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1.  A Prospective Cohort Study of the Effect of Depot Medroxyprogesterone Acetate on Detection of Plasma and Cervical HIV-1 in Women Initiating and Continuing Antiretroviral Therapy 
Depot medroxyprogesterone acetate (DMPA) use among HIV-1 infected women may increase transmission by increasing plasma and genital HIV-1 RNA shedding. We investigated associations between DMPA use and HIV-1 RNA in plasma and cervical secretions. 102 women initiated ART, contributing 925 follow-up visits over a median of 34 months. Compared to visits with no hormonal contraception exposure, DMPA exposure did not increase detection of plasma (adjusted odds ratio (AOR) 0.81, 95% CI 0.47–1.39) or cervical HIV-1 RNA (AOR 1.41, 95% CI 0.54–3.67). Our results suggest that DMPA is unlikely to increase infectivity in HIV-positive women who are adherent to effective ART.
doi:10.1097/QAI.0000000000000187
PMCID: PMC4419746  PMID: 24798764
hormonal contraception; HIV-1; antiretroviral therapy; DMPA
3.  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.
Background
Vaginal infections are common and have been associated with increased HIV-1 risk.
Methods
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 (ClinicalTrials.gov, NCT00170430).
Results
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.
Conclusions
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.
doi:10.1086/587490
PMCID: PMC4122228  PMID: 18444793
Bacterial vaginosis; vaginal candidiasis; Trichomonas vaginalis; Lactobacillus; HIV-1; randomized trial; women; Africa
4.  A Prospective Study of Risk Factors for Bacterial Vaginosis in HIV-1-Seronegative African Women 
Sexually transmitted diseases  2008;35(6):617-623.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/OLQ.0b013e31816907fa
PMCID: PMC3902781  PMID: 18418290
Bacterial vaginosis; vaginal washing; intravaginal practices; women; Africa
5.  HIV-1 superinfection is associated with accelerated viral load increase but has limited impact on disease progression 
AIDS (London, England)  2014;28(15):2281-2286.
Objective
HIV-1 superinfection occurs frequently in high-risk populations, but its clinical consequences remain poorly characterized. We undertook this study to determine the impact of HIV-1 superinfection on disease progression.
Design/methods
In the largest prospective cohort study of superinfection to date, we compared measures of HIV-1 progression in women who acquired superinfection with those who did not. Clinical and laboratory data were collected at quarterly intervals. Linear mixed effects models were used to compare post-acute viral load and CD4 T-cell counts over time in singly infected and superinfected women. Cox proportional hazards analysis was used to determine the effect of superinfection on time to clinical progression (CD4 < 200, ART initiation or death).
Results
Among 144 women, 21 of whom acquired superinfection during follow-up, the rate of viral load increase was higher in superinfected than singly infected women (p=0.0008). In adjusted analysis, superinfected women had lower baseline viral load before superinfection (p=0.05) and a trend for increased viral load at superinfection acquisition (p=0.09). We also observed a borderline association of superinfection with accelerated CD4 decline (p=0.06). However, there was no significant difference in time to clinical progression events.
Conclusions
These data suggest that superinfection is associated with accelerated progression in laboratory measures of HIV-1 disease, but has limited impact on the occurrence of clinical events. Our observation that superinfected individuals have lower baseline viral load prior to superinfection suggests there may be host or viral determinants of susceptibility to superinfection.
doi:10.1097/QAD.0000000000000422
PMCID: PMC4503239  PMID: 25102090
HIV-1; women; superinfection; progression; pathogenesis
6.  The Broad Neutralizing Antibody Responses after HIV-1 Superinfection Are Not Dominated by Antibodies Directed to Epitopes Common in Single Infection 
PLoS Pathogens  2015;11(7):e1004973.
HIV-1 vaccines designed to date have failed to elicit neutralizing antibodies (Nabs) that are capable of protecting against globally diverse HIV-1 subtypes. One relevant setting to study the development of a strong, cross-reactive Nab response is HIV-1 superinfection (SI), defined as sequential infections from different source partners. SI has previously been shown to lead to a broader and more potent Nab response when compared to single infection, but it is unclear whether SI also impacts epitope specificity and if the epitopes targeted after SI differ from those targeted after single infection. Here the post-SI Nab responses were examined from 21 Kenyan women collectively exposed to subtypes A, C, and D and superinfected after a median time of ~1.07 years following initial infection. Plasma samples chosen for analysis were collected at a median time point ~2.72 years post-SI. Because previous studies of singly infected populations with broad and potent Nab responses have shown that the majority of their neutralizing activity can be mapped to 4 main epitopes on the HIV-1 Envelope, we focused on these targets, which include the CD4-binding site, a V1/V2 glycan, the N332 supersite in V3, and the membrane proximal external region of gp41. Using standard epitope mapping techniques that were applied to the previous cohorts, the present study demonstrates that SI did not induce a dominant Nab response to any one of these epitopes in the 21 women. Computational sera delineation analyses also suggested that 20 of the 21 superinfected women’s Nab responses could not be ascribed a single specificity with high confidence. These data are consistent with a model in which SI with diverse subtypes promotes the development of a broad polyclonal Nab response, and thus would provide support for vaccine designs using multivalent HIV immunogens to elicit a diverse repertoire of Nabs.
Author Summary
Learning how to elicit a potent, cross-reactive neutralizing antibody (Nab) response capable of protecting against globally diverse human immunodeficiency virus-1 (HIV-1) subtypes is critical to the development of an HIV-1 vaccine. We and others have previously shown that HIV-1 superinfection (SI), or sequential infections from different partners, broadens and strengthens the Nab response. However, until now it was unclear whether SI also impacts the specificity, or epitope targets, of the antibody response. Previous studies have shown that the majority of singly infected individuals with broad and potent responses develop Nabs to 4 main epitopes on the HIV-1 Envelope. In contrast, here we show that none of the 21 SI cases in our Kenyan cohort developed Nabs that strongly target these epitopes. Our study helps to inform vaccine design by highlighting the prospect of eliciting broad and diverse HIV-specific Nab responses through sequential exposure to different HIV antigens.
doi:10.1371/journal.ppat.1004973
PMCID: PMC4497680  PMID: 26158467
7.  Association between alcohol use and sexually transmitted infection incidence among Kenyan women engaged in transactional sex 
AIDS and behavior  2014;18(7):1324-1329.
Few prospective studies have evaluated the association between alcohol use and STI acquisition among African women. We examined the association between baseline drinking frequency and STIs in a cohort of Kenyan women reporting transactional sex. The association between alcohol use and STI differed significantly by HIV status. Among 139 HIV-positive women, STI acquisition was significantly associated with consuming 1-7 drinks/week and marginally associated with ≥8 drinks/week in unadjusted analyses. However, no association between alcohol use and STIs was observed among 335 HIV-negative women. Addressing alcohol use within comprehensive HIV care may also reduce the burden of STIs among high-risk women.
doi:10.1007/s10461-013-0648-0
PMCID: PMC4007393  PMID: 24179037
alcohol use; STI; African women; prospective
8.  Prevalence and Correlates of Genital Warts in Kenyan Female Sex Workers 
Sexually transmitted diseases  2012;39(11):902-905.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1097/OLQ.0b013e318275ec7f
PMCID: PMC3506016  PMID: 23060082
genital warts; human immunodeficiency virus; human papilloma virus; Africa
9.  Systemic Cytokine Levels Show Limited Correlation with Risk of HIV-1 Acquisition 
It has been hypothesized that immune activation and inflammation may increase HIV-1 susceptibility and that cytokines may be useful biomarkers for risk. Within a prospective cohort, we conducted a nested case-control analysis of plasma cytokine levels among women who acquired HIV-1 <3 months after sampling, compared to three different control groups. We observed associations between lower IL-6 and IL-10 and higher IL-7 levels with HIV-1 acquisition, however these associations were inconsistent when comparing to different control groups. Inconsistent results within our study and among prior studies suggest that reproducible findings are needed before cytokines are useful biomarkers for HIV-1 susceptibility.
doi:10.1097/QAI.0000000000000104
PMCID: PMC4020985  PMID: 24413043
cytokines; HIV; acquisition; susceptibility; immune activation
10.  Cytochrome P450 2B6 genetic variants are associated with plasma nevirapine levels and clinical response in HIV-1 infected Kenyan women: a prospective cohort study 
Background
Polymorphisms in cytochrome P450 2B6 (CYP2B6) affect the steady state plasma concentration of nevirapine. CYP2B6 516G>T and 983T>C are common in African populations, but data on their influence on plasma nevirapine concentration and clinical response in African women are limited. We investigated the impact of CYP 516G>T and 983T>C on plasma nevirapine concentration and clinical outcomes in a prospective cohort study of HIV-infected Kenyan women.
Methods
Study subjects were 66 HIV-1-seropositive women taking nevirapine-based antiretroviral therapy. Plasma collected at week 12 was analyzed for nevirapine concentration by high performance liquid chromatography. Baseline samples were genotyped for CYP2B6 516G>T and 983T>C single nucleotide polymorphisms by real-time polymerase chain reaction. CD4 cell count, plasma viral load, and genotypic drug resistance in plasma and genital secretions were assessed at baseline and during follow up. We evaluated the effect of each genotype on plasma nevirapine concentration at week 12 and on change in CD4 cell count at months 3, 6 and 12. Associations between plasma nevirapine concentration and clinical outcomes were analyzed by logistic or linear regression.
Results
Women with CYP2B6 516TT genotype (n=9) had higher mean nevirapine plasma levels (14.33 μg/mL) compared to those with heterozygous 516GT (9.18 μg/mL; n=25) and wild- type 516GG (7.95 μg/mL; n=32) genotypes (P=0.01). Women heterozygous for the CYP2B6 983TC genotype (n=13) had higher mean nevirapine plasma levels (12.94 μg/mL), compared to women with the homozygous 983TT (8.35 μg/mL; n=53) genotype (P=0.007). In Generalized Estimating Equation analysis, plasma nevirapine levels predicted greater change in CD4 cell count after ART initiation (adjusted beta 119.4 cells/μL, 95% CI, 27.3–211.5 cells/μL, P=0.01). The CYP2B6 983TT genotype also predicted greater change in CD4 cell count (adjusted beta 68.6 cells/μL, 95% CI, 3.9–133.4 cells/μL, P=0.04). We found no associations between CYP2B6 genotypes and virologic response or toxicity.
Conclusions
CYP2B6 516G>T and CYP2B6 983T>C genotypes were strongly associated with plasma nevirapine concentration, which predicted immunologic response in women on nevirapine-based antiretroviral therapy. These data support continued work on the potential utility of human genetic testing to inform nevirapine dosage optimization for individual patients.
doi:10.1186/s12981-015-0052-0
PMCID: PMC4397818  PMID: 25878720
CYP2B6; Pharmacogenetics; Nevirapine; HIV infection; Antiretroviral therapy; Women
11.  Incident Herpes Simplex Virus Type 2 Infection Increases the Risk of Subsequent Episodes of Bacterial Vaginosis 
The Journal of Infectious Diseases  2013;209(7):1023-1027.
Herpes simplex virus type 2 (HSV-2) infected women have a higher prevalence of bacterial vaginosis (BV) compared to HSV-2-seronegative women. To explore the temporal association between these conditions, we evaluated the frequency of BV episodes before and after HSV-2 acquisition in a prospective study of 406 HSV-2/HIV-1-seronegative Kenyan women, of whom 164 acquired HSV-2. Incident HSV-2 was associated with increased likelihood of BV (adjusted OR, 1.28; 95% CI, 1.05–1.56; P = .01). Our findings strengthen the evidence for a causal link between genital HSV-2 infection and disruption of the vaginal microbiota.
doi:10.1093/infdis/jit634
PMCID: PMC3952675  PMID: 24273042
Bacterial vaginosis; herpes simplex virus type 2; women; Africa
12.  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.
Background
Few studies have examined the association between self-reported sexual risk behaviors and biological outcomes in HIV-1-seropositive African adults.
Methods
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).
Results
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).
Conclusions
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.
doi:10.1097/OLQ.0b013e31820369f6
PMCID: PMC3155001  PMID: 21217420
HIV-1; sexually transmitted disease; women; Africa; sexual risk behavior
13.  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.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001778.
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
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
14.  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.
doi:10.1371/journal.pone.0113543
PMCID: PMC4240588  PMID: 25415287
15.  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.
doi:10.1128/JVI.00187-14
PMCID: PMC4019101  PMID: 24623424
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.
Objective
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).
Design
Prospective cohort study.
Setting
FSW cohort in Mombasa, Kenya, 1993-2008.
Subjects
898 women contributed HIV-1-seropositive follow-up visits, of whom 129 initiated ART.
Intervention
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.
Results
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).
Conclusions
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.
doi:10.1097/QAD.0b013e32833616c7
PMCID: PMC2853894  PMID: 20179576
Antiretroviral therapy; sexual risk behaviour; human immunodeficiency virus type 1; sexually transmitted infection; Africa
17.  A Prospective Study of Vaginal Bacterial Flora and Other Risk Factors for Vulvovaginal Candidiasis 
The Journal of infectious diseases  2009;199(12):1883-1890.
Background:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
doi:10.1086/599213
PMCID: PMC2743896  PMID: 19456235
Vulvovaginal candidiasis; Lactobacillus; bacterial vaginosis; women
18.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0106383
PMCID: PMC4152282  PMID: 25181408
19.  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.
Objectives
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.
Methods
We conducted respondent-driven sampling of 300 MSM in Dar es Salaam and Tanga.
Results
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.
Conclusions
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.
doi:10.1136/bmjopen-2014-006175
PMCID: PMC4156794  PMID: 25168042
Sexually transmitted Infections; Men who have sex with men; Africa
20.  Endothelial Activation Biomarkers Increase after HIV-1 Acquisition: Plasma VCAM-1 Predicts Disease Progression 
AIDS (London, England)  2013;27(11):10.1097/QAD.0b013e328360e9fb.
Objective
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.
Design
HIV-1-seronegative Kenyan women were monitored monthly for seroconversion, and followed prospectively after HIV-1 acquisition.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAD.0b013e328360e9fb
PMCID: PMC3883757  PMID: 23807276
HIV-1; VCAM-1; ICAM-1; angiopoietin-1; angiopoietin-2; E-selectin; endothelial activation
21.  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.
Background
This analysis compared the frequency of persistent Trichomonas vaginalis (TV) among HIV-seropositive and HIV-seronegative women.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/OLQ.0b013e31828fce34
PMCID: PMC3676301  PMID: 23677023
Trichomonas vaginalis; metronidazole; efficacy; persistence; HIV infection; nevirapine; antiretroviral therapy
22.  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.
doi:10.1097/QAI.0b013e3182874d41
PMCID: PMC3625514  PMID: 23344546
antibody-dependent cell-mediated virus inhibition; ADCVI; HIV-1; superinfection; primary infection; clade A
23.  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.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1097/OLQ.0b013e318272fe45
PMCID: PMC3831875  PMID: 23407467
Chlamydia trachomatis; incidence; risk factors; women; Africa
24.  Correlates of Inappropriate Prescribing of Antibiotics to Patients with Malaria in Uganda 
PLoS ONE  2014;9(2):e90179.
Background
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.
Methods
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.
Findings
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).
Conclusion
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.
doi:10.1371/journal.pone.0090179
PMCID: PMC3938663  PMID: 24587264
25.  Evaluation of WHO screening algorithm for the presumptive treatment of asymptomatic rectal gonorrhoea and chlamydia infections in at-risk MSM in Kenya 
Objectives
The WHO recommends that men who have sex with men (MSM) reporting unprotected receptive anal intercourse (RAI) and either multiple partners or a partner with a sexually transmitted infection (STI) in the past 6 months should be presumptively treated for asymptomatic rectal Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infections. We evaluated this recommendation in a cohort of ‘high-risk’ MSM in Coastal Kenya.
Methods
We assessed presence of genitourinary and rectal symptoms, and determined prevalence and 3-month incidence of rectal NG and CT infections. We performed nucleic acid amplification testing of urine and rectal swab samples collected from MSM followed prospectively, and assessed predictive values of the WHO algorithm at baseline screening.
Results
Of 244 MSM screened, 240 (98.4%) were asymptomatic, and 147 (61.3%) reported any RAI in the past 6 months. Among 85 (35.4%) asymptomatic MSM meeting criteria for the WHO presumptive treatment (PT) recommendation, we identified 20 with rectal infections (six NG, 12 CT and two NG–CT co-infections). Among 62 asymptomatic MSM who did not meet criteria, we identified seven who were infected. The sensitivity and specificity of the WHO algorithm were 74.1% (95% CI 53.7% to 88.9%) and 45.8% (95% CI 36.7% to 55.2%), respectively. The 3-month incidence of any rectal NG or CT infection in asymptomatic men reporting any RAI was 39.7 (95% CI 24.3 to 64.8) per 100 person-years.
Conclusions
About one-third of asymptomatic MSM were eligible to receive PT for NG and CT infections. Among MSM who would qualify for PT of rectal STIs, the number needed to treat in order to treat one infection was four. Our results support the value of the WHO screening algorithm and recommended PT strategy in this population.
doi:10.1136/sextrans-2013-051078
PMCID: PMC3932748  PMID: 24327758
NEISSERIA GONORRHOEA; CHLAMYDIA TRACHOMATIS; MEN; TREATMENT; PUBLIC HEALTH

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