Epidemiology and Social: Concise Communications
Risk factors for HIV incidence in women participating in an HSV suppressive treatment trial in Tanzania
Watson-Jones, Deboraha,b; Baisley, Kathya,c; Weiss, Helen Aa; Tanton, Clarea,c; Changalucha, Johnc; Everett, Deana,c; Chirwa, Tobiasa,c; Ross, Davida; Clayton, Tima; Hayes, Richarda
aDepartment of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
bAfrican Medical and Research Foundation (AMREF), Tanzania
cNational Institute for Medical Research (NIMR), Mwanza, Tanzania.
Received 28 July, 2008
Revised 14 October, 2008
Accepted 21 October, 2008
Correspondence to Dr Deborah Watson-Jones, MD, Department of Infectious & Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Tel: +44 2079272116; fax: +44 2076127860; e-mail: firstname.lastname@example.org
Objectives: A randomized, double-blind, placebo-controlled trial (RCT) of herpes simplex virus type 2 suppressive therapy with acyclovir 400 mg twice daily conducted among women in northwestern Tanzania reported a similar rate of HIV acquisition in both trial arms (Current Controlled Trials number ISRCTN35385041). Risk factors for HIV incidence were examined in the context of 3-monthly follow-up visits offering both voluntary counselling and testing and care for sexually transmitted infections.
Design: Prospective cohort analysis of trial participants enrolled and followed for up to 30 months.
Methods: Risk factors for HIV acquisition were analysed using Cox regression.
Results: Overall, 821 herpes simplex virus type 2 seropositive, HIV seronegative women were randomized; 400 randomized to acyclovir and 421 to placebo; 659 (80.3%) completed follow-up. HIV incidence was 4.27 per 100 person-years. There was no overall impact of acyclovir on HIV incidence [hazard ratio = 1.01; 95% confidence interval (CI) 0.61–1.66]. HIV acquisition was independently associated with younger age at enrolment (age 16–19 vs. 30–35: hazard ratio = 4.02; 95% CI 1.67–9.68), alcohol consumption at enrolment (≥30 drinks/week vs. none: hazard ratio = 4.39, 95% CI 1.70–11.33), having paid sex within the previous 3 months (hazard ratio = 1.82, 95% CI 1.09–3.05), recent infection with gonorrhoea (hazard ratio = 3.62, 95% CI 1.62–8.08) and injections in the previous 3 months (hazard ratio = 3.45, 95% CI 1.62–7.34). There was some evidence of an association between HIV incidence and living in the recruitment community for less than 2 years (hazard ratio = 1.75, 95% CI 0.98–3.10) and exposure to hormonal contraception (hazard ratio = 1.60, 95% CI 0.93–2.76).
Conclusion: A high incidence of HIV was observed in this trial cohort, especially in young women. Interventions are needed to address the risk associated with alcohol use and to sustain control of other sexually transmitted infections.
Sub-Saharan Africa continues to suffer a devastating HIV epidemic with HIV rates especially high in groups such as bar and hotel workers [1–5]. Risk factors for HIV acquisition may change over time as the epidemic evolves, socioeconomic factors change and prevention messages potentially impact on behavioural and biological factors. For example, a reduction in high-risk sexual behaviour has been reported in Zambia , whereas recent studies have suggested a strong association between HIV acquisition and alcohol use in Africa .
In this article, we report factors associated with HIV incidence from the first randomized controlled trial to assess the impact of herpes suppressive therapy on HIV incidence (Current Controlled Trials number ISRCTN35385041).
Trial procedures have been described previously [5,8]. Tanzanian women aged 16–35 years working in bars, guesthouses and similar facilities in 19 communities were interviewed, tested for herpes simplex virus type 2 (HSV-2) and HIV antibodies and asked to reattend 2–3 months later.
At enrolment, HSV-2 seropositive participants were tested for pregnancy, interviewed and blood and genital samples collected. Women were randomized to receive a 4-month supply of acyclovir 400 mg twice daily (b.i.d.) or matching placebo and followed 3 monthly for up to 30 months depending on enrolment date.
At booked visits, pregnancy testing, family planning, STI syndromic management, HIV voluntary counselling and testing (VCT), risk reduction counselling, treatment for medical problems and condoms were provided. Participants were tested for syphilis at each visit. Vaginal and cervical specimens were collected at the 6, 12, 24 and 30 month visits. Genital examinations were performed at other visits if the participant complained of STI symptoms.
Sera were tested by HIV Enzyme-Linked ImmunoSorbent Assay (ELISA) (Murex HIV Ag/Ab Combination ELISA; Murex Biotech, Dartford, UK; Uni-FormII Ag/Ab micro ELISA system; bioMérieux, Basingstoke, UK). Repeatedly discordant samples were tested by HIV-1 p24 Ag EIA (Biorad Genetic Systems, Seattle, Washington, USA) and a line immunoassay (INNO-LIA HIV I/II, Innogenetics, Gent, Belgium) which was also used to confirm seroconversion samples . Diagnosis of other STIs has been previously described [5,8,9].
Data from the entire trial cohort were analysed, irrespective of withdrawal from tablets. Women were censored at the earliest of the date of HIV seroconversion, date last seen, or end of follow-up. Cox proportional hazards regression was used to estimate hazard ratios for HIV seroconversion which was assumed to take place midway between last negative and first positive serology results.
Potential determinants of HIV seroconversion were examined using a conceptual framework . Initially, univariate age-adjusted associations were examined (Table 1). All models included age, considered an a priori confounder. Baseline sociodemographic factors whose age-adjusted association reached statistical significance (P < 0.20) were included in a multivariate model. Those remaining independently associated with HIV seroconversion (P < 0.10) were retained in a core model. Baseline behavioural factors were added to this model one by one and significant factors (P < 0.20) included in a multivariate model. Those remaining significant (P < 0.10) were retained. Associations with time-varying behavioural and biological factors were determined in a similar way. The final model excluded factors one at a time until all remaining factors were significant at the P < 0.10 level.
Population attributable fraction (PAF) of HIV acquisition for predictors in the final model was estimated using adjusted hazard ratios.
Sociodemographic and behavioural characteristics
In total, 2719 subjects were screened and 821 HIV-negative women were enrolled (400 randomized to acyclovir, 421 to placebo). Median age at enrolment was 28 years. At screening, half of the participants reported drinking alcohol; 16.8% reported 10 or more drinks per week. At enrolment, 20% used injectable depot-medroxyprogesterone acetate (DMPA) and 10% combined oral contraceptive pills (COC) for contraception. At screening and enrolment, 515 women (62.7%) accepted VCT and were given their HIV result. A further 80 (9.7%) participants accepted VCT and were tested during follow-up.
Forty-five participants (5.5%) did not return after randomization. Women were followed for 1477 person-years (pyr), with a median duration of 2.50 years (range 0–2.78 years). Overall, 659 (80.3%) completed follow-up, defined as attending until the date of seroconversion or end of study. Sixty-three women seroconverted. HIV incidence was 4.27 per 100 pyr [95% confidence interval (CI) 3.33–5.46/100 pyr] with no significant difference between acyclovir and placebo arms (hazard ratio = 1.01; 95% CI 0.61–1.66). HIV incidence was 10.3 per 100 pyr among 16–19-year-olds, falling to 2.5 per 100 pyr among women aged 30–35 (P trend = 0.003, Table 1).
Age-adjusted risk factors for HIV incidence
Age-adjusted factors associated with HIV incidence included living in the screening site for less than 2 years, alcohol consumption, number of partners and paying partners in the past 3 months, receiving an injection outside the trial clinic since the previous visit, injections by the trial team at the previous visit, current hormonal contraception and gonorrhoea or chlamydial infection at the current visit (Table 1). Women with a positive pregnancy test at the current visit were less likely to have seroconverted to HIV.
In the final multivariate model (Table 2), HIV incidence was independently associated with younger age, living in the site for less than 2 years (adjusted hazard ratio = 1.75, 95% CI 0.98–3.10), increasing alcohol consumption at screening (≥30 drinks/week vs. none: adjusted hazard ratio = 4.39, 95% CI 1.70–11.33), having a paying partner in the past 3 months (adjusted hazard ratio = 1.82, 95% CI 1.09–3.05), injections outside the trial clinic since the last visit (adjusted hazard ratio = 3.45, 95% CI 1.62–7.34), currently using hormonal contraception (adjusted hazard ratio = 1.60, 95% CI 0.93–2.76) and gonorrhoea (adjusted hazard ratio = 3.62, 95% CI 1.62–8.08).
The estimated PAFs of HIV incidence for any alcohol use, hormonal contraception and paying partners were 40.1, 26.2, and 20.0%, respectively. The PAFs for injections and for gonorrhoea were lower at 9.0 and 8.0%, respectively.
Clinical symptoms in injection recipients
Clinical data on the eight seroconverters who reported receiving an injection outside the trial clinic were examined to investigate whether seroconversion symptoms may have preceded recent injections. Four women reported receiving quinine between 2 days and 2 months prior to the first positive HIV test for an apparently positive blood smear for malaria (symptoms included fever, headache, lethargy, cough, arthralgia). Two participants, one with headache and one complaining of fever and abdominal pain, received quinine for suspected malaria 1 month–6 weeks prior to the first positive HIV test. Another received penicillin for fever and joint pain 3 weeks before a positive HIV test, and one woman was given benzathine penicillin for syphilis treatment sometime between the last negative and first positive HIV test.
HIV incidence was very high among young women in this population, and we identified several potentially preventable factors strongly associated with incident HIV including consumption of alcohol. A relationship with alcohol has been observed in several recent African studies [7,11]. In our study, women consuming 10 or more drinks per week were at a more than three-fold increased risk of acquiring HIV than nondrinkers. Drinking establishments in sub-Saharan Africa are known HIV high transmission sites . Alcohol can lead to behavioural disinhibition with resultant risky sexual behaviour, partner violence and coercive sex, as documented in South Africa and Uganda [13–15]. As alcohol may be purchased for women by their clients, it may also be a proxy marker for sex with high-risk partners. Alcohol may also influence susceptibility to HIV at a biological level [16,17], possibly due to a suppressive effect on the degradation of the HIV envelope protein, gp120 .
We found an increased risk of HIV associated with current gonococcal infection as has been seen in sex workers in Nairobi  but no association with trichomonasis or Chlamydia trachomatis, unlike recent studies [19,20]. This may have been partly because women were diagnosed in the field and offered prompt treatment and because STI were diagnosed aetiologically at selected visits, with syndromic management being offered at other visits, so reducing study power to detect an association with HIV acquisition.
Condom use was not associated with a reduction in HIV incidence. As in other studies in East Africa , reported condom use during the trial remained disappointingly low, despite repeated education and counselling sessions on HIV prevention. Our results indicate the need for more intensive HIV prevention programmes in this population.
Genital ulcers were not significantly associated with HIV but may have been underestimated as participants were only examined every 6 months unless they had symptoms. There was no significant association between HIV acquisition and cervical ectopy in contrast to a South African study in which ectopy of more than 20% was associated with HIV incidence .
Hormonal contraception was associated with HIV incidence. This has been found in HSV-2 seronegative women in Uganda and Zimbabwe  and sex workers in Kenya  though no association between hormonal contraception and HIV incidence was observed in Cape Town . Our data suggest that hormonal contraception can increase the risk of HIV in high-risk women though it is possible that this association may in part be attributable to residual confounding by sexual behaviour.
VCT has been associated with self-reported behaviour change in Kenya . In common with studies in Uganda and Zimbabwe, we found no difference in HIV incidence between those who accepted or did not accept VCT [27,28]. Our selected trial population, however, received repeated risk reduction counselling irrespective of uptake of VCT, which may have diluted any impact that VCT could have had as an HIV prevention tool in this setting.
Injections given outside our research clinic were also associated with HIV acquisition. Estimates of the proportion of HIV infections attributable to injections in sub-Saharan Africa range from 1 to 30% [29,30]. However, the causal direction of this association is not straightforward. In our trial, the main reason for injections was malaria treatment. Overdiagnosis of malaria is common in sub-Saharan Africa [31,32], and our clinical data suggest that, in at least seven cases, injections were given to treat symptoms possibly related to a seroconversion illness which may have been misclassified as malaria or another infection. A similar temporal association between a possible seroconversion illness and injections has been seen in Uganda . If injections are given for symptoms related to seroconversion, this emphasizes the necessity to maintain safe injection practices as risks of onward transmission will be high at this stage of HIV infection due to high viral load.
We could not examine the independent effect of HSV-2 on HIV incidence. However, 80% of women in this population were found to be HSV-2 seropositive at screening . Our results will therefore be generalizable to many women in similar occupational settings. A further limitation is reliance on self-reported sexual behaviour as such information may be subject to social desirability bias [34,35]. Finally, with 63 seroconversions, the power of our study to detect significant associations with uncommon exposures will have been limited.
In conclusion, this prospective study has demonstrated a strong association between HIV incidence and young age, alcohol consumption, injections, payment for sex, gonococcal infection and hormonal contraception. Interventions are needed to address the risk associated with alcohol use and to sustain control of other STIs. In addition, prevention messages should be targeted to young women in this population. Further work is needed to examine the effect of injections and hormonal contraception on HIV incidence in high-risk settings.
We thank the trial participants; Mary Rusizoka and the HSV trial team; Koronel Kema, Paul Waibale, Obed Mrita, Fatma Mohammed of AMREF; the laboratory and data teams of the NIMR Mwanza Centre; David Mabey, Tamara Hurst and Fiona Marquet at LSHTM; Ian Hambleton and Louise Knight, LSHTM/NIMR; Anne Buvé, Eddy van Dyck and Tania Crucetti of the Institute of Tropical Medicine, Antwerp, Michel Alary of the University of Laval, Quebec; Peter Turner and Gerald Baldrey of Geita Gold Mine, Tanzania; and the Trial Steering and Data Monitoring Committees. The trial was funded by the Wellcome Trust and the UK Medical Research Council (MRC) with additional support from the Department of International Development. The London School of Hygiene and Tropical Medicine was the trial sponsor.
Author contributions: D.W.J. was principal investigator, supervised the trial and wrote the first draft of the article. D.W.J., R.H., D.R., T.Cl., and H.A.W. designed the study; K.B. and T.Ch. were responsible for data management for the trial; K.B. and H.A.W. conducted the analysis; J.C. and D.E. supervised the laboratory work; C.T. supervised fieldwork; all authors commented on drafts of the manuscript and approved the final version; D.W.J. and R.H. act as guarantors for the results presented in the article.
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