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1.  Improving Vaginal Health in Women at Risk for HIV-1: Results of a Randomized Trial 
The Journal of infectious diseases  2008;197(10):1361-1368.
Vaginal infections are common and have been associated with increased HIV-1 risk.
We conducted a randomized trial of monthly oral directly observed treatment for reducing vaginal infections in Kenyan women at risk for HIV-1. Trial interventions included metronidazole 2 grams plus fluconazole 150 milligrams versus identical metronidazole and fluconazole placebos. The primary endpoints were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis, and colonization with Lactobacillus (, NCT00170430).
Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary endpoints analysis. Median follow-up was 12 visits in both study arms (p=0.8). Compared to controls, women receiving the intervention had fewer episodes of BV (hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.49-0.63), and more frequent vaginal colonization with Lactobacillus species (HR 1.47, 95% CI 1.19-1.80) and hydrogen peroxide-producing Lactobacillus species (HR 1.63, 95% CI 1.16-2.27). Vaginal candidiasis (HR 0.84, 95% CI 0.67-1.04) and trichomoniasis (HR 0.55, 95% CI 0.27-1.12) were reduced in treated women compared to controls, although not significantly.
Periodic presumptive treatment reduced BV and promoted normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing HIV-1 risk.
PMCID: PMC4122228  PMID: 18444793
Bacterial vaginosis; vaginal candidiasis; Trichomonas vaginalis; Lactobacillus; HIV-1; randomized trial; women; Africa
2.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
PMCID: PMC4303292  PMID: 25612136
3.  A Prospective Study of Risk Factors for Bacterial Vaginosis in HIV-1-Seronegative African Women 
Sexually transmitted diseases  2008;35(6):617-623.
Bacterial vaginosis (BV) is common and has been associated with increased HIV-1 susceptibility. The objective of this study was to identify risk factors for BV in African women at high risk for acquiring HIV-1.
We conducted a prospective study among 151 HIV-1-seronegative Kenyan female sex workers. Non-pregnant women were eligible if they did not have symptoms of abnormal vaginal itching or discharge at the time of enrollment. At monthly follow-up, a vaginal examination and laboratory testing for genital tract infections were performed. Multivariate Andersen-Gill proportional hazards analysis was used to identify correlates of BV.
Participants completed a median of 378 (interquartile range 350–412) days of follow-up. Compared to women reporting no vaginal washing, those who reported vaginal washing 1–14 (adjusted hazard ratio [aHR] 1.29, 95% confidence interval [CI] 0.88–1.89), 15–28 (aHR 1.60, 95% CI 0.98–2.61), and >28 times/week (aHR 2.39, 95% CI 1.35–4.23) were at increased risk of BV. Higher BV incidence was also associated with the use of cloth for intravaginal cleansing (aHR 1.48, 95% CI 1.06–2.08) and with recent unprotected intercourse (aHR 1.75, 95% CI 1.47–2.08). Women using depot medroxyprogesterone acetate contraception were at lower risk for BV (aHR 0.59, 95% CI 0.48–0.73).
Vaginal washing and unprotected intercourse were associated with increased risk of BV. These findings could help to inform the development of novel vaginal health approaches for HIV-1 risk reduction in women.
PMCID: PMC3902781  PMID: 18418290
Bacterial vaginosis; vaginal washing; intravaginal practices; women; Africa
4.  Changes in Sexual Risk Behavior in the Mombasa Cohort: 1993–2007 
PLoS ONE  2014;9(11):e113543.
The Mombasa Cohort is an open cohort study following HIV-seronegative women reporting transactional sex. Established in 1993, the cohort provides regular HIV counseling and testing at monthly visits. Over time, HIV acquisition risk has declined steadily in this cohort. To evaluate whether this decline may reflect changes in sexual risk behavior, we investigated trends in condom use and partner numbers among women who participated in the Mombasa Cohort between 1993 and 2007. Multinomial logistic regression and generalized estimating equations were used to evaluate the association of calendar time and follow-up time with key risk behaviors, after adjustment for potential confounding factors. At enrollment visits by 1,844 women, the adjusted probability of never using condoms decreased over time, from 34.2% to 18.9%. Over 23,911 follow-up visits, the adjusted probabilities of reporting >2 partners decreased from 9.9% to 4.9% and inconsistent condom use decreased from 7.9% to 5.3% after ≥12 cohort visits. Important predictors of risk behavior were work venue, charging low fees for sex, and substance abuse. Women with a later sexual debut had less risky behavior. Although sexual risk has declined among women participating in the Mombasa Cohort, HIV acquisition continues to occur and interventions to promote and reinforce safer sex are clearly needed.
PMCID: PMC4240588  PMID: 25415287
5.  Prevalence and Correlates of Genital Warts in Kenyan Female Sex Workers 
Sexually transmitted diseases  2012;39(11):902-905.
Our goal in the present study was to investigate the prevalence and correlates of genital warts in a population of female sex workers in Mombasa, Kenya. Because of the high prevalence of HIV-1 in this population, we were particularly interested in the association between HIV-1 infection and genital warts.
We conducted a cross-sectional study of the prevalence and correlates of genital warts among high-risk women in Mombasa, Kenya. Between 2001 and 2007, 1182 women were enrolled, of whom 613 (51.4%) were HIV-1-seropositive. Chi square tests and logistic regression were used to examine the associations between genital warts and potential correlates.
Genital warts were identified on clinical examination in 27 (2.3%) women. Women who were HIV-1-seropositive were nearly 8 times as likely to have genital warts compared to HIV-1-seronegative women (OR 7.69, 95% CI 2.30–25.6).
Understanding the prevalence and correlates of genital warts will help to determine whether coverage for the wart-inducing subtypes 6 and 11 in an HPV vaccine is an important consideration in resource-limited countries.
PMCID: PMC3506016  PMID: 23060082
genital warts; human immunodeficiency virus; human papilloma virus; Africa
6.  Association between Cellular Immune Activation, Target Cell Frequency, and Risk of Human Immunodeficiency Virus Type 1 Superinfection 
Journal of Virology  2014;88(10):5894-5899.
We performed a case-control study of women at risk of HIV-1 superinfection to understand the relationship between immune activation and HIV-1 acquisition. An increase in the frequency of HIV-1 target cells, but not in other markers of T cell activation, was associated with a 1.7-fold increase in the odds of superinfection. This suggests that HIV-1 acquisition risk is influenced more by the frequency of target cells than by the generalized level of immune activation.
PMCID: PMC4019101  PMID: 24623424
7.  Developing Content for a mHealth Intervention to Promote Postpartum Retention in Prevention of Mother-To-Child HIV Transmission Programs and Early Infant Diagnosis of HIV: A Qualitative Study 
PLoS ONE  2014;9(9):e106383.
Maternal attendance at postnatal clinic visits and timely diagnosis of infant HIV infection are important steps for prevention of mother-to-child transmission (PMTCT) of HIV. We aimed to use theory-informed methods to develop text messages targeted at facilitating these steps.
We conducted five focus group discussions with health workers and women attending antenatal, postnatal, and PMTCT clinics to explore aspects of women's engagement in postnatal HIV care and infant testing. Discussion topics were informed by constructs of the Health Belief Model (HBM) and prior empirical research. Qualitative data were coded and analyzed according to the construct of the HBM to which they related. Themes were extracted and used to draft intervention messages. We carried out two stages of further messaging development: messages were presented in a follow-up focus group in order to develop optimal phrasing in local languages. We then further refined the messages, pretested them in individual cognitive interviews with selected health workers, and finalized the messages for the intervention.
Findings indicated that brief, personalized, caring, polite, encouraging, and educational text messages would facilitate women bringing their children to clinic after delivery, suggesting that text messages may serve as an important “cue to action.” Participants emphasized that messages should not mention HIV due to fear of HIV testing and disclosure. Participants also noted that text messages could capitalize on women's motivation to attend clinic for childhood immunizations.
Applying a multi-stage content development approach to crafting text messages – informed by behavioral theory – resulted in message content that was consistent across different focus groups. This approach could help answer “why” and “how” text messaging may be a useful tool to support maternal and child health. We are evaluating the effect of these messages on improving postpartum PMTCT retention and infant HIV testing in a randomized trial.
PMCID: PMC4152282  PMID: 25181408
8.  High HIV seroprevalence, rectal STIs and risky sexual behaviour in men who have sex with men in Dar es Salaam and Tanga, Tanzania 
BMJ Open  2014;4(8):e006175.
To assess HIV and sexually transmitted infection (STI) prevalence and associated risk factors in men who have sex with men (MSM) in two cities in mainland Tanzania.
We conducted respondent-driven sampling of 300 MSM in Dar es Salaam and Tanga.
In Dar es Salaam, 172 (86%) men (median age 23, IQR 21–28) consented to HIV/STI testing, and 30.2% were HIV seropositive. Only five reported a previous positive HIV test: >90% were new HIV detections. 2.5% were syphilis-exposed and none hepatitis B positive, but 21.4% had a curable STI. Over 90% of the gonorrhoea and chlamydia was rectal. In Tanga, 11.1% of MSM were HIV seropositive, 8% hepatitis B positive and 0% were syphilis-exposed, with 4.4% having a curable STI. Predictors of HIV infection were number of MSM known, city, identifying as gay and having first sex with a man. Predictors for STIs were recent unprotected receptive anal intercourse, and number of MSM seen in the last month. 30% of the sample reported that they sold sex. There was no significant association between HIV and STI infection.
HIV and STI rates were substantially lower in MSM in a provincial city than in a large metropolis and rates appear to depend on larger numbers of MSM known. Most HIV detected were new cases, and there was a high burden of asymptomatic curable rectal STIs (>1 in 5 MSM). Owing to stigma, MSM may not report homosexuality and thus not have rectal STIs treated. High need for tailored HIV testing and STI screening and treatment of MSM in Tanzania is apparent.
PMCID: PMC4156794  PMID: 25168042
Sexually transmitted Infections; Men who have sex with men; Africa
9.  Endothelial Activation Biomarkers Increase after HIV-1 Acquisition: Plasma VCAM-1 Predicts Disease Progression 
AIDS (London, England)  2013;27(11):10.1097/QAD.0b013e328360e9fb.
We aimed to determine whether endothelial activation biomarkers increase after HIV-1 acquisition, and whether biomarker levels measured in chronic infection would predict disease progression and death in HIV-1 seroconverters.
HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition.
Plasma levels of angiopoietins-1 and -2 (ANG-1, ANG-2) and soluble vascular cell adhesion marker-1 (VCAM-1), intercellular adhesion marker-1 (ICAM-1), and E-selectin were tested in stored samples from before infection, acute infection, and at two points during chronic infection. We used non-parametric tests to compare biomarkers before and after HIV-1 acquisition, and Cox proportional-hazards regression to analyze associations with disease progression (CD4 <200 cells/μL, Stage IV disease, or ART initiation) or death.
Soluble ICAM-1 and VCAM-1 were elevated relative to baseline in all post-infection periods assessed (p<0.0001). Soluble E-selectin and the ANG-2:ANG-1 ratio increased in acute infection (p=0.0001), and ANG-1 decreased in chronic infection (p=0.0004). Among 228 subjects followed over 1,028 person-years, 115 experienced disease progression or death. Plasma VCAM-1 levels measured during chronic infection were independently associated with time to HIV progression or death (aHR 5.36, 95% confidence interval 1.99–14.44 per log10 increase), after adjustment for set point plasma viral load, age at infection, and soluble ICAM-1 levels.
HIV-1 acquisition was associated with endothelial activation, with sustained elevations of soluble ICAM-1 and VCAM-1 post-infection. Soluble VCAM-1 may be an informative biomarker for predicting the risk of HIV-1 disease progression, morbidity, and mortality.
PMCID: PMC3883757  PMID: 23807276
HIV-1; VCAM-1; ICAM-1; angiopoietin-1; angiopoietin-2; E-selectin; endothelial activation
10.  A prospective cohort study comparing the effect of single-dose 2g metronidazole on Trichomonas vaginalis infection in HIV-seropositive versus HIV-seronegative women 
Sexually transmitted diseases  2013;40(6):499-505.
This analysis compared the frequency of persistent Trichomonas vaginalis (TV) among HIV-seropositive and HIV-seronegative women.
Data were obtained from women enrolled in an open cohort study of sex workers in Kenya. Participants were examined monthly, and those diagnosed with TV by saline microscopy were treated with single-dose 2g oral metronidazole. All women on antiretroviral therapy (ART) used nevirapine-based regimens. Generalized estimating equations with a logit link were used to compare the frequency of persistent TV (defined as the presence of motile trichomonads by saline microscopy at the next exam visit within 60 days) by HIV status.
Three-hundred and sixty participants contributed 570 infections to the analysis (282 HIV-seropositive and 288 HIV-seronegative). There were 42 (15%) persistent infections among HIV-seropositive participants versus 35 (12%) among HIV-seronegative participants (adjusted odds ratio [aOR]=1.14; 95% confidence interval [CI] (0.70, 1.87)). Persistent TV was highest among HIV-seropositive women using ART (21/64 [33%]) compared to HIV-seropositive women not using ART (21/217 [10%]). Concurrent bacterial vaginosis (BV) at TV diagnosis was associated with an increased likelihood of persistent TV (aOR=1.90; 95% CI 1.16, 3.09).
The frequency of persistent TV infection following treatment with single-dose 2g oral metronidazole was similar by HIV status. Alternative regimens, including multi-day antibiotic treatment, may be necessary to improve cure rates for women using nevirapine-based ART and women with TV and concurrent BV.
PMCID: PMC3676301  PMID: 23677023
Trichomonas vaginalis; metronidazole; efficacy; persistence; HIV infection; nevirapine; antiretroviral therapy
11.  Association between Participant Self-Report and Biological Outcomes Used to Measure Sexual Risk Behavior in HIV-1-Seropositive Female Sex Workers in Mombasa, Kenya 
Sexually transmitted diseases  2011;38(5):429-433.
Few studies have examined the association between self-reported sexual risk behaviors and biological outcomes in HIV-1-seropositive African adults.
We conducted a prospective cohort study in 898 HIV-1-seropositive women who reported engaging in transactional sex in Mombasa, Kenya. Primary outcome measures included detection of sperm in genital secretions, pregnancy, and sexually transmitted infections (STIs). Because three outcomes were evaluated, data are presented with odds ratios [OR] and 96.7% confidence intervals [CI] to reflect that we would reject a null hypothesis if a p-value were ≤0.033 (Simes’ methodology).
During 2,404 person-years of follow-up, self-reported unprotected intercourse was associated with significantly higher likelihood of detecting sperm in genital secretions (OR 2.32, 96.7% CI 1.93, 2.81), and pregnancy (OR 2.78, 96.7% CI 1.57, 4.92), but not with detection of STIs (OR 1.20, 96.7% CI 0.98, 1.48). At visits where women reported being sexually active, having >1 sex partner in the past week was associated with lower likelihood of detecting sperm in genital secretions (OR 0.74, 96.7% CI 0.56, 0.98). This association became non-significant after adjustment for reported condom use (adjusted OR 0.81, 96.7% CI 0.60, 1.08).
Combining behavioral and biological outcomes, which provide complementary information, is advantageous for understanding sexual risk behavior in populations at risk for transmitting HIV-1. The paradoxical relationship between higher numbers of sex partners and less frequent identification of sperm in genital secretions highlights the potential importance of context-specific behavior, such as condom use dependent on partner type, when evaluating sexual risk behavior.
PMCID: PMC3155001  PMID: 21217420
HIV-1; sexually transmitted disease; women; Africa; sexual risk behavior
12.  Antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity does not correlate with risk of HIV-1 superinfection 
Previous studies of HIV-infected women with high risk behavior have indicated that neither neutralizing antibody nor cellular immunity elicited by an initial HIV-1 infection is associated with protection against superinfection with a different HIV-1 strain. Here, we measured antibody-dependent cell-mediated virus inhibition (ADCVI) antibody activity in the plasma of 12 superinfected cases and 36 singly infected matched controls against 2 heterologous viruses. We found no association between plasma ADCVI activity and superinfection status. ADCVI antibody activity against heterologous virus elicited by the original infection may not contribute to preventing a superinfecting HIV-1.
PMCID: PMC3625514  PMID: 23344546
antibody-dependent cell-mediated virus inhibition; ADCVI; HIV-1; superinfection; primary infection; clade A
13.  Incidence and Correlates of Chlamydia trachomatis Infection in a High Risk Cohort of Kenyan Women 
Sexually transmitted diseases  2013;40(3):10.1097/OLQ.0b013e318272fe45.
In Africa, data on Chlamydia trachomatis infection are scarce because reliable diagnosis is costly and not widely available. Our objective was to evaluate the incidence and correlates of C. trachomatis infection among high-risk Kenyan women.
We conducted prospective cohort analyses using data from a cohort of women who reported transactional sex. C. trachomatis testing was performed using the Gen-Probe Aptima GC/CT Detection System. We used Andersen-Gill proportional hazards modeling to evaluate correlates of C. trachomatis.
Between August 2006 and December 2010, 865 women contributed 2011 person-years of observation. Sixty-four women experienced 101 episodes of C. trachomatis infection (incidence rate of 5.0/100 person-years). There was a large difference in incidence by age group: those below 25 years had an incidence of 27.6 per 100 person-years (95% CI 16.3 – 46.5), those 25 to 34 years old had an incidence of 8.4 per 100 person-years (95% CI 6.4 – 11.0), and those 35 years old and above had an incidence of 2.6 per 100 person-years (95% CI 1.8 – 3.6). In multivariate analyses, younger age (<25 years and 25–34 years versus ≥35 years; hazard ratio [HR] 8.49 95% CI 4.1–17.7 and HR 2.9 95% CI 1.7–5.0 respectively), depot medroxyprogesterone acetate use (HR 1.8 95% CI 1.1–3.0) and recent Neisseria gonorrhoeae infection (HR 3.3 95% CI 1.5–7.4) were significantly associated with increased risk of acquiring C. trachomatis infection.
The high incidence of C. trachomatis among younger high-risk women suggests the need for screening as an important public health intervention for this population.
PMCID: PMC3831875  PMID: 23407467
Chlamydia trachomatis; incidence; risk factors; women; Africa
14.  Correlates of Inappropriate Prescribing of Antibiotics to Patients with Malaria in Uganda 
PLoS ONE  2014;9(2):e90179.
In many rural areas of Uganda, febrile patients presenting to health facilities are prescribed both antimalarials and antibiotics, contributing to the overuse of antibiotics. We identified the prevalence and correlates of inappropriate antibiotic management of patients with confirmed malaria.
We utilized individual outpatient data from 36 health centers from January to September 2011. We identified patients who were prescribed antibiotics without an appropriate clinical indication, as well as patients who were not prescribed antibiotics when treatment was clinically indicated. Multivariate logistic regression models were used to identify clinical and operational factors associated with inappropriate case management.
Of the 45,591 patients with parasitological diagnosis of malaria, 40,870 (90%) did not have a clinical indication for antibiotic treatment. Within this group, 17,152 (42%) were inappropriately prescribed antibiotics. The odds of inappropriate prescribing were higher if the patient was less than five years old (aOR 1.96, 95% CI 1.75–2.19) and if the health provider had the fewest years of training (aOR 1.86, 95% CI 1.05–3.29). The odds of inappropriate prescribing were lower if patients had emergency triage status (aOR 0.75, 95% CI 0.59–0.96) or were HIV positive (aOR 0.31, 95% CI 0.20–0.45). Of the 4,721 (10%) patients with clinical indications for antibiotic treatment, 521 (11%) were inappropriately not prescribed antibiotics. Clinical officers were less likely than medical officers to inappropriately withhold antibiotics (aOR 0.54, 95% CI 0.29–0.98).
Over 40% of the antibiotic treatment in malaria positive patients is prescribed despite a lack of documented clinical indication. In addition, over 10% of patients with malaria and a clinical indication for antibiotics do not receive them. These findings should inform facility-level trainings and interventions to optimize patient care and slow trends of rising antibiotic resistance.
PMCID: PMC3938663  PMID: 24587264
15.  High HIV-1 incidence, correlates of HIV-1 acquisition, and high viral loads following seroconversion among men who have sex with men in Coastal Kenya 
AIDS (London, England)  2013;27(3):437-446.
HIV-1 incidence estimates and correlates of HIV-1 acquisition in African men who have sex with men are largely unknown.
Since 2005, HIV-1-uninfected men who reported sex with men and women (MSMW) or sex with men exclusively (MSME) were followed at scheduled visits for collection of behavioural and clinical examination data and plasma for HIV-1 testing. Urethral or rectal secretions were collected from symptomatic men to screen for gonorrhoea. Poisson regression methods were used to estimate adjusted incidence rate ratios (aIRR) to explore associations between risk factors and incident HIV-1 infection. Plasma viral loads (PVL) were assessed over two years following seroconversion.
Overall HIV-1 incidence in 449 men was 8.6 (95% confidence interval [CI]: 6.7–11.0) per 100 person-years (py). Incidence was 5.8 (95% CI: 4.2–7.9) per 100 py among MSMW, and 35.2 (95% CI: 23.8–52.1) per 100 py among MSME. Unprotected sex, receptive anal intercourse, exclusive sex with men, group sex, and gonorrhoea in the past 6 months were strongly associated with HIV-1 acquisition, adjusted for confounders. PVL in seroconverters was >4 log10 copies/mL at 230 (73.4%) of 313 visits in MSMW and 153 (75.0%) of 204 visits in MSME.
HIV-1 incidence is very high among MSM in coastal Kenya, and many seroconverters maintain high PVL for up to two years after infection. Effective HIV-1 prevention interventions, including treatment as prevention, are urgently needed in this population.
PMCID: PMC3929859  PMID: 23079811
HIV-1 incidence; MSM; gonorrhoea; anal intercourse; viral load; sexually transmitted infection; group sex; Africa
16.  Treatment with Antiretroviral Therapy is Not Associated with Increased Sexual Risk Behaviour in Kenyan Female Sex Workers 
AIDS (London, England)  2010;24(6):891-897.
The objective of this study was to test the hypothesis that sexual risk behaviour would increase following initiation of antiretroviral therapy (ART) in Kenyan female sex workers (FSWs).
Prospective cohort study.
FSW cohort in Mombasa, Kenya, 1993-2008.
898 women contributed HIV-1-seropositive follow-up visits, of whom 129 initiated ART.
Beginning in March 2004, ART was provided to women qualifying for treatment according to Kenyan National Guidelines. Participants received sexual risk reduction education and free condoms at every visit.
Main Outcome Measures
Main outcome measures included unprotected intercourse, abstinence, 100% condom use, number of sexual partners, and frequency of sex. Outcomes were evaluated at monthly follow-up visits using a one week recall interval.
Compared to non-ART-exposed follow-up, visits following ART initiation were not associated with an increase in unprotected sex (adjusted odds ratio [AOR] 0.86, 95% confidence interval [CI] 0.62-1.19, P=0.4). There was a non-significant decrease in abstinence (AOR 0.81, 95% CI 0.65-1.01, P=0.07), which was offset by a substantial increase in 100% condom use (AOR 1.54, 95% CI 1.07-2.20, P=0.02). Numbers of sex partners and frequency of sex were similar before versus after starting ART. A trend for decreased sexually transmitted infections following ART initiation provides additional support for the validity of the self-reported behavioural outcomes (AOR 0.67, 95% CI 0.44-1.02, P=0.06).
In the setting of ongoing risk reduction education and provision of free condoms, initiation of ART was not associated with increased sexual risk behaviour in this cohort of Kenyan FSWs.
PMCID: PMC2853894  PMID: 20179576
Antiretroviral therapy; sexual risk behaviour; human immunodeficiency virus type 1; sexually transmitted infection; Africa
17.  Genital Inflammation Predicts HIV-1 Shedding Independent of Plasma Viral Load and Systemic Inflammation 
In women, genital HIV-1 RNA levels predict the risk of HIV-1 transmission independent of plasma viral load. To better understand the factors that contribute to genital HIV-1 shedding, we evaluated the relationships between genital and plasma cytokine concentrations and HIV-1 RNA levels. Vaginal, but not plasma, levels of interferon gamma-induced protein 10 (IP-10) were significantly associated with vaginal viral load, independent of plasma viral load. Thus, efforts to decrease HIV-1 transmission must take into account the role of local inflammation, which is not necessarily reflected in plasma measurements.
PMCID: PMC3494808  PMID: 22878424
HIV-1; inflammation; cytokine; genital; shedding; transmission
18.  A Prospective Study of Vaginal Bacterial Flora and Other Risk Factors for Vulvovaginal Candidiasis 
The Journal of infectious diseases  2009;199(12):1883-1890.
It has been suggested that vaginal lactobacilli may reduce the risk of vulvovaginal candidiasis (VVC), but supporting data are limited. Our objective was to determine the relationship between vaginal bacterial flora and VVC.
We conducted a prospective cohort analysis among 151 Kenyan sex workers. At monthly follow-up, VVC was defined as the presence of yeast buds, pseudohyphae, or both on vaginal wet preparation or KOH preparation. Generalized estimating equations were used to identify correlates of VVC.
Participants returned for a median of 12 (interquartile range 11-12) visits. Vulvovaginal candidiasis was present at 162 visits, including 26 with symptomatic VVC. Bacterial vaginosis (BV) was associated with fewer episodes of VVC (adjusted odds ratio [aOR] 0.29, 95% confidence interval [CI] 0.16-0.50). After excluding women with concurrent BV, another possible cause of vaginal symptoms, the likelihood of symptomatic VVC was higher in those with yeast on vaginal wet preparation in the past 60 days (aOR 4.06, 95% CI 1.12-14.74) and those with concurrent vaginal Lactobacillus colonization (aOR 3.75, 95% CI 1.30-10.83).
Contrary to a commonly posed hypothesis of a protective effect, we found that vaginal Lactobacillus colonization was associated with a >4-fold increase in the likelihood of symptomatic VVC.
PMCID: PMC2743896  PMID: 19456235
Vulvovaginal candidiasis; Lactobacillus; bacterial vaginosis; women
19.  HIV-1 Superinfection Occurs Less Frequently Than Initial Infection in a Cohort of High-Risk Kenyan Women 
PLoS Pathogens  2013;9(8):e1003593.
HIV superinfection (reinfection) has been reported in several settings, but no study has been designed and powered to rigorously compare its incidence to that of initial infection. Determining whether HIV infection reduces the risk of superinfection is critical to understanding whether an immune response to natural HIV infection is protective. This study compares the incidence of initial infection and superinfection in a prospective seroincident cohort of high-risk women in Mombasa, Kenya. A next-generation sequencing-based pipeline was developed to screen 129 women for superinfection. Longitudinal plasma samples at <6 months, >2 years and one intervening time after initial HIV infection were analyzed. Amplicons in three genome regions were sequenced and a median of 901 sequences obtained per gene per timepoint. Phylogenetic evidence of polyphyly, confirmed by pairwise distance analysis, defined superinfection. Superinfection timing was determined by sequencing virus from intervening timepoints. These data were combined with published data from 17 additional women in the same cohort, totaling 146 women screened. Twenty-one cases of superinfection were identified for an estimated incidence rate of 2.61 per 100 person-years (pys). The incidence rate of initial infection among 1910 women in the same cohort was 5.75 per 100pys. Andersen-Gill proportional hazards models were used to compare incidences, adjusting for covariates known to influence HIV susceptibility in this cohort. Superinfection incidence was significantly lower than initial infection incidence, with a hazard ratio of 0.47 (CI 0.29–0.75, p = 0.0019). This lower incidence of superinfection was only observed >6 months after initial infection. This is the first adequately powered study to report that HIV infection reduces the risk of reinfection, raising the possibility that immune responses to natural infection are partially protective. The observation that superinfection risk changes with time implies a window of protection that coincides with the maturation of HIV-specific immunity.
Author Summary
HIV-infected individuals with continued exposure are at risk of acquiring a second infection, a process known as superinfection. Superinfection has been reported in various at-risk populations, but how frequently it occurs remains unclear. Determining the frequency of superinfection compared with initial infection can help clarify whether the immune response developed against HIV can protect from reinfection – critical information for understanding whether such responses should guide HIV vaccine design. In this study, we developed a sensitive high-throughput method to identify superinfection and used this to conduct a screen for superinfection in 146 women in a high-risk cohort. This enabled us to determine if first HIV infection affects the risk of second infection by comparing the incidence of superinfection in this group to the incidence of initial infection in 1910 women in the larger cohort. We found that the incidence of superinfection was approximately half that of initial infection after controlling for behavioral and clinical differences that might affect infection risk. These results suggest that the immune response elicited in natural HIV infection may provide partial protection against subsequent infection and indicate the setting of superinfection may shed light on the features of a protective immune response and inform vaccine design.
PMCID: PMC3757054  PMID: 24009513
20.  Antiretroviral Treatment Interruptions Predict Female Genital Shedding of Genotypically Resistant HIV-1 RNA 
Resistant viruses may emerge in the female genital tract during antiretroviral therapy (ART). Our objective was to identify predictors of drug-resistant HIV-1 RNA in genital secretions after initiation of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy.
We conducted a prospective cohort study with periodic evaluation of plasma and genital swab samples for HIV-1 RNA levels and antiretroviral resistance mutations.
First-line ART was initiated in 102 women. Plasma and genital HIV-1 RNA levels were measured at months 0, 3, 6, and 12. Genotypic resistance testing was performed for samples from all participants with RNA >1,000 copies/mL at month 6 or 12. Cox regression analysis was used to identify factors associated with incident genital tract resistance.
Detectable genital tract resistance developed in 5 women, all with detectable plasma resistance (estimated incidence, 5.5/100 person-years of observation). Treatment interruption >48 hours, adherence by pill count, adherence by visual analog scale, and baseline plasma viral load were associated with incident genital tract resistance. In multivariate analysis, only treatment interruption was associated with risk of detectable genital tract resistance (adjusted hazard ratio 14.2, 95% CI 1.3–158.4).
Treatment interruption >48 hours during NNRTI-based therapy led to a significantly increased risk of detecting genotypically resistant HIV-1 RNA in female genital tract secretions. Patient- and program-level interventions to prevent treatment interruptions could reduce the risk of shedding resistant HIV-1 during ART.
PMCID: PMC3404237  PMID: 22592588
HIV drug resistance; virus shedding; female; antiretroviral therapy; adherence
21.  A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy 
BMC Infectious Diseases  2013;13:263.
HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2.
Antiretroviral-naïve Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality.
The 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/μL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47–5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35–2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation.
Biomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection.
PMCID: PMC3679794  PMID: 23734875
HIV-1; HAART; ICAM-1; VCAM-1; E-selectin; Angiopoietin-1; Angiopoietin-2; Endothelium
22.  The post-trial effect of oral periodic presumptive treatment for vaginal infections on the incidence of bacterial vaginosis and Lactobacillus colonization 
Sexually Transmitted Diseases  2012;39(5):361-365.
We previously demonstrated a decrease in bacterial vaginosis (BV) and an increase in Lactobacillus colonization among randomized controlled trial (RCT) participants who received monthly oral periodic presumptive treatment (PPT) [2g metronidazole + 150mg fluconazole]. Post-trial data were analyzed to test the hypothesis that the treatment effect would persist following completion of one year of PPT.
Data were obtained from women who completed all 12 RCT visits and attended ≥1 post-trial visit within 120 days following completion of the RCT. We used Andersen-Gill proportional hazards models to estimate the post-trial effect of the intervention on the incidence of BV by Gram stain and detection of Lactobacillus species by culture.
The analysis included 165 subjects (83 active and 82 placebo). The post-trial incidence of BV was 260 per 100 person-years in the intervention arm versus 358 per 100 person-years in the placebo arm (hazard ratio [HR]=0.76; 95% confidence interval [CI]: 0.51–1.12). The post-trial incidence of Lactobacillus colonization was 180 per 100 person-years in the intervention arm versus 127 per 100 person-years in the placebo arm (HR=1.42; 95% CI: 0.85–2.71).
Despite a decrease in BV and an increase in Lactobacillus colonization during the RCT, the effect of PPT was not sustained at the same level following cessation of the intervention. New interventions that reduce BV recurrence and promote Lactobacillus colonization without the need for ongoing treatment are needed.
PMCID: PMC3335440  PMID: 22504600
Bacterial vaginosis; Lactobacillus; periodic presumptive treatment; suppressive treatment
23.  Prevalence, Clinical and Virologic Outcomes of Hepatitis B Virus Co-Infection in HIV-1 Positive Kenyan Women on Antiretroviral Therapy 
PLoS ONE  2013;8(3):e59346.
Sub-Saharan Africa carries a high burden of co-infection with HIV-1 and hepatitis B virus (HBV). In this region, individuals with HIV-1/HBV co-infection on antiretroviral therapy (ART) frequently receive lamivudine as the only agent active against HBV, raising concerns for development of HBV resistance to lamivudine. We aimed to determine the prevalence, clinical, and virologic outcomes of chronic HBV infection, including HBV resistance to lamivudine, in a cohort of HIV-1 seropositive Kenyan women on long-term ART.
In this prospective cohort study, HIV-1 seropositive women initiated three-drug ART regimens that included lamivudine as the single drug active against HBV. Archived samples were tested for HBsAg, with further testing to determine HBeAg seroprevalence, HBV DNA suppression, and lamivudine resistance. We estimated the prevalence of chronic HBV and examined associations between HBV co-infection and clinical and virologic outcomes with chi-square tests, logistic regression, Kaplan-Meier and Cox regression.
In a cohort of 159 women followed for a median of 3.4 years (interquartile range 1.4–4.5), 11 (6.9%; 95% CI 3.1–10.7) had chronic HBV infection. Of these, 9 (82%) achieved undetectable plasma HBV DNA levels. One woman developed lamivudine resistance, for an incidence of 3 per 100 person-years. The HBV co-infected women were at greater risk for abnormal ALT elevations compared to HIV-1 mono-infected women (HR 2.37; 95% CI 1.1–5.3). There were no differences between HBV-infected and uninfected women in mortality, CD4 count, or HIV-1 RNA suppression.
The prevalence of chronic HBV in this cohort was similar to recent studies from other African populations. Given our long-term follow-up, lamivudine resistance was lower than expected for HIV-1/HBV co-infected patients. Improved screening for HBV and extended follow-up of HIV-1/HBV co-infected individuals are needed to better understand the impact of different ART regimens on clinical outcomes in this population.
PMCID: PMC3601052  PMID: 23527168
24.  Cellular Immune Responses and Susceptibility to HIV-1 Superinfection: A Case-Control Study 
AIDS (London, England)  2012;26(5):643-646.
A case control study was performed to determine the effects of HIV-1-specific cellular immune responses on the odds of acquiring a second HIV-1 infection (superinfection). Changes in the frequency of cytokine-producing or cytolytic CD8+ or CD4+ T cells were not associated with significant alterations in the odds of superinfection, suggesting that HIV-1 specific cellular immune responses at the level induced by chronic infection do not appear to significantly contribute to protection from HIV-1 superinfection.
PMCID: PMC3511787  PMID: 22210637
HIV-1; cellular immunity; T cells; superinfection; re-infection
25.  Loss to Follow-Up as a Competing Risk in an Observational Study of HIV-1 Incidence 
PLoS ONE  2013;8(3):e59480.
Conventional survival estimates may be biased if loss to follow-up (LTF) is associated with the outcome of interest. Our goal was to assess whether the association between sexual risk behavior and HIV-1 acquisition changed after accounting for LTF with competing risks regression.
HIV-1-seronegative women who enrolled in a Kenyan sex worker cohort from 1993–2007 were followed prospectively and tested for HIV at monthly clinic visits. Our primary predictor was self-reported sexual risk behavior in the past week, analyzed as a time-dependent covariate. Outcomes included HIV-1 acquisition and LTF. We analyzed the data using Cox proportional hazards regression and competing risks regression, in which LTF was treated as a competing event.
A total of 1,513 women contributed 4,150 person-years (py), during which 198 (13.1%) acquired HIV-1 infection (incidence, 4.5 per 100 py) and 969 (64.0%) were LTF (incidence, 23.4 per 100 py). After adjusting for potential confounders, women reporting unprotected sex with multiple partners were less likely to be lost to follow-up (adjusted sub-hazard ratio (aSHR) 0.50, 95% confidence interval (CI) 0.32–0.76, relative to no sexual activity). The risk of HIV-1 acquisition after reporting unprotected sex with multiple partners was similar with Cox regression (adjusted hazard ratio (aHR) 2.41, 95% CI 1.36–4.27) and competing risks regression (aSHR 2.47, 95% CI 1.33–4.58).
Unprotected sex with multiple partners was associated with higher HIV-1 acquisition risk, but lower attrition. This differential attrition did not substantially bias Cox regression estimates when compared to competing risks regression results.
PMCID: PMC3595247  PMID: 23555041

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