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Human immunodeficiency virus 1 (HIV-1) exposed seronegative (HESN) individuals may have unique characteristics that alter susceptibility to HIV-1 infection. However, identifying truly exposed HESN is challenging. We utilized stored data and biospecimens from HIV-1 serodifferent couple cohorts, in which couples’ HIV-1 exposures were quantified based on unprotected sex frequency and viral load of the partner with HIV-1. We compared peripheral blood gene expression between 15 HESN and 18 seroconverters prior to infection. We found PTPRC (encoding CD45 antigen) and interferon-response pathways had significantly higher expression among individuals who went on to become seropositive and thus may be a signature for increased acquisition risk.

Background Pre-antiretroviral-treatment drug resistance (PDR) is a predictor of human immunodeficiency virus (HIV) treatment failure. We determined PDR prevalence and correlates in a Kenyan cohort. Methods We conducted a cross-sectional analysis of antiretroviral (ARV) treatment-eligible HIV-infected participants. PDR was defined as ≥2% mutant frequency in a participant's HIV quasispecies at pol codons K103N, Y181C, G190A, M184 V, or K65R by oligonucleotide ligation assay and Illumina sequencing. PDR prevalence was calculated by demographics and codon, stratifying by prior ARV experience. Poisson regression was used to estimate prevalence ratios. Results PDR prevalences (95% confidence interval [CI]) in 815 ARV-naive adults, 136 ARV-experienced adults, and 36 predominantly ARV-naive children were 9.4% (7.5%-11.7%), 12.5% (7.5%-19.3%), and 2.8% (0.1%-14.5%), respectively. Median mutant frequency within an individual's HIV quasispecies was 67%. PDR prevalence in ARV-naive women 18-24 years old was 21.9% (9.3%-40.0%). Only age in females associated with PDR: A 5-year age decrease was associated with adjusted PDR prevalence ratio 1.20 (95% CI, 1.06-1.36; P = .004). Conclusions The high PDR prevalence may warrant resistance testing and/or alternative ARVs in high HIV prevalence settings, with attention to young women, likely to have recent infection and higher rates of resistance. Clinical trials registration NCT01898754.

We assessed the association between recent bacterial vaginosis (BV) and incident Mycoplasma genitalium, a sexually transmitted bacterium associated with adverse female reproductive health outcomes. Female sex workers in Mombasa, Kenya, completed a monthly sexual behavior interview and clinical examination. During February 2005–February 2006, vaginal fluid specimens collected from women every other month were tested for M. genitalium by nucleic acid amplification testing. Vaginal microbiota were assessed monthly and categorized by Nugent score (0–3 = normal microbiota, 4–6 = intermediate microbiota disruption, and 7–10 = BV). A discrete failure time analysis for multiple events using logistic regression was employed to estimate the odds of incident M. genitalium infection at follow-up visits among women with BV (vs. normal microbiota) at the preceding visit. Among the 280 women, 54.3% were positive for human immunodeficiency virus. At baseline, 16.1% had prevalent M. genitalium infection and 40.4% had prevalent BV. There were 59 incident M. genitalium infections among 50 women, for an incidence rate of 34.6 cases per 100 person-years. Following adjustment for age, human immunodeficiency virus status, and time, prior BV was associated with a 3.5-fold increase in odds of incident M. genitalium (adjusted odds ratio = 3.49, 95% confidence interval: 1.86, 6.56). This strong association suggests that BV may enhance susceptibility to M. genitalium infection.

Objective. Tenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR). Methods. A subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00557245","term_id":"NCT00557245"}}NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion. Results. Of 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52–3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10–14.0; P > .99). Conclusions. Daily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.

SummaryInfants exposed to maternal HIV-1 provide an opportunity to assess correlates of HIV-1-specific interferon (IFN)-γ responses and may be informative in the development of HIV-1 vaccines. HIV-1-infected women with CD4 counts 200–500 cells/mm3 were randomized to short-course zidovudine/nevirapine (ZDV/NVP) or highly active anti-retroviral therapy (HAART) between 2003 and 2005. Maternal plasma and breastmilk HIV-1 RNA and DNA were quantified during the first 6–12 months postpartum. HIV-1 gag peptide-stimulated enzyme-linked immunospot (ELISPOT) assays were conducted in HIV-1-exposed, uninfected infants (EU), and correlates were determined using regression and generalized estimating equations. Among 47 EU infants, 21 (45%) had ≥1 positive ELISPOT result during follow-up. Infants had a median response magnitude of 177 HIV-1-specific spot-forming units (SFU)/106 peripheral blood mononuclear cells (PBMC) [interquartile range (IQR) = 117–287] directed against 2 (IQR = 1–3) gag peptide pools. The prevalence and magnitude of responses did not differ by maternal anti-retroviral (ARV) randomization arm. Maternal plasma HIV-1 RNA levels during pregnancy (P = 0·009) and breastmilk HIV-1 DNA levels at 1 month (P = 0·02) were associated with a higher magnitude of infant HIV-1-specific ELISPOT responses at 1 month postpartum. During follow-up, concurrent breastmilk HIV-1 RNA and DNA (cell-free virus and cell-associated virus, respectively) each were associated positively with magnitude of infant HIV-1-specific responses (P = 0·01). Our data demonstrate the importance of antigenic exposure on the induction of infant HIV-1-specific cellular immune responses in the absence of infection.

Cytomegalovirus (CMV) infection can cause substantial morbidity in infancy. During maternal primary or reinfection, in utero CMV transmission is associated with a high risk of congenital disease and permanent sensorineural deficits [1]. Premature infants acquiring CMV by breast milk are at risk of developing symptomatic disease in the neonatal period [2] and may also experience long-term cognitive and psychomotor development [3, 4]. In the setting of infant human immunodeficiency virus type 1 (HIV-1) infection, both in utero and postnatally acquired CMV are associated with accelerated HIV-1 disease progression, neurologic disease, and death [5, 6]. CMV can be transmitted from mother-to-infant in utero, intrapartum, or postpartum by exposure to breast milk or saliva. Endothelial and epithelial cells support productive CMV infection and may facilitate systemic dispersion of virus [7]. CMV is frequently detected in saliva, urine, semen, cervical secretions, and breast milk, but detection in blood is rare in the absence of significant immunosuppression. In the cervix of healthy, HIV-negative women, CMV can be detected in approximately 10% of nonpregnant women and 11%–35% of pregnant women in the third trimester [8–10]. A small study of women with CMV cervicitis found inclusion bodies within glandular epithelial cells, endothelial cells, and mesenchymal stromal cells [11], suggesting these cells might be involved in CMV reactivation in the cervix. In breast milk, nearly all healthy women have detectable CMV DNA [12, 13]. CMV is found in both whey and cellular fractions of breast milk [13] and could have multiple sources, including mammary epithelial cells and migrating monocyte/macrophages and lymphocytes. In the setting of maternal HIV-1 infection, local HIV-1 replication and immunosuppression within tissues could increase CMV shedding at sites relevant for CMV transmission. In Nairobi, Kenya, 97% of adult blood donors in the general population are CMV seropositive [14] and virtually all HIV-infected women are coinfected with CMV [15, 16]. We previously found the rate of congenital CMV infection was 6.3% in HIV-exposed but uninfected infants and 29% in HIV-infected infants; by 6 months of age, 90% of HIV-exposed but uninfected infants and 89% of HIV-infected infants had experienced plasma CMV DNAemia, and 46% of HIV-unexposed infants were CMV seropositive [16]. Preventing or delaying CMV infection may represent a novel strategy to improve the health of both HIV-infected and HIV-exposed uninfected infants in sub–Saharan Africa, but requires a better understanding of CMV replication and transmission in the setting of maternal HIV-1. Using specimens and data from a randomized trial of valacyclovir suppressive therapy in Nairobi, we examined associations between HIV-1 RNA level, immunosuppression, and CMV replication in different maternal compartments and identified maternal correlates of infant CMV infection.

Herpes simplex virus type 2 (HSV-2) is the most common cause of genital ulcer disease in the world, and sub-Saharan Africa bears a heavy burden of infections [1, 2]. Manifestations of HSV-2 infection range from asymptomatic or nonulcerative symptoms to periodic outbreaks of painful ulcers [3, 4]. There is a strong synergistic relationship between HSV-2 and human immunodeficiency virus type 1 (HIV-1), resulting in greater shedding and elevated infectiousness of both viruses [5–10]. HSV-2 can be managed with episodic antiviral medication (eg, acyclovir, valacyclovir, or famciclovir) to abort or reduce the duration of outbreaks or with daily suppressive treatment to prevent outbreaks and reduce asymptomatic viral shedding [11]. Although suppressive HSV-2 treatment reduces plasma HIV-1 viral load, a recent randomized trial failed to show a benefit of suppressive acyclovir therapy in reducing HIV-1 transmission [12]. However, daily suppressive therapy with valacyclovir decreases herpes transmission to sexual partners [13]. Prevention of new HSV-2 infections may be an effective HIV-1 prevention strategy, particularly among HIV-1-discordant couples in which either member of the couple is HSV-2 seronegative. While estimates vary due to population characteristics, 10%–25% of new HIV-1 infections in sub-Saharan Africa occur in HIV-1-discordant couples [14–17]. In this region, HSV-2 prevalence in one or both members of HIV-1-discordant couples is as high as 80% [18]. Yet there is limited knowledge about the timing and risk factors for HSV-2 acquisition in this high-risk population. Given the importance of HSV-2 in mediating HIV-1 transmission, we sought to better understand HSV-2 transmission in HIV-1-discordant couples by investigating its prevalence and incidence among stable HIV-1-discordant heterosexual couples in Nairobi, Kenya.

Background. Knowledge of factors that affect per-act infectivity of human immunodeficiency virus type 1 (HIV-1) is important for designing HIV-1 prevention interventions and for the mathematical modeling of the spread of HIV-1. Methods. We analyzed data from a prospective study of African HIV-1–serodiscordant couples. We assessed transmissions for linkage within the study partnership, based on HIV-1 sequencing. The primary exposure measure was the HIV-1–seropositive partners’ reports of number of sex acts and condom use with their study partner. Results. Of 3297 couples experiencing 86 linked HIV-1 transmissions, the unadjusted per-act risks of unprotected male-to-female (MTF) and female-to-male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010–.0037) and 0.0010 (95% CI, .00060–.0017), respectively. After adjusting for plasma HIV-1 RNA of the HIV-1–infected partner and herpes simplex virus type 2 serostatus and age of the HIV-1–uninfected partner, we calculated the relative risk (RR) for MTF versus FTM transmission to be 1.03 (P 5 .93). Each log10 increase in plasma HIV-1 RNA increased the per-act risk of transmission by 2.9-fold (95% CI, 2.2–3.8). Self-reported condom use reduced the per-act risk by 78% (RR 5 0.22 [95% CI, .11–.42]). Conclusions. Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1–uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision.

Background It has been suggested that vaginal colonization with 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 that involved 151 Kenyan sex workers. At monthly follow-up visits, VVC was defined as the presence of yeast buds, pseudohyphae, or both on a wet preparation (including potassium hydroxide preparation) of vaginal secretions. Generalized estimating equations were used to identify correlates of VVC. Results Participants returned for a median of 12 visits (interquartile range, 11-12 visits). VVC was identified at 162 visits, including 26 involving symptomatic VVC. Bacterial vaginosis 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 bacterial vaginosis, another possible cause of vaginal symptoms, the likelihood of symptomatic VVC was higher among those who had had yeast identified on wet preparation of vaginal secretions during 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 the commonly posited hypothesis that vaginal Lactobacillus colonization has a protective effect, we found that such colonization was associated with a nearly 4-fold increase in the likelihood of symptomatic VVC.

We conducted a prospective study among women in Mombasa, Kenya, to determine whether Trichomonas vaginalis infection was associated with an increased risk of human immunodeficiency virus type 1 (HIV-1) infection. At monthly follow-up visits, laboratory screening for HIV-1 and genital tract infections was conducted. Among 1335 HIV-1-seronegative women monitored for a median of 566 days, there were 806 incident T. vaginalis infections (23.6/100 person-years), and 265 women seroconverted to HIV-1 (7.7/100 person-years). Trichomoniasis was associated with a 1.52-fold (95% confidence interval, 1.04-2.24-fold) increased risk of HIV-1 acquisition after adjustment for potential confounding factors. Treatment and prevention of T. vaginalis infection could reduce HIV-1 risk in women.

BACKGROUND: Increasing evidence suggests that depot medroxyprogesterone acetate (DMPA) and intravaginal practices may be associated with an increased risk of HIV infection; however the mechanisms are not fully understood. This study evaluated the effect of DMPA and intravaginal practices on the genital mucosal proteome and microbiome to gain mechanistic insights. METHODS: Cervicovaginal secretions from 86 Kenyan women including self-reported DMPA (n=23) and non-hormonal contraceptive users (n=63) and women who practice vaginal drying (n=46) were analyzed using tandem-mass spectrometry in a cross sectional manner. RESULTS: We identified 473 human and 486 bacterial proteins from 18 different genera. DMPA use associated with increased hemoglobin and immune activation (HBD HBB ALAD IL36G) and decreased epithelial repair proteins (TFF3 F11R). Vaginal drying associated with increased hemoglobin and decreased phagocytosis factors (AZU1 MYH9 PLAUR PADI4). Injury signatures were exacerbated in DMPA users who also practiced vaginal drying. Vaginal drying associated with more diverse (H-index: 0.71 vs 0.45 p=0.0089) bacterial communities containing Gardnerella vaginalis whereas DMPA showed no significant changes in community composition or diversity. CONCLUSIONS: These findings provide new insights into the impact of DMPA and vaginal drying on mucosal barriers and future investigations are needed to confirm their relationship with HIV risk in women. (c) The Author 2016. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.