A 26-year-old white English male presented to the Hospital for Tropical Diseases, London with a two day history of fever, malaise, sore throat and rash. He had returned two days previously from a 5-month holiday in Zimbabwe. He reported several heterosexual contacts in Zimbabwe. On examination he was febrile (38 °C), had multiple painful mouth ulcers, a generalized maculopapular rash, nontender bilateral inguinal lymphadenopathy, and a painless ulcer on his glans penis, which he said had been present for 2 days. Serological tests for antibodies to syphilis and HIV 1 and 2 were negative. However, dark field examination of material from the ulcer revealed Treponema pallidum, and a serum assay for HIV P24 antigen was positive, leading to the diagnosis of early primary syphilis and HIV seroconversion illness. This man had presumably acquired syphilis and HIV infection from an HIV-positive sexual partner with primary or secondary syphilis. Figure 1 (woman with secondary syphilis, courtesy of John Richens) suggests that it is biologically plausible that HIV-positive individuals with syphilitic genital ulceration are more likely to transmit HIV to their sexual contacts than those without ulceration.
The term ‘epidemiological synergy’ has been used to describe the relationship between HIV infection and other sexually transmitted diseases (STDs) ( Wasserheit 1992; Fleming & Wasserheit 1999). HIV infection, by causing immunosuppression, increases the duration and severity of certain STDs, notably genital Herpes simplex virus infection ( Quinnan et al. 1984 ). Other STDs, by causing ulceration or inflammation of the genital tract, enhance the transmission of HIV by increasing the infectiousness of HIV-positive individuals and/or the susceptibility of HIV-negative persons. This paper assesses the evidence that other STDs facilitate HIV transmission.
The evidence comes from studies of four types: cross-sectional studies showing associations between HIV infection and other STDs; prospective studies in which risk factors for HIV seroconversion are assessed; laboratory-based studies in which the impact of STDs on HIV shedding is determined; and intervention trials, in which the impact of improved services for the treatment of STDs on HIV incidence is measured.
Numerous cross-sectional studies have found associations between HIV infection and other STDs; but this is hardly surprising, and does not imply a causal relationship, since all sexually transmitted infections share common behavioural risk factors. Moreover, even if it were possible to control for confounding due to sexual behaviour, cross-sectional studies tell us nothing about the direction of causality, since it is not clear whether subjects acquired HIV infection or the other STD first.
Prospective seroconversion studies are more helpful in this respect, although they are still subject to confounding due to sexual behaviour of subjects or their sexual partners. One of the most convincing of these was that of Cameron et al. (1989) , in which a cohort of HIV seronegative males attending the main STD clinic in Nairobi was followed. These men all reported sexual contact with a group of commercial sex workers (CSWs), at least 90% of whom were known to be HIV positive; thus almost all of them had recently acquired an STD from an HIV-positive female partner.
Prospective seroconversion studies
Of 293 subjects enrolled, 24 seroconverted during follow-up. Risk factors for HIV seroconversion were: multiple episodes of sex with CSWs (adjusted OR 3.2); being uncircumcised (adjusted OR 8.2); and having a genital ulcer at presentation (adjusted OR 4.7). In a subgroup of men who only admitted to one episode of sex with a CSW, 6/37 of those presenting with an ulcer seroconverted (16%). This is a remarkably high proportion compared with an estimated risk per episode of approximately 1 in 1000 among the wives of HIV-positive haemophiliacs in the USA ( Padian et al. 1987 ), implying that the presence of a genital ulcer increases the probability of transmission more than 100 fold. A longitudinal study conducted in the USA found syphilis to be a risk factor for HIV seroconversion. 5164 patients attending an STD clinic in Miami, Florida who had been tested twice for HIV, on different occasions, were identified. 204 of these seroconverted. Syphilis diagnosed between the two HIV tests was a significant risk factor for HIV seroconversion (adjusted incidence ratio 2.9, 95% CI 1.9–4.3) ( Otten et al. 1994 ). Figure 2 shows a uterine cervix with a mucopurulent discharge from the os, a typical finding in cervical infection with Neisseria gonorrhoeae or Chlamydia trachomatis ( Brunham et al. 1984 ). This discharge contains inflammatory cells, including cells expressing molecules to which HIV can attach, such as CD4 and the chemokine receptor CCR5, suggesting that nonulcerative STDs can make women more susceptible to HIV infection. This hypothesis is borne out by cohort studies of female sex workers in Nairobi and Kinshasa ( Plummer et al. 1991 ; Laga et al. 1993 ): gonococcal infection was associated with a significantly increased risk of HIV seroconversion in both cohorts. In Kinshasa, but not Nairobi, chlamydial infection was also significantly associated with risk of HIV seroconversion, and Trichomonas vaginalis was associated with almost double the risk (OR 1.9, 95% CI 0.9–4.1).
Impact of STDs on HIV shedding
Evidence that gonorrhoea and chlamydial infection increase the infectiousness of HIV-positive women, as well as the susceptibility of HIV-negative women, comes from studies of female sex workers in Abidjan and Mombasa: these showed that both infections were associated with an increased prevalence of HIV shedding in the genital tract, detected by polymerase chain reaction (PCR) targeting proviral DNA ( Ghys et al. 1997 ; Mostad et al. 1997 ). A study of HIV-positive men in Malawi showed that men with symptomatic gonorrhoea shed significantly more HIV RNA in seminal fluid than men without urethritis (median viral load 15.8 vs. 1.5 × 104 copies/ml, P < 0.001), and that shedding was significantly reduced two weeks after effective treatment ( Cohen et al. 1997 ).
While studies such as these show that it is biologically plausible that other STDs, both ulcerative and nonulcerative, facilitate HIV transmission, the final proof can only come from intervention trials. Two community randomised trials assessing the impact of improved STD control on HIV incidence have been reported, both of them conducted in rural communities close to Lake Victoria, in Tanzania and Uganda, respectively ( Grosskurth et al. 1995 ; Wawer et al. 1999 ). The Mwanza trial showed that improved STD management, using syndromic treatment in health centres and dispensaries, reduced the incidence of HIV infection by some 40%; whereas the trial in Rakai District, Uganda, found that periodic mass treatment of STDs had no impact on HIV incidence. How can these two apparently contradictory results be reconciled?
The Mwanza trial
In Mwanza, Tanzania, a community-randomised trial was conducted to measure the impact of improved clinical management of STDs, using the syndromic approach in rural health centres and dispensaries, on HIV incidence over a two-year period. A community was defined as the population served by a health centre and its satellite dispensaries. Communities were matched in six pairs according to geographical location and number of STD cases seen, and one member of each pair was selected at random to receive the intervention.
This consisted of: training of staff in syndromic management using protocols of demonstrated local efficacy; regular supervision of trained staff; a regular supply of effective drugs; and health education at village level to encourage those with genital tract symptoms to attend early for treatment. The impact of the intervention on the incidence of HIV and selected STDs was measured in a cohort of approximately 12 000 adults, about 1000 of whom were recruited in each of the 12 communities.
A sample of venous blood was collected from all participants at baseline and at follow-up two years later. Rapid plasma reagin (RPR) tests for syphilis were performed in the field, and all subjects with a positive test were treated with a single intramuscular injection of 2.4 million units benzathine penicillin. Sera were transported to a laboratory in Mwanza, where they were tested for antibodies to HIV (Vironostika HIV MIXT Microelisa, Organon Teknika, Boxtel, Netherlands). Positive samples were confirmed by a second ELISA (Wellcozyme HIV 1 & 2, Murex Diagnostics, Dartford, UK). Sera were also tested for antibodies to Treponema pallidum (TPHA, Fujirebio,
Tokyo, Japan), and the titre of positive samples determined in the RPR test, using doubling dilutions tested by the 25 VDRL carbon antigen (Murex Diagnostics, UK). Male subjects were asked to provide a first void urine sample, which was tested on the spot with a leucocyte esterase dipstick (LED) (Boehringer Mannheim, Germany). Urethral swabs were taken from those with a positive LED test, and tested for the presence of Neisseria gonorrhoeae by Gram stain, and the presence of Chlamydia trachomatis antigen by enzyme immunoassay (IDEIA Chlamydia, Novo Nordisk Diagnostics, Cambridge, UK).
At baseline, HIV prevalence was 3.8% in the intervention, and 4.4% in the comparison communities. At follow-up after two years, 71% of the cohort were seen, with similar rates of follow-up in intervention and comparison communities. The incidence of HIV infection over two years was 1.2% in the intervention group, and 1.9% in the comparison group. Allowing for the community randomised design and the effects of confounding factors, the estimated risk ratio was 0.58 (95% CI 0.42–0.79; P = 0.007). In other words, the incidence of HIV infection was approximately 40% lower in the intervention communities. The intervention also had a significant impact on the seroprevalence of syphilis, which was reduced by 10% to 40%, depending on the titre used to define a positive rapid plasma reagin (RPR) test; and on the prevalence of symptomatic (but not asymptomatic) urethritis in men, which was reduced from 2.5% to 1.6% (P = 0.08) ( Mayaud et al. 1997 ). There were no differences in reported sexual behaviour between the two arms of the trial, or over time.
The conclusion of the Mwanza trial is that improved case management of symptomatic STD patients presenting to health facilities can significantly reduce HIV incidence, presumably by reducing the duration of disease, and hence the infectiousness of HIV-positive and the susceptibility of HIV-negative individuals.
The Rakai trial
In Rakai, Uganda, a community randomised trial of mass treatment for STDs was conducted in rural communities with little access to health care. Ten community clusters were randomly assigned to intervention or control groups. All consenting residents aged 15–59 years were enrolled; visited at home every 10 months; interviewed; asked to provide biological samples for assessment of HIV and other STDs; and provided with mass treatment (azithromycin, ciprofloxacin and metronidazole in the intervention group; and vitamins and antihelminthics in the control group).
7871 individuals were enrolled in the intervention, and 7256 in the control communities. Subjects were interviewed at home concerning health, treatment-seeking and sexual behaviour, and the following samples were collected: Venous blood for HIV-1, syphilis and Herpes simplex virus type 2 (HSV-2) serology; first catch urine for the detection of N. gonorrhoeae and C. trachomatis by ligase chain reaction (LCR) (Abbott Laboratories , IL, USA); and from women, a self-administered vaginal swab for gram stain and T. vaginalis culture (InPouch TV, BioMed Diagnostics , San Jose, CA, USA). Syphilis screening was performed in the field using the toluidine red unheated serum (TRUST) test, and all those with a positive result were treated with a single intramuscular injection of 2.4 million units benzathine penicillin. A confirmatory test (TPHA, Fujirebio, Tokyo, Japan) was performed in the main laboratory. Two different enzyme immunoassays (EIAs) were used for HIV-1 (Organon Teknika, Charlotte, NC, USA and Cambridge Biotech, Worcester, MA, USA), and discordant samples were resolved by Western Blot (HIV-1 WB Bio-Merieux-Vitek , St Louis, MA, USA).
Baseline HIV seroprevalence was 16.1% in the intervention, and 15.5% in the control cohort. Approximately 70% of eligible individuals enumerated at baseline received mass treatment at each round. At the third visit (20 months after baseline), 78% (6143/7871) in the intervention, and 76% (5543/7256) in the control cohort were seen and re-tested. The incidence of HIV-1 infection was 1.5 per 100 person years in both intervention and comparison cohorts (adjusted rate ratio 0.97, 95% CI 0.81–1.15). The prevalence of syphilis was 5.6% in the intervention, and 6.8% in the comparison cohort (adjusted prevalence ratio 0.80, 95% CI 0.71–0.89). The prevalences of T. vaginalis infection in women were 9.5% and 14.4%, respectively (adjusted PR 0.59, 95% CI 0.38–0.91). There was no significant difference in the prevalence of bacterial vaginosis, gonorrhoea or chlamydial infection between the intervention and control groups. As in the Mwanza trial, there was no difference in reported sexual behaviour between the two arms.
The conclusion from the Rakai trial is that mass treatment for STDs, administered to a general rural population, is not an effective HIV control strategy. This is perhaps not surprising, given that the study population was chosen because it was situated within easy reach of a road, and even rural populations in Africa are now highly mobile. Moreover, only 70% coverage was achieved, and no STD treatment facilities were available between rounds of mass treatment. These factors are reflected in the small impact that the intervention had on the prevalence of the target STDs.
Other possible reasons for the different results obtained in Mwanza and Rakai are: The HIV prevalence was much higher in Rakai. Mathematical models suggest that STD control would have a greater impact on HIV incidence early in the epidemic ( Robinson et al. 1997 ); moreover, in a mature epidemic, a higher proportion of genital ulcers is likely to be due to HSV-2, treatment for which was not available at either study site ( Kamya et al. 1995 ). Symptomatic STDs, which were targeted in Mwanza, may play a more important role in facilitating HIV transmission than the asymptomatic STDs targeted in Rakai.
Public health implications of the Mwanza and Rakai trials
There can now be little doubt that other STDs facilitate the heterosexual transmission of HIV-1, and that this has been an important factor in the rapid spread of HIV infection in developing countries. STD control must remain high on the public health agenda, as it is one of the few intervention strategies that has been formally shown to reduce the incidence of HIV infection. The impact on HIV incidence is likely to be highest in populations with a high STD and low HIV prevalence; but this is not a reason to neglect STD control in populations with a high HIV prevalence. STDs are an important cause of morbidity in their own right, and cause more severe morbidity in HIV-positive individuals. Moreover, even in populations with a high HIV prevalence, persons with STDs have an increased risk of acquiring and transmitting HIV infection; and STD control will help to reduce the alarmingly high incidence of HIV infection in young people in these populations.
What is the most cost-effective strategy for STD control in developing countries? Primary prevention through health education, if effective in promoting changes in sexual behaviour, will prevent both HIV and other STDs, but few studies have formally evaluated its impact, and the optimum strategies to achieve changes in behaviour have not been identified.
Syndromic management can be useful and cost-effective in men with urethral discharge and in patients of both sexes with genital ulcers, provided the aetiologies of these syndromes and the antimicrobial susceptibility of common pathogens have been determined locally. It is less useful in women complaining of vaginal discharge, and may lead to considerable over-treatment in populations with a low prevalence of STDs ( Hawkes et al. 1999 ), with a consequent waste of scarce resources. Moreover, many STDs are asymptomatic in women. There is an urgent need for cheap, rapid, simple diagnostic tests for STDs in women that can be used for screening and case-finding; especially for gonorrhoea and chlamydial infection.
The high prevalence of asymptomatic STDs in many vulnerable populations in developing countries, the lack of simple, cheap screening tests, and the difficulty of partner notification suggest that presumptive mass treatment may have an important part to play in STD control in developing countries, especially if it can be targeted to high-risk groups. Computer simulations using data from the Mwanza study suggest that it may have a considerable impact in populations with a high prevalence of STDs, and a low but rising HIV prevalence ( Van Vliet et al. 2000 ). A combination of a single round of mass treatment with improved syndromic case management was predicted to lead to a rapid, steep and sustained reduction in HIV incidence, reaching 63% after 5 years. Mass treatment should not be considered as an alternative to effective case management of symptomatic STD patients, but rather as a possible adjunct to it, especially in high risk populations. The challenge is to implement such targeted programmes without stigmatization.
Herpes simplex virus type 2 (HSV 2) is increasingly recognized as an important cause of genital ulceration in populations with a high HIV prevalence in developing countries ( Morse et al. 1997 ). Epidemiological synergy is particularly evident in the interaction between these two organisms, since each appears to increase the shedding of the other in the genital tract ( Mbopi-Keou et al. 1999 ). Antiviral treatment for HSV 2 is not widely available in developing countries; there is an urgent need for a vaccine against this highly prevalent infection ( Obasi et al. 1999 ).
STD control remains an extremely important public health priority in developing countries, to prevent both HIV infection and the sequelae of STDs. The development and rigorous evaluation of new intervention strategies against STDs should remain high on the international public health agenda.