Efficacy of single versus four repeated doses of praziquantel against Schistosoma mansoni infection in school-aged children from Côte d'Ivoire based on Kato-Katz and POC-CCA: An open-label, randomised controlled trial (RePST).

BACKGROUND: Preventive chemotherapy with praziquantel (PZQ) is the cornerstone of schistosomiasis control. However, a single dose of PZQ (40 mg/kg) does not cure all infections. Repeated doses of PZQ at short intervals might increase efficacy in terms of cure rate (CR) and intensity reduction rate (IRR). Here, we determined the efficacy of a single versus four repeated treatments with PZQ on Schistosoma mansoni infection in school-aged children from Côte d'Ivoire, using two different diagnostic tests. METHODS: An open-label, randomized controlled trial was conducted from October 2018 to January 2019. School-aged children with a confirmed S. mansoni infection based on Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) urine cassette test were randomly assigned to receive either a single or four repeated doses of PZQ, administered at two-week intervals. The primary outcome was the difference in CR between the two treatment arms, measured by triplicate KK thick smears 10 weeks after the first treatment. Secondary outcomes included CR estimated by POC-CCA, IRR by KK and POC-CCA, and safety of repeated PZQ administration. PRINCIPAL FINDINGS: During baseline screening, 1,022 children were assessed for eligibility of whom 153 (15%) had a detectable S. mansoni infection, and hence, were randomized to the standard treatment group (N = 70) and the intense treatment group (N = 83). Based on KK, the CR was 42% (95% confidence interval (CI) 31-52%) in the standard treatment group and 86% (95% CI 75-92%) in the intense treatment group. Observed IRR was 72% (95% CI 55-83%) in the standard treatment group and 95% (95% CI 85-98%) in the intense treatment group. The CR estimated by POC-CCA was 18% (95% CI 11-27%) and 36% (95% CI 26-46%) in the standard and intense treatment group, respectively. Repeated PZQ treatment did not result in a higher number of adverse events. CONCLUSION/SIGNIFICANCE: The observed CR using KK was significantly higher after four repeated treatments compared to a single treatment, without an increase in adverse events. Using POC-CCA, the observed CR was significantly lower than measured by KK, indicating that PZQ may be considerably less efficacious as concluded by KK. Our findings highlight the need for reliable and more accurate diagnostic tools, which are essential for monitoring treatment efficacy, identifying changes in transmission, and accurately quantifying the intensity of infection in distinct populations. In addition, the higher CR in the intense treatment group suggests that more focused and intense PZQ treatment can help to advance schistosomiasis control. TRIAL REGISTRATION: www.clinicaltrials.gov NCT02868385

HIV-seroconversion among HIV-1 serodiscordant married couples in Tanzania: a cohort study.

BACKGROUND: Heterosexual transmission is the main driver of the HIV epidemic in Tanzania. Only one estimate of the incidence rate of intra-marital HIV seroconversion in Tanzania has been reported and was derived from data collected between 1991 and 1995. Moreover, little is known about the specific risk factors for intra-marital seroconversion in Tanzania. Improved evidence around factors that increase the risk of HIV transmission to a serodiscordant spouse is needed to develop and improve evidence-based interventions. We sought to investigate the rate of intra-marital HIV seroconversion among HIV sero-discordant couples in Tanzania as well as its associated risk factors. METHODS: We identified all HIV positive individuals in the TAZAMA HIV-serosurvey cohort and followed up their serodiscordant spouse from 2006 to 2016. The rate of seroconversion was analyzed by survival analysis using non-parametric regressions with exponential distribution. RESULTS: We found 105 serodiscordant couples, 14 of which had a seroconverting spouse. The overall HIV-1 incidence rate among spouses of people with HIV-1 infection was 38.0 per 1000 person/years [22.5-64.1]. Notably, the HIV-1 incidence rate among HIV-1 seronegative male spouses was 6.7[0.9-47.5] per 1000 person/years, compared to 59.3 [34.4-102.1] per 1000 person/years among female spouses. Sex of the serodiscordant spouse was the only significant variable, even after adjusting for other variables (Hazard rate = 8.86[1.16-67.70], p = 0.036). CONCLUSIONS: Our study suggests that rates of HIV-1 seroconversion of sero-discordant partners are much higher within marriage than in the general population in Tanzania. The major risk factor for HIV-1 seroconversion is sex of the serodiscordant spouse, with female spouses being at very high risk of acquiring HIV infection. This suggests that future programs that target serodiscordant couples could be a novel and effective means of preventing HIV-1 transmission in Tanzania

Effect of high-intensity versus low-intensity praziquantel treatment on HIV disease progression in HIV and Schistosoma mansoni co-infected patients: a randomised controlled trial

Background: It has been hypothesised that Schistosoma co-infection exacerbates HIV progression, and hence anthelminthic intervention in co-infected individuals will delay it. We evaluated effects of high-intensity versus low-intensity praziquantel treatment of schistosomiasis on HIV disease progression among co-infected patients from fishing populations around Lake Victoria, Uganda. Methods: Between August 2012 and September 2015, we conducted an open-label randomised, controlled trial. Adults, antiretroviral therapy-naïve, CD4 counts ≥350 cells/μl, HIV and S. mansoni co-infected, were randomised 1:1 to praziquantel (40mg/kg) given quarterly (starting at enrolment) or annually (starting 12 weeks after enrolment; such that low-intensity participants were still untreated when sampled at 12 weeks). A non-randomised HIV-positive S. mansoni-negative comparison group was recruited. The primary outcome was mean change in plasma viral load at 12 and 60 weeks. Results: In total 363 participants (high-intensity 113, low-intensity 113, comparison group 137) were recruited; 96 (85.0%), 97 (85.8%) and 107 (78.1%) completed 60 weeks of follow up, respectively. Adjusting for baseline age and viral load, the geometric mean ratio (aGMR [95%CI]) viral load for high-intensity vs low-intensity groups at 12 weeks was 0.90 [0.65, 1.25] p=0.55 and at 60 weeks 1.88 [0.78, 4.53] p=0.16. Results in the comparison group were similar to trial arms. High-intensity, compared to low-intensity, treatment resulted in substantially lower S. mansoni prevalence at all follow up visits (p&lt;0.05). Conclusions: In communities with a high burden of both S. mansoni and HIV infection, high-intensity treatment of S. mansoni does not delay HIV progression despite relevant benefit for parasite clearance. Trial registration: ISRCTN15371662 (17/11/2016)</ns4:p

Impact of schistosome infection on long-term HIV/AIDS outcomes.

BACKGROUND: Africa bears the burden of approximately 70% of global HIV infections and 90% of global schistosome infections. We sought to investigate the impact of schistosome infection at the time of HIV-1 seroconversion on the speed of HIV-1 disease progression, as measured by the outcome CD4+ T-cell (CD4) counts <350 cells/μL and/or death. We hypothesized that people who had been infected with Schistosoma spp. at the time they acquired HIV-1 infection would have impaired antiviral immune response, thus leading them to progress twice as fast to a CD4 count less than 350 cells/μL or death than would people who had been free of schistosomes at time of HIV-1 seroconversion. METHODS AND PRINCIPAL FINDINGS: We conducted a longitudinal study in Tanzania from 2006 to 2017 using stored blood spot samples, demographic surveillance and sero-survey data from the community, and a review of clinical charts. A competing risk analysis was performed to look at the difference in time to reaching CD4 counts < 350 cells/μL and/or death in HIV-1-infected people who were infected versus not infected with Schistosoma spp. at time of HIV-1 seroconversion. We found an 82% reduction in risk of reaching the outcome in seroconverters who had been infected with Schistosoma (subHazard Ratio = 0.18[0.068,0.50], p = 0.001) after adjusting for age, occupation, clinic attendance and time-dependent covariates. CONCLUSIONS: Our study demonstrates that people with schistosome infection at the time of HIV-seroconversion develop adverse HIV outcomes more slowly than those without. The findings are contrary to our original hypothesis. Our current longitudinal findings suggest complex interactions between HIV-1 and schistosome co-infections that may be modulated over time. We urge new immunological studies to investigate the long-term impact of schistosome infection on HIV-1 viral load and CD4 counts as well as related immunologic pathways

Female Genital Schistosomiasis and HIV-1 Incidence in Zambian Women: A Retrospective Cohort Study.

BACKGROUND: Female genital schistosomiasis (FGS) has been associated with prevalent HIV-1. We estimated the incidence of HIV-1 infection in Zambian women with and without FGS. METHODS: Women (aged 18-31, nonpregnant, sexually active) were invited to participate in this study in January-August 2018 at the final follow-up of the HPTN 071 (PopART) Population Cohort. HIV-1-negative participants at enrollment (n = 492) were included in this analysis, with testing to confirm incident HIV-1 performed in HPTN 071 (PopART). The association of incident HIV-1 infection with FGS (Schistosoma DNA detected by polymerase chain reaction [PCR] in any genital specimen) was assessed with exact Poisson regression. RESULTS: Incident HIV-1 infections were observed in 4.1% (20/492) of participants. Women with FGS were twice as likely to seroconvert as women without FGS but with no statistical evidence for a difference (adjusted rate ratio, 2.16; 95% CI, 0.21-12.30; P = .33). Exploratory analysis suggested an association with HIV-1 acquisition among women with ≥2 positive genital PCR specimens (rate ratio, 6.02; 95% CI, 0.58-34.96; P = .13). CONCLUSIONS: Despite higher HIV seroconversion rates in women with FGS, there was no statistical evidence of association, possibly due to low power. Further longitudinal studies should investigate this association in a setting with higher schistosomiasis endemicity

Association of Female Genital Schistosomiasis With the Cervicovaginal Microbiota and Sexually Transmitted Infections in Zambian Women.

BACKGROUND: The cervicovaginal microbiota, including sexually transmitted infections (STIs), have not been well described in female genital schistosomiasis (FGS). METHODS: Women (aged 18-31, sexually active, nonpregnant) were invited to participate at the final follow-up of the HPTN 071 (PopART) Population Cohort in January-August 2018. We measured key species of the cervicovaginal microbiota (Lactobacillus crispatus, L. iners, Gardnerella vaginalis, Atopobium vaginae, and Candida) and STIs (Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, and Mycoplasma genitalium) using quantitative PCR (qPCR). We evaluated associations of the microbiota and STI presence and concentration with FGS (qPCR-detected Schistosoma DNA in any of 3 genital specimens). RESULTS: The presence and concentration of key cervicovaginal species did not differ between participants with (n = 30) or without FGS (n = 158). A higher proportion of participants with FGS had T. vaginalis compared with FGS-negative women (P = .08), with further analysis showing that T. vaginalis was more prevalent among women with ≥2 Schistosoma qPCR-positive genital specimens (50.0%, 8/16) than among FGS-negative women (21.5%, 34/158; P = .01). CONCLUSIONS: We found weak evidence of an association between the presence of T. vaginalis and FGS, with a stronger association in women with a higher-burden FGS infection. Additional research is needed on potential between-parasite interactions, especially regarding HIV-1 vulnerability

Sensitive diagnostic tools and targeted drug administration strategies are needed to eliminate schistosomiasis.

Although preventive chemotherapy has been instrumental in reducing schistosomiasis incidence worldwide, serious challenges remain. These problems include the omission of certain groups from campaigns of mass drug administration, the existence of persistent disease hotspots, and the risk of recrudescent infections. Central to these challenges is the fact that the diagnostic tools currently used to establish the burden of infection are not sensitive enough, especially in low-endemic settings, which results in underestimation of the true prevalence of active Schistosoma spp infections. This central issue necessitates that the current schistosomiasis control strategies recommended by WHO are re-evaluated and, possibly, adapted. More targeted interventions and novel approaches have been used to estimate the prevalence of schistosomiasis, such as establishing infection burden by use of precision mapping, which provides high resolution spatial information that delineates variations in prevalence within a defined geographical area. Such information is instrumental in guiding targeted intervention campaigns. However, the need for highly accurate diagnostic tools in such strategies is a crucial factor that is often neglected. The availability of highly sensitive diagnostic tests also opens up the possibility of applying strategies of sample pooling to reduce the cost of control programmes. To interrupt the transmission of, and eventually eliminate, schistosomiasis, better local targeting of preventive chemotherapy, in combination with highly sensitive diagnostic tools, is crucial

Validation and Optimization of Host Immunological Bio-Signatures for a Point-of-Care Test for TB Disease.

The development of a non-sputum-based, point-of-care diagnostic test for tuberculosis (TB) is a priority in the global effort to combat this disease, particularly in resource-constrained settings. Previous studies have identified host biomarker signatures which showed potential, but there is a need to validate and refine these for development as a test. We recruited 1,403 adults presenting with symptoms suggestive of pulmonary TB at primary healthcare clinics in six countries from West, East and Southern Africa. Of the study cohort, 326 were diagnosed with TB and 787 with other respiratory diseases, from whom we randomly selected 1005 participants. Using Luminex® technology, we measured the levels of 20 host biomarkers in serum samples which we used to evaluate the diagnostic accuracy of previously identified and novel bio-signatures. Our previously identified seven-marker bio-signature did not perform well (sensitivity: 89%, specificity: 60%). We also identified an optimal, two-marker bio-signature with a sensitivity of 94% and specificity of 69% in patients with no history of previous TB. This signature performed slightly better than C-reactive protein (CRP) alone. The cut-off value for a positive diagnosis differed for human immuno-deficiency virus (HIV)-positive and -negative individuals. Notably, we also found that no signature was able to diagnose TB adequately in patients with a prior history of the disease. We have identified a two-marker, pan-African bio-signature which is more robust than CRP alone and meets the World Health Organization (WHO) target product profile requirements for a triage test in both HIV-negative and HIV-positive individuals. This signature could be incorporated into a point-of-care device, greatly reducing the necessity for expensive confirmatory diagnostics and potentially reducing the number of cases currently lost to follow-up. It might also potentially be useful with individuals unable to provide sputum or with paucibacillary disease. We suggest that the performance of TB diagnostic signatures can be improved by incorporating the HIV-status of the patient. We further suggest that only patients who have never had TB be subjected to a triage test and that those with a history of previous TB be evaluated using more direct diagnostic techniques

A cluster randomized controlled trial for assessing POC-CCA test based praziquantel treatment for schistosomiasis control in pregnant women and their young children: study protocol of the freeBILy clinical trial in Madagascar.

BACKGROUND: Mass drug administration (MDA) of praziquantel is one of the main control measures against human schistosomiasis. Although there are claims for including pregnant women, infants and children under the age of 5 years in high-endemic regions in MDA campaigns, they are usually not treated without a diagnosis. Diagnostic tools identifying infections at the primary health care centre (PHCC) level could therefore help to integrate these vulnerable groups into control programmes. freeBILy (fast and reliable easy-to-use-diagnostics for eliminating bilharzia in young children and mothers) is an international consortium focused on implementing and evaluating new schistosomiasis diagnostic strategies. In Madagascar, the study aims to determine the effectiveness of a test-based schistosomiasis treatment (TBST) strategy for pregnant women and their infants and children up until the age of 2 years. METHODS: A two-armed, cluster-randomized, controlled phase III trial including 5200 women and their offspring assesses the impact of TBST on child growth and maternal haemoglobin in areas of medium to high endemicity of Schistosoma mansoni. The participants are being tested with the point of care-circulating cathodic antigen (POC-CCA) test, a commercially available urine-based non-invasive rapid diagnostic test for schistosomiasis. In the intervention arm, a POC-CCA-TBST strategy is offered to women during pregnancy and 9 months after delivery, for their infants at 9 months of age. In the control arm, study visit procedures are the same, but without the POC-CCA-TBST procedure. All participants are being offered the POC-CCA-TBST 24 months after delivery. This trial is being integrated into the routine maternal and child primary health care programmes at 40 different PHCC in Madagascar's highlands. The purpose of the trial is to assess the effectiveness of the POC-CCA-TBST for controlling schistosomiasis in young children and mothers. DISCUSSION: This trial assesses a strategy to integrate pregnant women and their children under the age of 2 years into schistosomiasis control programmes using rapid diagnostic tests. It includes local capacity building for clinical trials and large-scale intervention research. TRIAL REGISTRATION: Pan-African Clinical Trial Register PACTR201905784271304. Retrospectively registered on 15 May 2019

Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis.

HIV-1 infection disproportionately affects women in sub-Saharan Africa, where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap. Female genital schistosomiasis (FGS), an inflammatory disease caused by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection. Elevated levels of the chemokines MIP-1α (CCL-3), MIP-1β (CCL-4), IP-10 (CXCL-10), and IL-8 (CXCL-8) in cervicovaginal lavage (CVL) have been associated with HIV-1 acquisition. We hypothesize that levels of cervicovaginal cytokines may be raised in FGS and could provide a causal mechanism for the association between FGS and HIV-1. In the cross-sectional BILHIV study, specimens were collected from 603 female participants who were aged 18-31 years, sexually active, not pregnant and participated in the HPTN 071 (PopART) HIV-1 prevention trial in Zambia. Participants self-collected urine, and vaginal and cervical swabs, while CVLs were clinically obtained. Microscopy and Schistosoma circulating anodic antigen (CAA) were performed on urine. Genital samples were examined for parasite-specific DNA by PCR. Women with FGS (n=28), defined as a positive Schistosoma PCR from any genital sample were frequency age-matched with 159 FGS negative (defined as negative Schistosoma PCR, urine CAA, urine microscopy, and colposcopy imaging) women. Participants with probable FGS (n=25) (defined as the presence of either urine CAA or microscopy in combination with one of four clinical findings suggestive of FGS on colposcope-obtained photographs) were also included, for a total sample size of 212. The concentrations of 17 soluble cytokines and chemokines were quantified by a multiplex bead-based immunoassay. There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. An exploratory analysis of those women with a higher FGS burden, defined by ≥2 genital specimens with detectable Schistosoma DNA (n=15) showed, after adjusting for potential confounders, a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women, with differences unlikely to be due to chance (p=0.037 for IL-4 and p<0.001 for IL-5 after adjusting for multiple testing). FGS may alter the female genital tract immune environment, but larger studies in areas of varying endemicity are needed to evaluate the association with HIV-1 vulnerability