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1.  Patterns of human herpesvirus-8 oral shedding among diverse cohorts of human herpesvirus-8 seropositive persons 
Human herpesvirus-8 (HHV-8), the etiologic agent of Kaposi sarcoma (KS), establishes lifelong latent infection with periodic lytic replication (“shedding”) at mucosal sites, especially the oropharynx. Patterns of HHV-8 shedding are not well understood, and require elucidation to better predict risk of HHV-8 related malignancies in those infected. We sought to characterize patterns of HHV-8 oropharyngeal shedding among diverse cohorts that enrolled HHV-8 seropositive persons.
We quantified HHV-8 oral shedding using PCR among HHV-8 seropositive persons who collected at least 14 days of oral swabs in 22 studies on 3 continents. We excluded persons taking antivirals during sampling or any prior use of antiretrovirals in those who were HIV-infected.
248 participants were enrolled from the US, Peru, Cameroon, Uganda, and Kenya; 61 % were men, 58 % were HIV seropositive, and 16 % had KS. Overall, 3,123 of 10,557 samples (29.6 %) had HHV-8 detected. Quantity of virus shed was highly correlated with shedding rate, (ρ = 0.72, p < 0.0001). HHV-8 was detected in ≥1 sample in 55 % of participants with a median of 7 % of days in the US and Kenya, 0 % in Uganda and Peru, and 18 % in Cameroon. Median episode duration was three days, and episodes with high median quantity lasted longer (42 vs 3 days, p < 0.0001). In persons with multiple observations over time, 66 % of shedding rate variance was attributable to differences between individuals.
In HHV-8 infected individuals from diverse settings, oral mucosal shedding rate, quantity, and duration were correlated; individual shedding was highly variable. Studies are needed to determine factors accounting for between-person variation and the relationship of HHV-8 shedding to development of associated diseases.
PMCID: PMC4748452  PMID: 26865856
Herpesviridae infections; Herpesvirus 8, Human; Kaposi sarcoma-associated herpesvirus (KSHV); Sarcoma, Kaposi; HIV infections; Virus replication
2.  Trichomonas vaginalis Infection: Can We Afford to Do Nothing? 
The Journal of infectious diseases  2008;197(4):487-489.
PMCID: PMC4568437  PMID: 18275270
3.  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.
PMCID: PMC4419746  PMID: 24798764
hormonal contraception; HIV-1; antiretroviral therapy; DMPA
5.  Short Communication: Fc Gamma Receptors IIa and IIIa Genetic Polymorphisms Do Not Predict HIV-1 Disease Progression in Kenyan Women 
Genetic polymorphisms of the Fc gamma receptors (FcγR) IIa and IIIa have been implicated in the rate of HIV-1 disease progression, but results are inconsistent. We aimed to determine the association between these polymorphisms and disease progression in a cohort of HIV-1 seroconverters from Mombasa, Kenya. Neither FcγRIIa nor FcγRIIIa genotypes were predictive of set point viral load, viral load increase, CD4 decline, or HIV-1 disease progression (time to CD4 count <200 cells/mm3, death, or treatment initiation). Our results suggest that FcγR polymorphisms might not be an important indicator of viral control and disease progression in this population.
PMCID: PMC4348085  PMID: 25312792
6.  Patient-Delivered Partner Treatment for Chlamydia, Gonorrhea, and Trichomonas Infection Among Pregnant and Postpartum Women in Kenya 
Sexually transmitted diseases  2015;42(11):637-642.
Patient-delivered partner treatment (PDPT) for sexually transmitted infections (STIs) increases rates of partner treatment and decreases reinfection, but has not been evaluated during pregnancy.
This prospective cohort was nested within a larger study of peripartum HIV acquisition. Participants with microbiologic diagnosis of Chlamydia trachomatis, Neisseria gonorrhoeae, and/or Trichomonas vaginalis were screened for participation. Questionnaires were administered to determine PDPT acceptability and barriers. Women were reassessed at least 30 days to determine partner treatment and reinfection. Women whose partners did or did not receive PDPT were compared.
One hundred twelve (22.2%) women in the parent cohort had a treatable STI; 78 within the PDPT study period, of whom 66 were eligible and 59 (89.3%) accepted PDPT. Fifty-one women had PDPT outcome data, 37 (73%) of whom reported partners treated with PDPT. Fourteen women (27%) refused or did not deliver partner treatment. Median age was 22 years (interquartile range, 20–26 years) and 88% were married. Compared with women who delivered PDPT, those who did not were more likely to have a partner living far away (23% vs. 0%, P = 0.004) and to report current intimate partner violence (14% vs. 0%, P = 0.02). Reported PDPT barriers included fear of partner’s anger/abuse (5%) and accusations of being STI source (5%).
Patient-delivered partner treatment was acceptable and feasible for pregnant/postpartum Kenyan women and may reduce recurrent STIs in pregnancy.
PMCID: PMC4758370  PMID: 26462189
7.  Genital Shedding of Resistant Human Immunodeficiency Virus-1 Among Women Diagnosed With Treatment Failure by Clinical and Immunologic Monitoring 
Open Forum Infectious Diseases  2016;3(1):ofw019.
Detection of resistant HIV-1 in genital secretions of women failing first-line therapy was associated with a greater number of resistance mutations in plasma. While genital resistance emerged later than plasma resistance, genital shedding could increase risk for transmitted drug resistance.
Background. The accumulation of human immunodeficiency virus (HIV) resistance mutations can compromise treatment outcomes and promote transmission of drug-resistant virus. We conducted a study to determine the duration and evolution of genotypic drug resistance in the female genital tract among HIV-1-infected women failing first-line therapy.
Methods. Treatment failure was diagnosed based on World Health Organization (WHO) clinical or immunologic criteria, and second-line therapy was initiated. Stored plasma and genital samples were tested to determine the presence and timing of virologic failure and emergence of drug resistance. The median duration of genital shedding of genotypically resistant virus prior to regimen switch was estimated.
Results. Nineteen of 184 women were diagnosed with treatment failure, of whom 12 (63.2%) had confirmed virologic failure at the switch date. All 12 women with virologic failure (viral load, 5855–1 086 500 copies/mL) had dual-class resistance in plasma. Seven of the 12 (58.3%) had genital HIV-1 RNA levels high enough to amplify (673–116 494 copies/swab), all with dual-class resistance. The median time from detection of resistance in stored samples to regimen switch was 895 days (95% confidence interval [CI], 130–1414 days) for plasma and 629 days (95% CI, 341–984 days) for genital tract secretions.
Conclusions. Among women diagnosed with treatment failure using WHO clinical or immunologic criteria, over half had virologic failure confirmed in stored samples. Resistant HIV-1 RNA was shed in the genital tract at detectable levels for ≈1.7 years before failure diagnosis, with steady accumulation of mutations. These findings add urgency to the ongoing scale-up of viral load testing in resource-limited settings.
PMCID: PMC4784013  PMID: 26966695
antiretroviral therapy; female; HIV; viral drug resistance; virus shedding
8.  Targeted screening of at-risk adults for acute HIV-1 infection in sub-Saharan Africa 
AIDS (London, England)  2015;29(0 3):S221-S230.
Patients with acute HIV-1 infection (AHI) have elevated infectivity, but cannot be diagnosed using antibody-based testing. Approaches to screen patients for AHI are urgently needed to enable counselling and treatment to reduce onward transmission.
We pooled data from four African studies of high-risk adults that evaluated symptoms and signs compatible with acute retroviral syndrome and tested for HIV-1 at each visit. AHI was defined as detectable plasma viral load or p24 antigen in an HIV-1-antibody-negative patient who subsequently seroconverted. Using generalized estimating equation, we identified symptoms, signs, and demographic factors predictive of AHI, adjusting for study site. We assigned a predictor score to each statistically significant predictor based on its beta coefficient, summing predictor scores to calculate a risk score for each participant. We evaluated the performance of this algorithm overall and at each site.
We compared 122 AHI visits with 45 961 visits by uninfected patients. Younger age (18–29 years), fever, fatigue, body pains, diarrhoea, sore throat, and genital ulcer disease were independent predictors of AHI. The overall area under the receiver operating characteristics curve (AUC) for the algorithm was 0.78, with site-specific AUCs ranging from 0.61 to 0.89. A risk score of at least 2 would indicate AHI testing for 5–50% of participants, substantially decreasing the number needing testing.
Our targeted risk score algorithm based on seven characteristics reduced the number of patients needing AHI testing and had good performance overall. We recommend this risk score algorithm for use by HIV programs in sub-Saharan Africa with capacity to test high-risk patients for AHI.
PMCID: PMC4714928  PMID: 26562811
9.  Factors Associated with Mortality in Febrile Patients in a Government Referral Hospital in the Kenema District of Sierra Leone 
There is a paucity of data on the etiologies and outcomes of febrile illness in rural Sierra Leone, especially in the Lassa-endemic district of Kenema. We conducted a retrospective study of patients with subjective or documented fever (T ≥ 38.0°C) who were admitted to a rural tertiary care hospital in Kenema between November 1, 2011 and October 31, 2012. Of 854 patients admitted during the study period, 429 (50.2%) patients had fever on admission. The most common diagnoses were malaria (27.3%), pneumonia (5.1%), and Lassa fever (4.9%). However, 53.4% of febrile patients had no diagnosis at discharge. The in-hospital mortality rate was 18.9% and associated with documented temperature ≥ 38.0°C (adjusted odds ratio [AOR] = 2.89, P = 0.001) and lack of diagnosis at discharge (AOR = 2.04, P = 0.03). Failure to diagnose the majority of febrile adults and its association with increased mortality highlight the need for improved diagnostic capacity to improve patient outcomes.
PMCID: PMC4347375  PMID: 25404077
10.  Genital infections and syndromic diagnosis among HIV-infected women in HIV care programs in Kenya 
Control of genital infections remains challenging in most regions. Despite advocacy by the World Health Organization (WHO) for syndromic case management, there are limited data on the syndromic approach, especially in HIV care settings. This study compared the syndromic approach against laboratory diagnosis among women in HIV care in Kenya.
A mobile team visited 39 large HIV care programs in Kenya and enrolled participants using population-proportionate sampling. Participants provided behavioral and clinical data with genital and blood specimens for lab testing.
Among 1,063 women, 68.4% had been on antiretroviral therapy >1 year; 58.9% were using cotrimoxazole prophylaxis; 51 % had CD4+T-lymphocytes < 350 cells/mL. Most women (63.1%) reported at least one genital symptom. Clinical signs were found in 63% of women; and 30.8% had an etiological diagnosis. Bacterial vaginosis (17.4%), vaginal candidiasis (10.6%) and trichomoniasis (10.5%) were the most common diagnoses. Using laboratory diagnoses as gold standard, sensitivity and positive predictive value of the syndromic diagnosis for vaginal discharge were 47.6% and 52.7%, respectively, indicating a substantial amount of overtreatment. A systematic physical examination increased by 9.3% the positive predictive value for genital ulcer disease.
Women attending HIV care programs in Kenya have high rates of vaginal infections. Syndromic diagnosis was a poor predictor of those infections.
PMCID: PMC4511718  PMID: 25614522
Genital infections; syndromic management; vaginal discharge; Kenya
11.  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
12.  An Effective Intervention to Reduce Intravaginal Practices Among HIV-1 Uninfected Kenyan Women 
AIDS Research and Human Retroviruses  2014;30(11):1046-1054.
Intravaginal practices (IVP) are common among African women and are associated with HIV acquisition. A behavioral intervention to reduce IVP is a potential new HIV risk-reduction strategy. Fifty-eight HIV-1-uninfected Kenyan women reporting IVP and 42 women who denied IVP were followed for 3 months. Women using IVP attended a skill-building, theory-based group intervention occurring weekly for 3 weeks to encourage IVP cessation. Vaginal swabs at each visit were used to detect yeast, to detect bacterial vaginosis, and to characterize the vaginal microbiota. Intravaginal insertion of soapy water (59%) and lemon juice (45%) was most common among 58 IVP women. The group-counseling intervention led to a decrease in IVP from 95% (54/58) at baseline to 0% (0/39) at month 3 (p=0.001). After 3 months of cessation, there was a reduction in yeast on vaginal wet preparation (22% to 7%, p=0.011). Women in the IVP group were more likely to have a Lactobacillus iners-dominated vaginal microbiota at baseline compared to controls [odds ratio (OR), 6.4, p=0.006] without significant change in the microbiota after IVP cessation. The group counseling intervention was effective in reducing IVP for 3 months. Reducing IVP may be important in itself, as well as to support effective use of vaginal microbicides, to prevent HIV acquisition.
PMCID: PMC4208596  PMID: 25265254
13.  Elevation of Soluble Intercellular Adhesion Molecule-1 Levels, but Not Angiopoietin 2, in the Plasma of Human Immunodeficiency Virus–Infected African Women with Clinical Kaposi Sarcoma 
Circulating levels of endothelial activation biomarkers are elevated in during infection with human immunodeficiency virus 1 (HIV-1) and may also be increased in Kaposi sarcoma (KS). We compared 23 HIV-1-seropositive women with clinically diagnosed KS with 46 randomly selected controls matched for visit year, CD4 count, and antiretroviral therapy status. Conditional logistic regression was used to identify differences between cases and controls. The odds of clinical KS increased with increasing plasma viral load and with intercellular adhesion molecule 1 (ICAM-1) levels above or equal to the median. There was a borderline association between increasing plasma angiopoietin 2 levels and KS. In multivariable modeling including plasma viral load, angiopoietin 2, and ICAM-1, plasma ICAM-1 levels above or equal to the median remained associated with clinical KS (odds ratio = 14.2, 95% confidence interval = 2.3–87.7). Circulating ICAM-1 levels should be evaluated as a potential biomarker for disease progression and treatment response among HIV-infected KS patients.
PMCID: PMC4183391  PMID: 25002294
14.  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
15.  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
16.  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.
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.
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).
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.
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.
PMCID: PMC4503239  PMID: 25102090
HIV-1; women; superinfection; progression; pathogenesis
17.  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.
PMCID: PMC4497680  PMID: 26158467
18.  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.
PMCID: PMC4007393  PMID: 24179037
alcohol use; STI; African women; prospective
19.  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.
PMCID: PMC4020985  PMID: 24413043
cytokines; HIV; acquisition; susceptibility; immune activation
20.  Cytochrome P450 2B6 genetic variants are associated with plasma nevirapine levels and clinical response in HIV-1 infected Kenyan women: a prospective cohort study 
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.
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.
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.
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.
PMCID: PMC4397818  PMID: 25878720
CYP2B6; Pharmacogenetics; Nevirapine; HIV infection; Antiretroviral therapy; Women
21.  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.
PMCID: PMC3952675  PMID: 24273042
Bacterial vaginosis; herpes simplex virus type 2; women; Africa
22.  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
23.  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
24.  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
25.  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

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