Zipime-Weka-Schista study protocol: a longitudinal cohort study and economic evaluation of an integrated home-based approach for genital multipathogen screening in women, including female genital schistosomiasis, human papillomavirus, Trichomonas and HIV in Zambia.

INTRODUCTION: Multiplathogen home-based self-sampling offers an opportunity to increase access to screening and treatment in endemic settings with high coinfection prevalence of sexually transmitted (HIV, Trichomonas vaginalis (Tv), human papillomavirus (HPV)) and non-sexually transmitted pathogens (Schistosoma haematobium (Sh)). Chronic coinfections may lead to disability (female genital schistosomiasis) and death (cervical cancer). The Zipime-Weka-Schista (Do self-testing sister!) study aims to evaluate the validity, acceptability, uptake, impact and cost-effectiveness of multipathogen self-sampling for genital infections among women in Zambia. METHODS AND ANALYSIS: This is a longitudinal cohort study aiming to enrol 2500 non-pregnant, sexually active and non-menstruating women aged 15-50 years from two districts in Zambia with 2-year follow-up. During home visits, community health workers offer HIV and Tv self-testing and cervicovaginal self-swabs for (1) HPV by GeneXpert and, (2) Sh DNA detection by conventional (PCR)and isothermal (recombinase polymerase assay) molecular methods. Schistosoma ova and circulating anodic antigen are detected in urine. At a clinic follow-up, midwives perform the same procedures and obtain hand-held colposcopic images. High-risk HPV positive women are referred for a two-quadrant cervical biopsy according to age and HIV status. A cost-effectiveness analysis is conducted in parallel. ETHICS AND DISSEMINATION: The University of Zambia Biomedical Research Ethics Committee (UNZABREC) (reference: 1858-2021), the London School of Hygiene and Tropical Medicine (reference: 25258), Ministry of Health and local superintendents approved the study in September 2021.Written informed consent was obtained from all participants prior to enrolment. Identifiable data collected are stored securely and their confidentiality is protected in accordance with the Data Protection Act 1998.

Female genital schistosomiasis burden and risk factors in two endemic areas in Malawi nested in the Morbidity Operational Research for Bilharziasis Implementation Decisions (MORBID) cross-sectional study.

BACKGROUND: Female genital schistosomiasis (FGS), caused by the parasite Schistosoma haematobium (Sh), is prevalent in Sub-Saharan Africa. FGS is associated with sexual dysfunction and reproductive morbidity, and increased prevalence of HIV and cervical precancerous lesions. Lack of approved guidelines for FGS screening and diagnosis hinder accurate disease burden estimation. This study evaluated FGS burden in two Sh-endemic areas in Southern Malawi by visual and molecular diagnostic methods. METHODOLOGY/PRINCIPAL FINDINGS: Women aged 15-65, sexually active, not menstruating, or pregnant, were enrolled from the MORBID study. A midwife completed a questionnaire, obtained cervicovaginal swab and lavage, and assessed FGS-associated genital lesions using hand-held colposcopy. 'Visual-FGS' was defined as specific genital lesions. 'Molecular-FGS' was defined as Sh DNA detected by real-time PCR from swabs. Microscopy detected urinary Sh egg-patent infection. In total, 950 women completed the questionnaire (median age 27, [IQR] 20-38). Visual-and molecular-FGS prevalence were 26·9% (260/967) and 8·2% (78/942), respectively. 6·5% of women with available genital and urinary samples (38/584) had egg-patent Sh infection. There was a positive significant association between molecular- and visual-FGS (AOR = 2·9, 95%CI 1·7-5·0). 'Molecular-FGS' was associated with egg-patent Sh infection (AOR = 7·5, 95% CI 3·27-17·2). Some villages had high 'molecular-FGS' prevalence, despite <10% prevalence of urinary Sh among school-age children. CONCLUSIONS/SIGNIFICANCE: Southern Malawi carries an under-recognized FGS burden. FGS was detectable in villages not eligible for schistosomiasis control strategies, potentially leaving girls and women untreated under current WHO guidelines. Validated field-deployable methods could be considered for new control strategies.

A cross-sectional pilot household study of Schistosoma mansoni burden and associated morbidities in Lake Albert, Uganda.

OBJECTIVES: Schistosomiasis is persistent in Lake Albert, Uganda, but local data are limited. This study aims to describe the local burden of moderate-to-heavy infection and associated morbidity in all ages and identify factors associated with these outcomes to guide further research. METHODS: This cross-sectional pilot study was conducted in July-August, 2022 in four village sites (Walukuba, Rwentale, Kyabarangwa and Runga) of the Praziquantel in Preschoolers (PIP) trial. Residents (approximately four per household) of any age of households of PIP participants were eligible, but individuals <10 years were only enrolled if no older individuals were available. Socio-demographic information, household location, single stool Kato-Katz and hepatic ultrasound results were obtained for a convenience sampled subset of trial households. The primary outcome, moderate-to-heavy infection (≥100 eggs per gram of faeces), was analysed using mixed-effects logistic regression, with a household random effect. Univariate analyses were used for the secondary outcome, periportal fibrosis (Niamey protocol ultrasound image pattern C-F). RESULTS: Of 243 participants with a median age of 22 (interquartile range 12-33) years from 66 households, 49.8% (103/207 with a Kato-Katz result) had moderate-to-heavy infection and 11.2% (25/224 with ultrasound data) had periportal fibrosis. Moderate-to-heavy infection clustered by household (intraclass correlation coefficient = 0.11) and, in multivariable analysis, varied by village (Walukuba vs. Kyabarangwa adjusted odds ratio [aOR] 0.11, 95% CI 0.02-0.71), was highest in participants aged 10-15 years (vs. 5-9 years aOR 6.14, 95% CI 1.61-23.38) and lower in those reporting praziquantel treatment in the past year (aOR 0.39, 95% CI 0.18-0.88). CONCLUSIONS: In this setting, schistosome infection and morbidity are pervasive in all age groups. More intensive interventions are needed, for example more frequent praziquantel treatment, under investigation in the PIP trial and improved water and sanitation. More research is needed to understand local treatment barriers and optimal control strategies.

Female Genital Schistosomiasis Lesion Resolution Post-Treatment with Praziquantel in Zambian Adults.

We evaluated changes in female genital schistosomiasis (FGS) 6 to 12 months after praziquantel treatment among 43 adult Zambian women. Most women (60%) experienced decreased FGS severity and 23% experienced complete lesion resolution. This is the first study to demonstrate a meaningful effect of praziquantel treatment of FGS in adult women.

Time to bring female genital schistosomiasis out of neglect.

BACKGROUND: Female genital schistosomiasis (FGS) is a chronic gynaecological disease affecting girls and women in sub-Saharan Africa (SSA), caused by the parasite Schistosoma (S.) haematobium. FGS is associated with sexual dysfunction, reproductive tract morbidity and increased prevalence of HIV and cervical precancer lesions. SOURCE OF DATA: Key peer-reviewed published literature. AREAS OF AGREEMENT: FGS screening and diagnosis require costly equipment and specialized training, seldom available in resource-limited settings. FGS surveillance is not included in wider schistosomiasis control strategies. The interplay of FGS with other SRH infections is not fully understood. Integration of FGS within sexual and reproductive health (SRH) control programmes needs to be explored. AREAS OF CONTROVERSY: There are no standardized methods for individual or population-based FGS screening and diagnosis, hindering accurate disease burden estimates and targeted resource allocation. Treatment recommendations rely on public health guidelines, without rigorous clinical evidence on efficacy. GROWING POINTS: Integrating FGS screening with SRH programmes offers an opportunity to reach at-risk women with limited access to healthcare services. Home-based self-sampling coupled with handheld colposcopes operated by primary healthcare workers show promise for FGS diagnosis and surveillance at scale. AREAS TIMELY FOR DEVELOPING RESEARCH: There is growing interest in decentralizing strategies for FGS screening and diagnosis. The accurate predictions on the 'cost-effectiveness' of these approaches will determine their affordability and feasibility within the overburdened health systems in SSA. Clinical trials are needed to optimize FGS treatment. Longitudinal studies can expand on the epidemiological knowledge on co-morbidities and integration within other SRH interventions.

Relationships Between Schistosoma mansoni Infection Intensity and Nutritional Status and Anemia Among Preschool-aged Children in Uganda.

In a cross-sectional analysis of 354 Ugandan children (age 12-48 months) infected with Schistosoma mansoni, we assessed relationships between infection intensity and nutritional morbidities. Higher intensity was associated with an increased risk for anemia (RR = 1.05, 95% confidence interval [CI] 1.01-1.10) yet not associated with risk for underweight, stunting, or wasting.

Baseline Liver Ultrasound Findings in Preschool Children From the Praziquantel in Preschoolers Trial in Lake Albert, Uganda.

BACKGROUND: Periportal fibrosis is a late-stage manifestation of chronic infection with Schistosoma mansoni . Praziquantel (PZQ), the only drug available for the treatment of schistosomiasis, has limited effect in treating established morbidity. Preschool-age children (PSAC) are not considered to be an at-risk population for severe morbidity. However, the prevalence of periportal fibrosis in PSAC in S. mansoni endemic settings is unknown. METHODS: As part of a phase II clinical trial comparing different dosing regimens of PZQ in children age 12-47 months infected with S. mansoni in Uganda ("praziquantel in preschoolers" trial), we present baseline results assessing liver ultrasound (US) findings as per the WHO Niamey Protocol. RESULTS: A total of 7/347 (2%) PSAC had Image Pattern C with pipe stems and echogenic rings suggestive of periportal fibrosis, 29/347 (8%) had Image Pattern B and 58 (17%) had evidence of periportal thickening There were higher adjusted odds of periportal thickening with older age [odds ratio (OR): 1.04; 95% confidence interval (CI): 1.00-1.07], primary maternal education (OR: 1.04; 95% CI: 1.00-1.07) and being taken to the lake weekly (OR: 3.02; 95% CI: 1.19-7.63). A further 44/347 children (13%) had a rounded caudal liver edge which was associated with high S. mansoni infection intensity (adjusted OR: 3.31; 95% CI: 1.46-7.51). CONCLUSIONS: Incipient schistosomiasis-related liver morbidity was detected in young children enrolled in the praziquantel in preschoolers trial. Adequate age-adjusted reference measurements for liver ultrasound findings in very small children are lacking but urgently needed. Schistosomiasis-related fibrosis may be delayed or averted with early and repeated PZQ treatment.

A 14-year follow-up of ultrasound-detected urinary tract pathology associated with urogenital schistosomiasis in women living in the Msambweni region of coastal Kenya.

BACKGROUND: Complications of urogenital schistosomiasis include acute inflammatory and chronic fibrotic changes within the urogenital tract. Disease burden of this neglected tropical disease is often underestimated, as only active, urine egg-patent Schistosoma infection is formally considered. Previous studies have focussed on short-term effects of praziquantel treatment on urinary tract pathology, demonstrating that acute inflammation is reversible. However, the reversibility of chronic changes is less well studied. METHODS: Our study compared, at two time points 14 y apart, urine egg-patent infection and urinary tract pathology in a cohort of women living in a highly endemic area having intermittent praziquantel treatment(s). In 2014 we matched 93 women to their findings in a previous study in 2000. RESULTS: Between 2000 and 2014 the rate of egg-patent infection decreased from 34% (95% confidence interval [CI] 25 to 44) to 9% (95% CI 3 to 14). However, urinary tract pathology increased from 15% (95% CI 8 to 22) to 19% (95% CI 11 to 27), with the greatest increase seen in bladder thickening and shape abnormality. CONCLUSIONS: Despite praziquantel treatment, fibrosis from chronic schistosomiasis outlasts the presence of active infection, continuing to cause lasting morbidity. We suggest that future efforts to eliminate persistent morbidity attributable to schistosomiasis should include intensified disease management.

Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022.

In September 2022, the Drug Discovery Unit at the University of Dundee, UK, organised an international meeting at the Wellcome Collection in London to explore the current clinical situation and challenges associated with treating schistosomiasis. The aim of this meeting was to discuss the need for new treatments in view of the clinical situation and to ascertain what the key requirements would be for any potential new anti-schistosomals. This information will be essential to inform ongoing drug discovery efforts for schistosomiasis. We also discussed the potential drug discovery pathway and associated criteria for progressing compounds to the clinic. To date, praziquantel (PZQ) is the only drug available to treat all species causing schistosomiasis, but it is often unable to completely clear parasites from an infected patient, partially due to its inactivity against juvenile worms. PZQ-mediated mass drug administration campaigns conducted in endemic areas (e.g., sub-Saharan Africa, where schistosomiasis is primarily prevalent) have contributed to reducing the burden of disease but will not eliminate the disease as a public health problem. The potential for Schistosoma to develop resistance towards PZQ, as the sole treatment available, could become a concern. Consequently, new anthelmintic medications are urgently needed, and this Perspective aims to capture some of the learnings from our discussions on the key criteria for new treatments.

Visual diagnosis of female genital schistosomiasis in Zambian women from hand-held colposcopy: agreement of expert image review.

Female genital schistosomiasis (FGS) can occur in S. haematobium infection and is caused by parasite egg deposition in the genital tract. Confirming a diagnosis of FGS is challenging due to the lack of a diagnostic reference standard. A 2010 expert-led consensus meeting proposed visual inspection of the cervicovaginal mucosa as an adequate reference standard for FGS diagnosis. The agreement of expert human reviewers for visual-FGS has not been previously described. Methods: In two Zambian communities, non-menstruating, non-pregnant, sexually-active women aged 18-31 years participating in the HPTN 071 (PopART) Population-Cohort were enrolled in a cross-sectional study. Self-collected genital swabs and a urine specimen were collected at a home visit; trained midwives performed CVL and hand-held colposcopy at a clinic visit. S. haematobium eggs and circulating anodic antigen (CAA) were detected from urine. Two expert reviewers independently diagnosed visual-FGS as the presence of sandy patches, rubbery papules or abnormal blood vessels in digital cervicovaginal images obtained by hand-held colposcopy. PCR-FGS was defined as Schistosoma DNA detected by real-time PCR in any genital specimen (CVL or genital swab). Results: Of 527 women with cervicovaginal colposcopic images, 468/527 (88.8%) were deemed interpretable by Reviewer 1 and 417/527 (79.1%) by Reviewer 2. Visual-FGS was detected in 35.3% (165/468) of participants by expert review of colposcopic images by Reviewer 1 and in 63.6% (265/417) by Reviewer 2. Cohen's kappa statistic for agreement between the two expert reviewers was 0.16, corresponding to "slight" agreement. The reviewers made concordant diagnoses in 38.7% (204/527) participants (100 negative, 104 positive) and discordant diagnoses in 31.8% (168/527) participants. Conclusions: The unexpectedly low level of correlation between expert reviewers highlights the imperfect nature of visual diagnosis for FGS based on cervicovaginal images obtained with a hand-held colposcope. This finding is a call to action for improved point-of-care diagnostics for female genital schistosomiasis.

The Presence of Hemoglobin in Cervicovaginal Lavage Is Not Associated With Genital Schistosomiasis in Zambian Women From the BILHIV Study.

Background: Female genital schistosomiasis (FGS) occurs when Schistosoma haematobium eggs are deposited in reproductive tissue. Female genital schistosomiasis in the cervical mucosa is associated with increased vascularity. If FGS is associated with the presence of hemoglobin in cervicovaginal lavage (CVL), the use of urinary reagent strips to detect hemoglobin in CVL could supplement FGS diagnosis. Methods: Nonmenstruating, nonpregnant, sexually active women aged 18-31 participating in the HPTN 071 (PopART) Population-Cohort were invited in 2 Zambian communities. Genital self-swabs and a urine specimen were collected at a home visit, and CVL and hand-held colposcopy were performed at a midwife led clinic visit. Urinary reagent strips were used to identify hemoglobin in CVL. Eggs and circulating anodic antigen (CAA) were detected from urine. Visual-FGS was defined as the presence of sandy patches, rubbery papules, or abnormal blood vessels. Polymerase chain reaction (PCR)-FGS was defined as Schistosoma deoxyribonucleic acid detected by real-time PCR on CVL or cervical or vaginal swab. Results: Of 209 women with home genital swabs and companion CVL specimens, 66% (138 of 209) had detectable CVL hemoglobin, 13.4% (28 of 209) had PCR-defined FGS, and 17.2% (36 of 209) had visual-FGS. Active Schistosoma infection, diagnosed by CAA or urine microscopy, was present in 21.0% (44 of 209) participants. Active Schistosoma infection (P = .4), PCR-FGS (P = 0.7), and visual-FGS (P = 0.3) were not associated with CVL hemoglobin presence. Results did not differ in subgroups with high infection burden (cycle threshold < 35 or 2-3 positive genital PCR). Conclusions: Polymerase chain reaction-FGS, visual-FGS, and active Schistosoma infection were not associated with the presence of CVL hemoglobin. Further research is needed to establish accessible community-based FGS diagnostics.

An update on female and male genital schistosomiasis and a call to integrate efforts to escalate diagnosis, treatment and awareness in endemic and non-endemic settings: The time is now.

The last decades have brought important insight and updates in the diagnosis, management and immunopathology of female genital schistosomiasis (FGS) and male genital schistosomiasis (MGS). Despite sharing a common parasitic aetiological agent, FGS and MGS have typically been studied separately. Infection with Schistosoma haematobium manifests with gender-specific clinical manifestations and consequences of infection, albeit having a similar pathogenesis within the human genital tract. Schistosoma haematobium is a known urinary bladder carcinogen, but its potential causative role in other types of neoplasia, such as cervical cancer, is not fully understood. Furthermore, the impact of praziquantel treatment on clinical outcomes remains largely underexplored, as is the interplay of FGS/MGS with relevant reproductive tract infections such as HIV and Human Papillomavirus. In non-endemic settings, travel and immigrant health clinics need better guidance to correctly identify and treat FGS and MGS. Our review outlines the latest advances and remaining knowledge gaps in FGS and MGS research. We aim to pave a way forward to formulate more effective control measures and discuss elimination targets. With a growing community awareness in health practitioners, scientists and epidemiologists, alongside the sufferers from these diseases, we aspire to witness a new generation of young women and men free from the downstream disabling manifestations of disease.

Validation of the isothermal Schistosoma haematobium Recombinase Polymerase Amplification (RPA) assay, coupled with simplified sample preparation, for diagnosing female genital schistosomiasis using cervicovaginal lavage and vaginal self-swab samples.

BACKGROUND: Female genital schistosomiasis (FGS) is a neglected and disabling gynecological disease that can result from infection with the parasitic trematode Schistosoma haematobium. Accurate diagnosis of FGS is crucial for effective case management, surveillance and control. However, current methods for diagnosis and morbidity assessment can be inaccessible to those at need, labour intensive, costly and unreliable. Molecular techniques such as PCR can be used to reliably diagnose FGS via the detection of Schistosoma DNA using cervicovaginal lavage (CVL) samples as well as lesser-invasive vaginal self-swab (VSS) and cervical self-swab samples. PCR is, however, currently unsuited for use in most endemic settings. As such, in this study, we assessed the use of a rapid and portable S. haematobium recombinase polymerase amplification (Sh-RPA) isothermal molecular diagnostic assay, coupled with simplified sample preparation methodologies, to detect S. haematobium DNA using CVL and VSS samples provided by patients in Zambia. METHODOLOGY/PRINCIPAL FINDINGS: VSS and CVL samples were screened for FGS using a previously developed Sh-RPA assay. DNA was isolated from VSS and CVL samples using the QIAamp Mini kit (n = 603 and 527, respectively). DNA was also isolated from CVL samples using two rapid and portable DNA extraction methods: 1) the SpeedXtract Nucleic Acid Kit (n = 223) and 2) the Extracta DNA Tissue Prep Kit (n = 136). Diagnostic performance of the Sh-RPA using VSS DNA extacts (QIAamp Mini kit) as well as CVL DNA extracts (QIAamp Mini kit, SpeedXtract Nucleic Acid Kit and Extracta DNA Tissue Prep Kit) was then compared to a real-time PCR reference test. Results suggest that optimal performance may be achieved when the Sh-RPA is used with PuVSS samples (sensitivity 93.3%; specificity 96.6%), however no comparisons between different DNA extraction methods using VSS samples could be carried out within this study. When using CVL samples, sensitivity of the Sh-RPA ranged between 71.4 and 85.7 across all three DNA extraction methods when compared to real-time PCR using CVL samples prepared using the QIAamp Mini kit. Interestingly, of these three DNA extraction methods, the rapid and portable SpeedXtract method had the greatest sensitivity and specificity (85.7% and 98.1%, respectively). Specificity of the Sh-RPA was >91% across all comparisons. CONCLUSIONS/SIGNIFICANCE: These results supplement previous findings, highlighting that the use of genital self-swab sampling for diagnosing FGS should be explored further whilst also demonstrating that rapid and portable DNA isolation methods can be used to detect S. haematobium DNA within clinical samples using RPA. Although further development and assessment is needed, it was concluded that the Sh-RPA, coupled with simplified sample preparation, shows excellent promise as a rapid and sensitive diagnostic tool capable of diagnosing FGS at the point-of-care in resource-poor schistosomiasis-endemic settings.

Impact of a Novel, Low-Cost and Sustainable Health Education Program on the Knowledge, Attitudes, and Practices Related to Intestinal Schistosomiasis in School Children in a Hard-to-Reach District of Madagascar.

Schistosomiasis control requires multisectoral approaches including praziquantel treatment, access to safe water, sanitation and hygiene, and health education. Community input can help ensure health education programs are culturally appropriate to effectively direct protective behavior change. This study reports on the three-stage development of an education program for Malagasy children, with an impact evaluation on their knowledge, attitudes, and practices (KAP) related to intestinal schistosomiasis. A cross-sectional study took place in 2017 with follow-up in 2018 in the hard-to-reach Marolambo district, Madagascar. A novel schistosomiasis education program (SEP) was designed in collaboration with researchers, stakeholders, and local community and included cartoon books, games, songs, puzzles, and blackboard lessons, costing $10 USD per school. KAP questionnaires were completed by 286 children pre-SEP and 273 children post-SEP in 2017, and by 385 and 337 children pre-SEP and post-SEP, respectively, in 2018. Improvements were observed in responses to all questions between pre- and post-education answers in 2017 (53-77%, P < 0.0001) and 2018 (72-98%, P < 0.0001) and in the pre-education answers between years (53-72%, P < 0.0001). Praziquantel mass drug administration attendance improved, rising from 64% to 91% (P < 0.0001), alongside improved latrine use, from 89% to 96% (P = 0.005). This community-consulted and -engaged SEP resulted in substantial improvements in children's understanding of schistosomiasis, with improvements in praziquantel uptake and latrine use. Socioculturally tailored education programs can help gain schistosomiasis control. Continued investment in SEP will help promote the future well-being of children through increased participation in control and treatment activities.

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.

The praziquantel in preschoolers (PIP) trial: study protocol for a phase II PK/PD-driven randomised controlled trial of praziquantel in children under 4 years of age.

BACKGROUND: Over 200 million individuals worldwide are infected with Schistosoma species, with over half of infections occurring in children. Many children experience first infections early in life and this impacts their growth and development; however praziquantel (PZQ), the drug used worldwide for the treatment of schistosomiasis, only has regulatory approval among adults and children over the age of four, although it is frequently used "off label" in endemic settings. Furthermore, pharmacokinetic/pharmacodynamics (PK/PD) evidence suggests the standard PZQ dose of 40 mg/kg is insufficient in preschool-aged children (PSAC). Our goal is to understand the best approaches to optimising the treatment of PSAC with intestinal schistosomiasis. METHODS: We will conduct a randomised, controlled phase II trial in a Schistosoma mansoni endemic region of Uganda and a Schistosoma japonicum endemic region of the Philippines. Six hundred children, 300 in each setting, aged 12-47 months with Schistosoma infection will be randomised in a 1:1:1:1 ratio to receive either (1) 40 mg/kg PZQ at baseline and placebo at 6 months, (2) 40 mg/kg PZQ at baseline and 40 mg/kg PZQ at 6 months, (3) 80 mg/kg PZQ at baseline and placebo at 6 months, or (4) 80 mg/kg PZQ at baseline and 80 mg/kg PZQ at 6 months. Following baseline treatment, children will be followed up for 12 months. The co-primary outcomes will be cure rate and egg reduction rate at 4 weeks. Secondary outcomes include drug efficacy assessed by novel antigenic endpoints at 4 weeks, actively collected adverse events and toxicity for 12 h post-treatment, morbidity and nutritional outcomes at 6 and 12 months, biomarkers of inflammation and environmental enteropathy and PZQ PK/PD parameters. DISCUSSION: The trial will provide valuable information on the safety and efficacy of the 80 mg/kg PZQ dose in PSAC, and on the impact of six-monthly versus annual treatment, in this vulnerable age group. TRIAL REGISTRATION: ClinicalTrials.gov NCT03640377 . Registered on 21 Aug 2018.

Population pharmacokinetics and pharmacodynamics of investigational regimens' drugs in the TB-PRACTECAL clinical trial (the PRACTECAL-PKPD study): a prospective nested study protocol in a randomised controlled trial.

INTRODUCTION: Drug-resistant tuberculosis (TB) remains a global health threat, with little over 50% of patients successfully treated. Novel regimens like the ones being studied in the TB-PRACTECAL trial are urgently needed. Understanding anti-TB drug exposures could explain the success or failure of these trial regimens. We aim to study the relationship between the patients' exposure to anti-TB drugs in TB-PRACTECAL investigational regimens and their treatment outcomes. METHODS AND ANALYSIS: Adults with multidrug-resistant TB randomised to investigational regimens in TB-PRACTECAL will be recruited to a nested pharmacokinetic-pharmacodynamic (PKPD) study. Venous blood samples will be collected at 0, 2 and 23 hours postdose on day 1 and 0, 6.5 and 23 hours postdose during week 8 to quantify drug concentrations in plasma. Trough samples will be collected during week 12, 16, 20 and 24 visits. Opportunistic samples will be collected during weeks 32 and 72. Drug concentrations will be quantified using liquid chromatography-tandem mass spectrometry. Sputum samples will be collected at baseline, monthly to week 24 and then every 2 months to week 108 for MICs and bacillary load quantification. Full blood count, urea and electrolytes, liver function tests, lipase, ECGs and ophthalmology examinations will be conducted at least monthly during treatment.PK and PKPD models will be developed for each drug with nonlinear mixed effects methods. Optimal dosing will be investigated using Monte-Carlo simulations. ETHICS AND DISSEMINATION: The study has been approved by the Médecins sans Frontières (MSF) Ethics Review Board, the LSHTM Ethics Committee, the Belarus RSPCPT ethics committee and PharmaEthics and the University of Witwatersrand Human Research ethics committee in South Africa. Written informed consent will be obtained from all participants. The study results will be shared with public health authorities, presented at scientific conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04081077; Pre-results.

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.

Prevalence of intestinal schistosomiasis in pre-school aged children: a pilot survey in Marolambo District, Madagascar.

School-aged children (SAC) have a considerable burden of intestinal schistosomiasis in Madagascar yet its burden in pre-school aged children (PSAC) is currently overlooked. To assess the at-risk status of PSAC, we undertook a pilot epidemiological survey in June 2019 examining children (n = 89), aged 2-4-years of balanced gender, in six remote villages in Marolambo District, Madagascar. Diagnosis included use of urine-circulating cathodic antigen (CCA) dipsticks and coproscopy of stool with duplicate Kato-Katz (K-K) thick smears. Prevalence of intestinal schistosomiasis by urine-CCA was 67.4% (95% confidence interval [CI]: 56.5-77.2%) and 35.0% (95% CI: 24.7-46.5%) by K-K. The relationship between faecal eggs per gram (epg) and urine-CCA G-scores (G1 to G10) was assessed by linear regression modelling, finding for every increment in G-score, epg increased by 20.4 (6.50-34.4, P = 0.006). Observed proportions of faecal epg intensities were light (78.6%), moderate (17.9%) and heavy (3.6%). Soil-transmitted helminthiasis was noted, prevalence of ascariasis was 18.8% and trichuriasis was 33.8% (hookworm was not reported). Co-infection of intestinal schistosomiasis and soil-transmitted helminthiasis occurred in 36.3% of PSAC. These results provide solid evidence highlighting the overlooked burden of intestinal schistosomiasis in PSAC, and they also offer technical  guidance for better surveillance data for the Madagascan national control programme.