Many of the most important research findings on STIs in the past 30 years have come from sub-Saharan Africa. African researchers and their international collaborators have led the way in the development and validation of syndromic STI management, in furthering our understanding of the interactions between HIV and other STIs, in the development of evidence-based strategies for the control of HIV and other STIs in high risk groups and in the general population, and in clinical, microbiological and epidemiological studies on syphilis, chancroid and ophthalmia neonatorum. This review summarises the major achievements of STI researchers in Africa in the past 30 years, and discusses the reasons underlying the success of STI research in Africa.
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During the past 30 years there has been a dramatic increase in the quality and quantity of research on sexually transmitted infections (STI), generating a substantial body of new knowledge. Much of this research has been performed in sub-Saharan Africa. This review aims to summarise what has been learned about STI from research conducted in Africa in the past 30 years.
Symptomatic STI are usually managed syndromically in both developed and developing countries, either because laboratory tests are not available, or because it is considered important to treat patients presumptively at their first visit while awaiting results from the laboratory. Between 1976 and 1978 the WHO designed, implemented and evaluated the initial flowcharts for the syndromic management of STI in Swaziland in an urban hospital outpatient department and a rural health centre. In 1978 WHO convened a meeting in Nairobi to draw up guidelines for the syndromic management of STI. From 1979 to 1984 WHO training courses on ‘simplified approach to STI patient management based on STI syndromes’ were conducted, mostly in sub-Saharan Africa. From 1984 to 1991 The WHO ‘green books’, including ‘Simplified (syndromic) approach WHO/VDT/85.437’ were published based on field experience from countries such as Kenya, Swaziland and Zimbabwe.1
In 1981 Zimbabwe introduced the concept of comprehensive primary health care in its healthcare policy, which meant that STI care had to be provided at primary healthcare clinics instead of specialised STI clinics.2 3 To ensure standardised treatment of STI and to respond to the workload of STI, Zimbabwe was one of the first countries to introduce standard guidelines and flowcharts for the syndromic management of STI at the primary healthcare level, thereby effectively decentralising the management of STI to all clinics without laboratory facilities by 1989. This programme was extremely successful, with the vast majority of cases being successfully managed at the primary care level.4
A series of evaluations of the syndromic management flowcharts was commissioned by WHO and UNAIDS in the 1990s, and the results were published as a supplement in Sexually Transmitted Infections in 1998. Of the 16 study sites, 10 were in Africa. The main conclusions from these studies were that the flowcharts for urethral discharge and genital ulcer are reasonably sensitive and specific, whereas the flowchart for vaginal discharge is neither sensitive nor specific.5
Studies on chancroid
In the early 1980s, following an outbreak of chancroid in Manitoba, Allan Ronald set up a new collaboration between the University of Manitoba, the Institute of Tropical Medicine (ITM), Antwerp and the Department of Microbiology at the University of Nairobi, with the aim of studying the diagnosis, clinical features, epidemiology and management of chancroid. This fruitful collaboration, later expanded to include the University of Washington in Seattle, continues to this day. The initial studies led to a number of seminal publications on chancroid. The optimal culture media for the isolation of Haemophilus ducreyi from clinical specimens were defined; the most effective treatment regimens were established through clinical trials; and the epidemiology was studied in high-risk groups, confirming that asymptomatic carriage of H ducreyi was rare.6–9
The group based at the University of Nairobi, and their international collaborators, were well placed to study the HIV epidemic when it started to affect the patients they were studying at the STI clinic in the early 1980s. They set up the Pumwani sex worker cohort and, in collaboration with immunologists from Oxford University, were able to identify genetic and immunological correlates of resistance to HIV infection among those with multiple exposures, and of long-term non-progression among those who acquired HIV. The Oxford group extended these studies to West Africa, identifying immunological correlates of protection in high-risk groups in The Gambia and Guinea Bissau.10
STI control in populations at high risk of STI
Effective services were provided for the treatment and prevention of STI among sex workers and their clients in Nairobi, which served as a model for other pioneering studies of STI control in populations at high risk of STI in Kinshasa in the Democratic Republic of the Congo (formerly Zaire) and Abidjan (Cote d'Ivoire), led by the group from ITM, Antwerp. These demonstration projects showed that it was possible to reduce the incidence of HIV and other STI, even among sex workers with large numbers of partners, through programmes of health education, condom promotion and prompt syndromic management of curable STI.11–14 A similar programme set up in Benin by collaborators from Laval University in Quebec, targeting clients as well as sex workers, also showed an impressive reduction in the incidence and prevalence of HIV and other STI.15 When the Kenyan government introduced user fees for STI patients, the Nairobi group were able to show that this greatly reduced the number of patients attending government STI clinics, with a serious adverse impact on STI control; an important lesson for health policy makers worldwide.16
The role of penicillinase-producing Neisseria gonorrhoeae as a cause of ophthalmia neonatorum became evident in the 1970s, and this required non-penicillin regimens for treatment. Clinical trials showed the efficacy of single-dose regimens of intramuscular ceftriaxone in Kenya17 and intramuscular kanamycin in Zimbabwe.18 Researchers in Kenya demonstrated the efficacy of 1% tetracycline eye ointment and 2.5% povidone–iodine solution in ophthalmia prophylaxis.19 20
Syphilis in pregnancy
The low coverage of syphilis screening and treatment in antenatal clinics, and the importance of on-site screening and treatment, were well documented by the research group in Nairobi. In Kenya a centralised system was operative in which women were bled at the first antenatal visit and the blood transported to a central laboratory for testing with the rapid plasma reagin test. When a pilot project was implemented in Nairobi in 1992 to decentralise the testing of blood to local clinics, the percentage of pregnant women screened increased from 60% to 100% and the percentage of seroreactive women adequately treated rose from 9% to 87%. In addition, during the pilot project almost 50% of the women's sexual partners were also treated for syphilis.21 A comprehensive study conducted in Mwanza, Tanzania, documented the impact of syphilis on pregnancy outcome. The study showed that syphilis was responsible for 50% of stillbirths in Mwanza, and that a pregnant woman with high titre active syphilis (rapid plasma reagin titre ≥1:8) had a 49% chance of an adverse pregnancy outcome (25% stillbirth; 20% premature; 33% low birth weight). This group showed, for the first time, that a single intramuscular dose of benzathine penicillin 2.4 million units, given before 28 weeks' gestation, prevented adverse pregnancy outcomes due to syphilis. This was shown to be a highly cost-effective intervention, at US$10.6 per disability-adjusted life-year saved, if the impact on stillbirth was considered.22–24
Modifiable risk factors for HIV transmission
Researchers in Zimbabwe demonstrated the role of genital ulcerative conditions in male to female transmission of HIV in a study conducted in a cohort of HIV serodiscordant couples enrolled in Harare. Men who reported a history of genital ulcer disease were significantly more likely to have a wife who was HIV seropositive (RR 1.94; 95% CI 1.62 to 15.13).25 This difference persisted even when the man's stage of disease was controlled.
The Nairobi group demonstrated the role of other STI in facilitating the sexual transmission of HIV, and the fact that uncircumcised men were at increased risk of acquiring HIV. They showed that, in men who had acquired an STI from a sex worker, risk factors for HIV seroconversion were a genital ulcer at presentation (RR 4.7; 95% CI 1.3 to 17.0) and being uncircumcised (RR 8.2; 95% CI 3.0 to 23.0). In a subgroup of men who only admitted to a single contact with a sex worker, six out of 37 of those presenting with an ulcer acquired HIV, compared with none out of 36 of those with no ulcer. Of 19 uncircumcised men who presented with an ulcer, five (26%) acquired HIV after a single sexual act with a sex worker.26 This study attracted considerable international interest, and led to intervention trials to evaluate the impact of improved STI control, and of male circumcision, on HIV incidence.27 All these studies were conducted in Africa by consortia including African, European and American universities and research institutes that are still actively involved in research on STI.
STI control for HIV prevention
A community-randomised intervention trial conducted in Mwanza Region, Tanzania, aimed to test the hypothesis that improved management of curable STI at the primary healthcare level would reduce the incidence of HIV infection in the general adult population. This study demonstrated that through improved management of STI HIV incidence could be reduced significantly: the incidence of HIV over 2 years was 38% lower in the intervention sites than in the comparison communities.28 The prevalence of active syphilis was reduced by 29%, and the prevalence of urethritis in men by approximately half in the intervention, compared with the comparison communities. There was no measurable difference in sexual behaviour between the intervention and comparison arms. The investigators concluded that improved clinical management of curable STI reduced the incidence of HIV by reducing the duration of symptomatic STI. The study was a collaboration between the National Institute for Medical Research, Tanzania, the Tanzanian Ministry of Health, the African Medical Research Foundation and the London School of Hygiene and Tropical Medicine (LSHTM).
Two further community-randomised trials were subsequently conducted in south western Uganda: a trial of periodic mass treatment for STI in Rakai district (a collaboration between the Universities of Columbia, Johns Hopkins and Makerere, with the Ugandan Ministry of Health) and a trial of health education with or without improved syndromic management of curable STI in Masaka district (a collaboration between the UK Medical Research Council, the Uganda Virus Research Institute, LSHTM and the Ugandan Ministry of Health). Neither of these trials showed any impact on HIV incidence. In Rakai, mass treatment, consisting of ciprofloxacin 250 mg, azithromycin 1 g and metronidazole 2 g, was given every 10 months to adults in intervention communities. Coverage was approximately 70% overall, and little impact was seen on the prevalence of the targeted STI: the only significant reductions were in the prevalence of active syphilis (by 20% overall), and in the prevalence of Trichomonas vaginalis infection in women (by 41%).29 In the Masaka trial, there were significant reductions in the incidence (48%) and prevalence (42%) of active syphilis, and a reduction in the prevalence of gonorrhoea (72%) in the arm that received improved syndromic management, compared with the comparison arm.30
The inability to reproduce the results of the Mwanza study in the two subsequent studies has led to further analysis of data from the three studies together. It has been suggested that the difference may be because the HIV epidemic in Uganda is more mature, with a falling incidence of HIV infection, change in sexual risk-taking behaviour and lower prevalences of curable STI, with the main cause of genital ulcers being infection with herpes simplex virus (HSV), for which treatment was not included in the interventions.31
A study among HIV-discordant couples in the Rakai cohort highlighted the importance of genital ulcer disease in facilitating HIV transmission, showing that a history of an ulcer in either partner increased the risk of HIV transmission no matter what the HIV viral load was in the infected partner.32 An association was also found between bacterial vaginosis and HIV infection in Rakai.33
The Nairobi group conducted an individually randomised controlled trial of monthly azithromycin (1 g) to prevent HIV infection in a cohort of female sex workers. The incidence of N gonorrhoeae, Chlamydia trachomatis and T vaginalis infection was reduced in the intervention arm, but there was no significant impact on the incidence of HIV infection, suggesting that these infections do not increase susceptibility to HIV infection in women.34 The incidence of HIV infection was significantly higher among women infected with N gonorrhoeae or C trachomatis at the previous visit, suggesting that these infections may increase the infectiousness of HIV-positive male partners. This study also found that women who were seropositive for HSV-2 were six times as likely to acquire HIV.
The importance of genital herpes infection
Researchers in the Zimbabwe AIDS Prevention Project demonstrated a high prevalence of HSV-2 infection in a cohort of male factory workers in Harare (40% positive).35 Studies conducted in Mwanza, Tanzania, also demonstrated high prevalence rates of infection: 50% of women and 25% of men were HSV-2 seropositive by the age of 25 years.36 Other studies confirmed the high prevalence of HSV-2 in other African countries.37 The importance of HSV-2 in facilitating the sexual transmission of HIV was demonstrated in a case–control study of HIV seroconverters in the Mwanza cohort, which found that 22% of new HIV infections in women and 74% in men could be attributed to the co-factor effect of HSV-2.38 The importance of HSV-2 infection in facilitating HIV transmission between men and women, and between men who have sex with men, was confirmed in other populations.39
As attention focused on HSV-2 as a modifiable risk factor for HIV transmission, a meeting was convened by the WHO, LSHTM, University of Washington, ITM and the MRC Clinical Trials Unit to discuss the research agenda. The conclusion was that, in the absence of an effective vaccine against HSV-2, suppressive treatment trials were needed to determine the impact of HSV-2 on HIV shedding and HIV acquisition. A number of major studies to determine the impact of suppressive herpes treatment on HIV shedding in HIV-positive people, and on the risk of HIV acquisition in HIV-negative people, were completed in Africa.
A randomised controlled trial in HIV-positive, HSV-2-seropositive women in Burkina Faso showed that suppression of HSV-2 replication with twice daily valacyclovir reduced the frequency of HIV shedding in cervicovaginal lavage fluid, and reduced the HIV viral load in cervicovaginal lavage fluid among shedders. Moreover, the plasma HIV viral load was also reduced in the valacyclovir arm.40
Two large randomised, placebo controlled trials measured the impact of suppressive treatment with acyclovir on the incidence of HIV infection in HSV-2-seropositive African women at high risk of HIV. Disappointingly, neither showed any impact on HIV incidence. In the first study, 821 high-risk women were followed for up to 30 months in the Mwanza region. Little impact was seen on HSV-2 shedding, and none on HIV incidence overall. Not unexpectedly, adherence to treatment with a twice daily regimen over a prolonged period was not perfect in asymptomatic women, with only just over 50% of women taking more than 90% of their tablets in both study arms. Among those who took more than 90% of their tablets, HIV incidence was lower in the acyclovir arm (2.5 vs 4.3 per 100 person-years), but this difference was not statistically significant.41 The second, multicentre study enrolled women at high risk of HIV infection at several African centres, as well as men who have sex with men in the USA and Peru. A total of 3172 individuals was followed for up to 18 months and adherence was 85% overall. No impact was seen on HIV incidence in spite of a 47% reduction in the incidence of genital ulcers in the acyclovir arm.42 Although the results of these trials were disappointing, they have shed new light on the pathophysiology of genital HSV infection and its interaction with HIV.43
Impact of male circumcision on HIV incidence
The association between male circumcision and protection from HIV infection was first noted by the Nairobi group, as described above. They published further observational data showing a geographical association between high rates of circumcision in men and low HIV prevalence in Africa, and set up a randomised controlled trial to study the effect of male circumcision on HIV incidence in Kenyan men aged 16–24 years. This trial showed that male circumcision reduced HIV incidence by just over half.44 Two other African studies, in Rakai and South Africa, showed a similar impact.45 46
A large multicentre collaborative study was conducted in three centres in Africa (one centre in Zimbabwe and two in Uganda). This study was aimed at examining the feasibility and efficacy of highly active antiretroviral therapy (ART) when high-level laboratory monitoring is not available. The study demonstrated that ART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of the CD4 cell count from the second year of ART to guide when to switch to second-line treatment.47 This landmark study has demonstrated that the lack of advanced laboratory monitoring facilities in resource-constrained settings does not preclude the provision of highly active ART.
Numerous studies have been carried out that have consolidated existing knowledge in the field of sexually transmitted diseases. Studies have demonstrated the role of mycoplasma in the aetiology of pelvic inflammatory disease, urethritis and genital ulcer disease.48 Studies in sub-Saharan Africa have also shown that donovanosis still exists in some parts of Africa and that this diagnosis should be borne in mind in persons presenting with genital ulcers.49 Studies among populations at high risk of acquiring and transmitting STI, such as sex workers, have enabled experience to be gained on the use of periodic presumptive treatment interventions to control STI, and provided data for modelling to estimate the impact of the intervention on HIV transmission.50
Sub-Saharan Africa has been at the forefront of STI research for the past three decades. Successful research has depended on long-term, carefully nurtured international partnerships and collaborations, and a few inspirational individuals. Groups working in Africa have shown an unusually collegiate spirit and willingness to share expertise, knowledge, methodology and results. The Network of AIDS Researchers of Eastern and Southern Africa was formed in 1988 and this set the pace of collaboration between researchers working in southern and eastern Africa and researchers from Europe and the USA. Early activities of the Network of AIDS Researchers of Eastern and Southern Africa focused on capacity building with training in research methodology and data analysis and later the group addressed pressing issues that included HIV counselling.
The global impact of studies conducted in sub-Saharan Africa includes the change in the management of patients presenting with symptoms and signs of STI: the syndromic case management approach is now used throughout the world to provide high quality acceptable care for STI care seekers. Studies have also provided the evidence for implementing certain STI control interventions. Medical education at the undergraduate and postgraduate levels has accepted the need to review and revise teaching curricula that now respond more to the needs of affected people. The overall effect of studies on the pandemic is more complex to assess as numerous variables need to be considered. However, it can be said that the results of several studies have been accepted as strong scientific evidence by local and national leaders and policy makers when control strategies and interventions are planned and implemented. Working with international partners has led to local capacity building both in Africa and elsewhere, as a result of the many training programmes that are linked to specific projects. Many tertiary training institutions in sub-Saharan Africa have benefited from international expertise participating in local training and teaching activities, and many international partners have gained considerable experience and recognition from participating in, and/or implementing, studies on STI in Africa.
Sub-Saharan Africa has been at the forefront of STI research for the past three decades.
Landmark studies have been conducted in Africa on syndromic management, on syphilis, chancroid, herpes, ophthalmia neonatorum and interactions between HIV and other STI.
High quality studies in Africa have provided important information to the benefit of STI control programmes worldwide.
Successful research has depended on long-term, carefully nurtured international partnerships and collaborations and a few inspirational individuals.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.
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