The cervicovaginal environment and HIV incidence in Zambian women with female genital schistosomiasis

Abstract

Background: In 2019, an estimated 56 million women were living with female genital schistosomiasis (FGS), a neglected tropical disease that results when eggs from the waterborne parasite Schistosoma (S.) haematobium are deposited in reproductive tissues. FGS has been associated with important sexual and reproductive health consequences, including ectopic pregnancy, infertility, and human immunodeficiency virus (HIV-1)acquisition. Inflammation in the female genital tract is likewise associated withHIV-1 acquisition and non-optimal cervicovaginal microbiota have also been associated with adverse reproductive consequences, including pelvic inflammatory disease, infections of pregnancy and the post-partum period and HIV-1acquisition. The cervicovaginal environment of women with FGS has not been fully described. The overall aim of this PhD thesis was to describe the cervicovaginal microbiota (including STI) and the cervicovaginal immune environment, focusing on cytokines and chemokines, in Zambian women with and without FGS and to explore the association of FGS with HIV-1 incidence. Methods: This PhD work was nested within the bilharzia and HIV (BILHIV) study, which recruited women aged 18-31, sexually active, and not pregnant from the HPTN 071 (PopART) Population Cohort, from which longitudinal information on HIV-1 infection status was available. Women enrolled in the BILHIV study (n=603) were assessed for FGS through self-collected genital swabs and clinic-collected CVL (n=527). For this PhD work, all BIL HIV participants with FGS (n=30) and all participants with probable FGS (n=25) were selected, and three FGS negative participants were selected for every FGS and probable FGS participant using a random number generator, frequency matched by age to participants with FGS. Among selected participants, cervicovaginal microbiota and STI were quantified using PCR and the associations of presence, median (IQR), and log concentration mean with FGS status were assessed. The concentrations of 17 soluble cytokines and chemokines were quantified in cervicovaginal lavage (CVL) by a multiplex bead-based immunoassay to evaluate the association between FGS and concentration of cervicovaginal cytokines and chemokines. To explore the association of FGS with HIV-1 incidence, the rate of HIV-1 seroconversion was assessed among women who wereHIV-1 negative at enrolment in the HPTN 071 (PopART) Population Cohort (n=492) and associations with FGS were evaluated with exact Poisson regression. Results: Of 603 women enrolled in BILHIV, 5.0% (30/603) had FGS, defined as PCR-detected Schistosoma DNA in any of three genital specimens (cervical swab, vaginal swab, or CVL). The prevalence of schistosome infection in the study population was 5.5% (33/603) by urine microscopy and 15.1% (91/601) by urine CAA. The presence and concentration of cervicovaginal species did not differ between participants with or without FGS. However, a higher proportion of participants with FGS had T. vaginalis compared to FGS negative women (p=0.08). An exploratory analysis suggested an association of T. vaginalis presence with FGS among women with ≥2 Schistosoma PCR positive genital specimens (50.0%, 8/16) compared with FGS negative (21.5% 34/158, p=0.01). There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. After adjusting for potential confounders, an exploratory analysis of women with genital specimens with detectable Schistosoma DNA (n=15) showed a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women. After adjusting for multiple testing, the association between IL-4 (p=0.037) and IL-5(p<0.001)and FGS were unlikely to be due to chance. Incident HIV-1 infections were observed in 4.1% (20/492) participants. Women with FGS were twice as likely to seroconvert as women without FGS but with no statistical evidence for a difference (RR 2.16, 95%CI[0.21±12.30], p=0.33). Exploratory analysis suggested a po int estimate consistent with increased risk of HIV-1 acquisition among women with ≥2 positive genital PCR specimens (RR 6.02, [0.58±34.96]), p=0.13), without statistical evidence of a difference after adjusting for potential confounders. Conclusion: FGS may alter the cervicovaginal environment, particularly in high burden infections. There are higher HIV-1seroconversion rates in women with FGS, although power to detect an association was limited in this analysis. The burden of disease should be assessed and correlated with outcomes in participants with FGS. Ideally, a longitudinal study would evaluate the interaction between FGS, HIV-1, and the cervicovaginal environment to provide additional depth to these findings.