation of the study. R Gopal did the HSV2 testing. A Ojwiya did the HIV-1 and syphilis testing. P Hughes did the chlamydia and gonorrhoea testing. L M Carpenter planned the statistical analysis and contributed to interpretation of data. J Whitworth contributed to design and implementation of study, analysis and interpretation of data, and drafting the report. All investigators contributed to writing of the report. Conflict of interest statement None declared. Acknowledgments This study was supported by the Medical Research Council and the UK Department for International Development with partial funding from initially the Global Programme on AIDS and later United Nations Programme on AIDS. We thank the entire survey, intervention, and analytical teams and in particular, Dominique Ricard, Sylvia Kiwuwa, Peter Kintu, Andrew Nunn, and the late Januario Nabaitu. We also thank the study populations for their commitment and cooperation with the study and Sylvester Sempala, director of the Uganda Virus Research Institute. We also thank David Brown for arranging HSV2 testing at Central Public Health Laboratories, Colindale. This report is dedicated to Daan Mulder and other MRC team members who have died before completion of this study.

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