HIV Transmission and Sexually Transmitted Infections

CME Genitourinary medicine

HIV transmission and Observational studies hypothesis that STIs are cofactors for transmission was provided by studies of Genital ulcer disease from herpes, HIV levels in the genital tract before and sexually transmitted syphilis and chancroid was identified after treatment for STIs. RNA concentra- early as an important risk factor for HIV tions were measured in seminal and blood infections acquisition in men (both homosexual plasma from 135 HIV-1-seropositive men and heterosexual) and heterosexual in Malawi (86 had urethritis and 49 con- women. A study in 1983–1986 into the trols without urethritis).6 The seminal Phillip Hay MBBS FRCP, Reader in cause of proctitis in 200 homosexual plasma concentrations were eight times Genitourinary and HIV Medicine, St George’s men found that infection with HIV was higher in men with urethritis (12.4 × 104 Hospital, University of London independently associated with a history vs 1.51 × 104 copies/ml), despite similar of syphilis, serologic evidence of syphilis, CD4 counts and blood plasma viral RNA Clin Med 2008;8:323–6 a history of herpes simplex virus (HSV) concentrations. Gonorrhoea was associ- 2 infection and antibody to HSV-2. ated with the greatest concentration of HIV is a sexually transmitted infection A prospective study in Nairobi of 422 seminal HIV-1 in semen (15.8 × 104 (STI) which causes AIDS and death in men who acquired STIs following sex copies/ml). After antimicrobial therapy most of those infected after a median of with female commercial sex workers the seminal plasma HIV-1 RNA concen- 3 8–10 years. Where antiretroviral therapy (CSW), 85% of whom were seropositive, tration decreased significantly to 8.91 × is available, HIV is now regarded as a found that newly acquired HIV infection 104 copies/ml at one week and 4.12 × 104 manageable chronic condition. Preven- was significantly associated with the copies/ml at two weeks. Blood plasma tion remains a high priority and the acquisition of genital ulcer disease viral RNA concentrations did not change. potential to reduce the number of those (relative risk (RR) 4.7) and with being Among 609 HIV-1-seropositive acquiring HIV through better control of uncircumcised (RR 8.2). The frequency women in Abidjan, Côte d’Ivoire, HIV-1 STIs remains tantalising. This article will of HIV-1 infection in a subgroup of 73 shedding was significantly more frequent review the evidence that STIs are impor- seronegative men who reported a single in immunosuppressed women and those tant cofactors for HIV transmission and prostitute sexual contact was 8.2% during with gonorrhoea (adjusted odds ratio acquisition. 12 weeks of observation. No man without (AOR) 1.9), chlamydia (AOR 2.5) and a HIV itself is sexually transmitted so it a genital ulcer seroconverted, whereas cervical or vaginal ulcer (AOR 3.9).7 is often difficult to exclude confounding 43% of uncircumcised men who acquired HIV-1 shedding decreased from 42–21% from observational studies.1 The time an ulcer seroconverted to HIV-1 after a (p<0.005) in women whose STI was sequence of infections cannot be ascer- single sexual exposure. cured. tained easily in cross-sectional studies so Another study from Nairobi looked at Bacterial vaginosis (BV) is not regarded longitudinal studies are required. Studies risk factors for seroconversion in 124 as an STI, but it is a genital infection and of the effect of STIs on genital tract seronegative female CSWs, 83 (67%) of has been associated with elevated levels of 4 shedding of HIV provide biological whom seroconverted. Genital ulcers pro-inflammatory cytokines and reduced plausibility for mechanisms to associate (mean annual episodes 1.32 in serocon- levels of protective molecules such as increased transmission from those with verting women vs 0.48 in seronegative secretory leukocyte protease inhibitor and STIs. Randomised controlled studies women) and Chlamydia trachomatis infec- immunoglobulin A, which might affect (RCTs) of the impact on HIV serocon- tions (odds ratio (OR) 3.6) were associ- susceptibility to HIV. The strongest obser- version rates of interventions to control ated with HIV infection. Stepwise logistic vational data linking BV with HIV acqui- other STIs are the best measure of their regression analysis confirmed indepen- sition is from the study of 1,196 HIV-1 importance. dent associations between HIV-1 infection seronegative pregnant women in Malawi. and oral contraceptive and condom use, BV was significantly associated with genital ulcers and C. trachomatis. both antenatal (AOR 3.7) and postnatal Key Points Another study of 431 female CSWs in (AOR 2.3) HIV seroconversion.8 Kinshasa reported adjusted ORs for HIV Sexually transmitted infections (STIs) seroconversion of 4.8 for gonorrhoea, are risk factors for both HIV 3.6 for chlamydial infection and 1.9 for Community level sexually transmission and acquisition trichomoniasis.5 Genital ulcers were transmitted infection interventions There is limited evidence from more frequent in cases than controls but randomised controlled trials that much less common than other STIs. The observations discussed above led to control of STIs reduce HIV the hypothesis that interventions to incidence at a population level Genital tract HIV shedding reduce the prevalence of STIs would KEY WORDS: HIV incidence, HIV reduce the incidence of HIV. Potential transmission, sexually transmitted Viral load correlates with the risk of trans- interventions at a community-level infections mitting HIV. Biological plausibility of the included campaigns:9

• to promote safer sex first was a randomised controlled com- group B than in group C (syphilis inci- to improve STI treatment-seeking munity-based trial in Rakai of home- dence RR 0.52, gonorrhoea prevalence • 11 behaviour based mass antibiotic treatment. ratio 0.25). There was an increase in • to improve STI treatment services Intervention treatment with azithro- condom use in all three arms. (attitudes of care providers, case mycin, ciprofloxacin, and metronidazole was compared with control communities management and contact treatment) Rakai, rural Uganda receiving vitamins and antihelminthic for the integration of STI case • drugs, administered every 10 months to In an additional study in Rakai, the effect findings in family planning and all consenting adults (15–59 years). An of the treatment on pregnant women was antenatal care services open cohort was used to incorporate studied.13 There were reductions in STIs: STI screening programmes • newly arrived residents at each study trichomoniasis (RR 0.28), BV (RR 0.78), • mass treatment of whole round (total subjects 12,726). More than gonorrhoea and/or chlamydial infection communities for STIs. 80% of eligible adults received treatment. (RR 0.43) and adverse pregnancy out- Several large RCTs (discussed below) The baseline prevalence of HIV-1 infec- comes such as early neonatal mortality were undertaken to investigate whether tion was 15.9%. The study was stopped (RR 0.83, 95%CI 0.71–0.97). There was controlling STIs can reduce the incidence after three of the planned five treatment no reduction in incidence of HIV or of HIV in a community. Such studies courses because of the lack of effect syphilis. need to establish whether the interven- found in a planned interim analysis. At tion has reduced both the incidence/ 20-month follow-up, the prevalence of prevalence of STIs and the incidence of syphilis (5.6% vs 6.8%, RR 0.80) and tri- Review of intervention studies HIV infection. chomoniasis (9.3% vs 14.4%, RR 0.59) The conclusion from a review of the was significantly lower in the interven- intervention studies by the Cochrane Mwanza, Tanzania tion groups than in the controls. The collaboration was that there is limited incidence of HIV-1 infection was 1.5 per RCT evidence that STI control is an Twelve communities (ca 1,200 evaluable 100 person-years in both groups. effective HIV prevention strategy.9 There adults) and their associated primary care was, however, recognition of a benefit in clinics were randomised.10 Baseline HIV Mwanza which has an emerging HIV prevalence was 3.8% and 4.4% in the Masaka, rural Uganda epidemic (low and slowly rising preva- intervention and control communities, In the second study all adults living in 18 lence) and where STI treatment services respectively. The control communities communities in the Masaka district were are poor and STIs highly prevalent. Both had no additional interventions. Inter- 12 randomised into three groups. It the Masaka and Rakai studies demon- vention communities received improved included 12,819 from a total population strated no benefits from mass treatment syndromic STI case management com- of 96,000 aged 13 and older. The aim of prising: of populations. The proportion of HIV the study was to examine the role of seroconversions attributable to sympto- establishing an STI reference clinic • behavioural interventions alone, or in matic cofactors in the Rakai setting was in the district combination with improved manage- modest. The symptom most consistently • staff training ment of STIs, in reducing the incidence associated with HIV risk was genital of HIV-1 and other STIs: • regular supply of basic drugs ulcer disease, which was mainly caused • regular supervision of clinic staff • Group A: behavioural interventions by incurable HSV-2 or other non-STI • STI health education. alone. pathogens. There was a reduction in syphilis and • Group B: behavioural and STI interventions. symptomatic urethritis in the intervention Possible hypotheses to explain group. The incidence of HIV infection was • Group C (controls): the routine the different trial findings 1.2% and 1.9% in the intervention and government health services. control groups, respectively (OR 0.58, The incidence rate ratio (IRR) of HIV-1 Several hypotheses have been suggested 95% confidence interval (CI) 0.42–0.70), was 0.94 (p=0.72) in group A and 1.00 to explain the contrasting results of the corresponding to a 38% reduction (p=0.98) in group B compared with Mwanza, Rakai and Masaka trials.1,14,15 (95%CI 15–55%) in the intervention group C; the prevalence ratio of condom Curable STI probably played a more group. use with last casual partner was 1.12 important role in HIV transmission in (95%CI 0.99–1.25) in group A and 1.27 Mwanza than in the other two commu- (95%CI 1.02–1.56) in group B. HSV-2 nities. The epidemic in Uganda was more Rakai, rural Uganda incidence was lower in group A than in mature and generalised than in Mwanza, Following this initial positive study two group C (IRR 0.65, 95% CI 0.53–0.80) and with different transmission dynamics. subsequent studies in rural Uganda failed both incidence of active syphilis and In Rakai, HIV-1 infection was more to demonstrate reductions of HIV. The prevalence of gonorrhoea were lower in prevalent than most other STIs.

Further analyses from Rakai show that There was no difference in HIV infec- ilarly declined from baseline in the valaci- HIV-1 viral load was the main determi- tion rates among the 821 women clovir group, from 29.4% in the baseline nant of transmission risk, and suggest enrolled (aciclovir vs placebo RR 1.12). phase to 4.4% in the treatment phase, as that in discordant couples the effect of Adherence to treatment appeared to be compared with no change in the placebo viral load on transmission is substan- poor. Intriguingly, a subgroup analysis of group (RR 0.16). tially greater than that of STI symptoms those who took more than 90% of their 16 in either partner. Genital herpes is now pills showed a lower HIV incidence rate: Conclusions thought to be the most important 2.5 vs 4.3 per 100 person-years (RR 0.58, cofactor in mature epidemics and was 95%CI 0.3–1.4), but the numbers were There is no doubt that STIs are risk fac- not affected by the treatments in Rakai too low to reach statistical significance. tors for both HIV transmission and where HSV-2 was detected by PCR in The choice of agent may have been acquisition. The relative contribution of 45% of genital ulcers. BV is an additional important. individual STIs to an epidemic varies at risk factor for which the Rakai interven- Another Tanzanian study explored the different times and places depending on tion did not make a significant long-term potential for aciclovir to reduce genital the maturity of the epidemic and their reduction. HIV or HSV-2 shedding in 383 HIV- relative prevalence. The disappointing Untreated symptomatic STIs may have positive/HSV-2-positive coinfected results of the mass treatment studies a greater cofactor effect on HIV-1 trans- women.18 At baseline, 53% had HIV show that, although improved STI con- mission than symptomless infections, detectable in their genital secretions and trol is not the solution, it can make an since symptomatic STIs are likely to be 14% had HSV-2. At six and 12 months, impact, as shown in the Mwanza study. associated with a greater degree of women taking aciclovir had a trend to Similarly, the biological plausibility that inflammation. In Rakai, only limited ser- lower genital shedding of HIV (OR 0.83, suppressing genital herpes needs further vices were available to treat symptomatic 95%CI 0.56–1.26). When the investiga- testing. Whatever the outcome of such STIs between rounds of mass treatment. tors excluded women who had blood or studies, controlling STIs can still have an Substantial STI prevalence was seen at semen in their lavage, the relationship impact on morbidity. Additionally, the end of each 10-month follow-up strengthened between aciclovir use and although the pregnancy study in Rakai period, suggesting a high rate of infec- lower genital shedding of HIV (OR 0.64, did not show a reduction in HIV acquisition and reinfection after mass treatment 95%CI 0.39–1.04) but remained non- tion, there were reductions in adverse in this open cohort. significant. Again, only about half the pregnancy outcomes such as neonatal The population-attributable fraction cohort took more than 90% of their mortality.13 of HIV-1 infections due to STIs varied. In treatment. There was also no significant Rakai, only 10% of new HIV-1 infections effect on HSV-2 genital shedding. References were attributable to STI symptoms or treatable STIs, and there was no signifi- 1 Grosskurth H, Gray R, Hayes R, Mabey D, Valaciclovir Wawer M. Control of sexually transmitted cant difference between intervention and diseases for HIV-1 prevention: under- comparison groups. By contrast, in Whether use of a more potent agent such standing the implications of the Mwanza Mwanza 43% of new HIV-1 infections as valaciclovir and improved adherence and Rakai trials. Lancet 2000;355:1981–7. among men in the comparison group would produce more positive results 2 Stamm WE, Handsfield HH, Rompalo AM could be attributed to symptomatic STIs needs to be tested. A study of valaciclovir et al. The association between genital ulcer disease and acquisition of HIV infection in or new episodes of syphilis compared has shown a more impressive effect on homosexual men. JAMA 1988;260:1429–33. with 11% in the intervention group. genital tract viral shedding. In Burkina 3 Cameron DW, Simonsen JN, D’Costa LJ Faso, HSV-2/HIV-1 seropositive women et al. Female to male transmission of not eligible for antiretroviral therapy were human immunodeficiency virus type 1: Herpes suppression randomised to valaciclovir 500 mg twice risk factors for seroconversion in men. Lancet 1989;ii:403–7. daily or placebo.19 There were 136 evalu- Aciclovir 4 Plummer FA, Simonsen JN, Cameron DW able subjects in each arm, with mean CD4 et al. Cofactors in male-female sexual Genital herpes has emerged as an impor- count of 446 cells/mm3. There was a sig- transmission of human immunodeficiency tant potential risk factor for HIV trans- nificant decrease in the frequency of gen- virus type 1. J Infect Dis 1991;163:233–9. mission. In Tanzania, Watson-Jones et al ital HIV-1 RNA (OR 0.41) and in the 5 Laga M, Manoka A, Kivuvu M et al. Non- ulcerative sexually transmitted diseases as tested the hypothesis that suppressing mean HIV viral load (–0.29 logRNA/ml) risk factors for HIV-1 transmission in herpes with aciclovir 400 mg twice daily in the valaciclovir arm. HSV suppressive women: results from a cohort study. AIDS would reduce the rate of acquisition of therapy also reduced the mean plasma 1993;7:95–102. HIV in HSV-2 antibody-positive women.17 HIV-1 RNA level by 0.53 logRNA/ml. 6 Cohen MS, Hoffman IF, Royce RA et al. This is the first study to test whether a Significantly fewer women in the valaci- Reduction of concentration of HIV-1 in semen after treatment of urethritis: continuous antiherpes regimen reduces clovir group shed HSV-2 (19.1% vs implications for prevention of sexual the risk of contracting HIV in people 54.4%, RR 0.35). The proportion of transmission of HIV-1. AIDSCAP Malawi already infected with genital herpes. women with at least one genital ulcer sim- Research Group. Lancet 1997;349:1868–73.

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