Short-course amphotericin B in addition to sertraline and fluconazole for treatment of HIV-associated cryptococcal meningitis in rural Tanzania.

BACKGROUND: Cryptococcal meningitis accounts for 15% of all AIDS mortality globally. Most cases in low- and middle-income countries are treated with fluconazole monotherapy, which is associated with a high mortality. New available therapies are needed. Short-course amphotericin B has been shown to be a safe and efficient therapeutic option. Sertraline has in vitro fungicidal activity against Cryptococcus and bi-directional synergy with fluconazole. METHODS: We conducted an open-label clinical trial to assess the safety and efficacy of sertraline 400 mg/day and fluconazole 1200 mg/day (n = 28) vs sertraline, fluconazole and additional 5 days of amphotericin B deoxycholate 0.7-1 mg/kg (n = 18) for cryptococcal meningitis. RESULTS: Two-week survival was 64% (18/28) without amphotericin and 89% (16/18) with amphotericin, and 10-week survival was 21% (6/28) vs 61% (11/18), respectively (P = .012). The cerebrospinal fluid (CSF) Cryptococcus clearance rate was 0.264 log10 colony-forming units (CFU)/mL of CSF/day (95% CI: 0.112-0.416) without amphotericin and 0.473 log10 CFU/mL/day (95% CI: 0.344-0.60) with short-course amphotericin (P = .03). Sertraline was discontinued in one participant due to side effects. Four participants receiving amphotericin B experienced hypokalemia <2.4 mEq/L. CONCLUSIONS: Short-course amphotericin substantially increased CSF clearance and 10-week survival. Adjunctive sertraline improved 2-week CSF fungal clearance but did not improve 10-week mortality compared with published data using fluconazole 1200 mg/day monotherapy (early fungicidal activity 0.15 log10 CFU/mL/day).

Female genital schistosomiasis is a neglected public health problem in Tanzania: Evidence from a scoping review.

Schistosoma haematobium, the parasite that causes urogenital schistosomiasis, is widely prevalent in Tanzania. In addition to well-known effects on the urinary tract, S. haematobium also causes clinically- evident damage to the reproductive tract in approximately half of infected women, which is known as female genital schistosomiasis (FGS). FGS has major gynecologic and social consequences on women's reproductive health, yet little information is available regarding FGS in Tanzania. To cover that gap, we conducted the present scoping review to examine the epidemiology of FGS in Tanzania (both in the mainland and Zanzibar island) and to make recommendations for future work in this area. The available evidence from community-based and hospital-based retrospective studies indicates that FGS is a significant health problem in the country. Very few community-based studies have been reported from mainland Tanzania, and Zanzibar. Our review highlights the scarcity of efforts to address FGS in Tanzania and the need for additional community-based studies. The studies will help us understand the true burden of the disease nationwide, to assess the impact of praziquantel on FGS lesions, and to address social and mental health in relation to FGS. This review emphasizes integration of delivery of FGS related services in primary health care systems through the reproductive health clinics which covers sexually transmitted infections, HIV and cervical cancer screening. These actions are essential if this neglected gynecological disease is to be addressed in Tanzania.

High sensitivity but low specificity of the risk factors and symptoms questionnaire in diagnosing female genital schistosomiasis among sexually active women with genital lesions in selected villages of Maswa District, North-Western Tanzania.

BACKGROUND: The diagnosis of Female Genital Schistosomiasis (FGS) which is a clinical feature of urogenital schistosomiasis caused by Schistosoma haematobium is challenging, especially in primary healthcare facilities characterized by low resources which are dependent by the majority of the FGS endemic communities. To facilitate and improve diagnosis in these settings, a simple risk factors and symptoms tool has been developed to help healthcare workers at primary healthcare facilities identify and manage FGS cases. However, the sensitivity and specificity of the tool are not known. Therefore, the objective of this study was to assess the performance of risk factors and symptoms tools in diagnosing FGS in adolescent girls and women of reproductive age in selected villages of north-western Tanzania. METHODS: A community-based analytical cross-sectional study was conducted among 347 women aged 18-49 years in Maswa District, north-western Tanzania. A single urine sample was collected from each participant and screened for S. haematobium eggs using a urine filtration technique. Consenting participants (n = 177), underwent thorough speculum examination by trained gynaecologists using a digital portable colposcopy to capture images of the cervix and vagina. All the captured pictures were examined independently by two pairs (2 gynaecologists in each pair) of qualified obstetricians and gynaecologists. A descriptive analysis and logistic regression were used to demonstrate the prevalence, symptoms, and risk factors of FGS. RESULTS: The mean age of 347 women enrolled in the study was 30 years (Standard Deviation (SD) ±7.7) and the prevalence of women with symptoms suggestive of FGS was 15.8% (95% CI; 10.8%- 22.0) by colposcope and 87% (95% CI; 83.0%-90.4%) using the risk factor and symptom checklist. The overall sensitivity, specificity, positive and negative predictive value of symptoms and risk factors checklist tool for diagnosing FGS schistosomiasis (≥7 score points) using colposcope as a reference test were 85.7% (95%CI; 80.6%- 90.9%), 8.7% (95%CI; 4.6%-12.9%), 15.0% (95%CI; 9.7%-20.3%) and 76.5% (95%CI; 70.2%-82.7%). Multivariate analysis showed that female genital schistosomiasis using a risk factor and symptom checklist was associated with fetching water in contaminated fresh water (aOR:21.8, 95%CI;2.8-171.2, P <0.003), self-reported pelvic pain (aOR:5.3, 95%CI; 1.1-25.9, P< 0.04) and having any urinary symptoms (aOR:12.2, 95%CI; 1.5-96.3, P<0.018). Urine microscopy results were available for 345 participants, of these, 3.5% (12/345) (95% CI; 1.8%-6.0%) were positive for S. haematobium infection. CONCLUSION: Female genital schistosomiasis and urinary-related symptoms are common in the current study population. The risk factor and symptoms checklist for diagnosis of FGS achieved high sensitivity but low specificity for women who scored ≥7 points using colposcope as a reference diagnostic test. At present, the call to integrate FGS into the reproductive health services for women has received much attention, however, the diagnostic part of FGS remains a challenge, thus there is a need to continue evaluating this tool in different population and age structures in endemic areas.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to multidose vaccination regimens or no vaccination: An updated systematic review of evidence from clinical trials.

Objectives: This study systematically reviewed the published literature from clinical trials on the efficacy and immunogenicity of single-dose HPV vaccination compared to multidose schedules or no HPV vaccination. Methods: Four databases were searched for relevant articles published from Jan-1999 to Feb-2023. Articles were assessed for eligibility for inclusion using pre-defined criteria. Relevant data were extracted from eligible articles and a descriptive quality assessment was performed for each study. A narrative data synthesis was conducted, examining HPV infection, other clinical outcomes and immunogenicity responses by dose schedule. Results: Fifteen articles reporting data from six studies (all in healthy young females) were included. One article was included from each of three studies that prospectively randomised participants to receive a single HPV vaccine dose versus one or more comparator schedule(s). The other 12 articles reported data from three studies that randomised participants to receive multidose HPV vaccine (or control vaccine) schedules; in those studies, some participants failed to complete their allocated schedule, and evaluations were conducted to compare participants who actually received one, two or three doses. Across all efficacy studies, the incidence or prevalence of HPV16/18 infection was very low among HPV-vaccinated participants, regardless of the number of doses received; with no evidence for a difference between dose groups. In immunogenicity studies, HPV16/18 antibody seropositivity rates were high among all HPV-vaccinated participants. Antibody levels were significantly lower with one dose compared to two or three doses, but levels with one dose were stable and sustained to 11 years post-vaccination. Conclusions: Results from this review support recent World Health Organization recommendations allowing either one- or two-dose HPV vaccination in healthy young females. Longer-term efficacy and immunogenicity data from ongoing studies are awaited. Randomised trials of single-dose HPV-vaccination are urgently needed in other populations, e.g. boys, older females and people with HIV.

Assessing the prevalence of Female Genital Schistosomiasis and comparing the acceptability and performance of health worker-collected and self-collected cervical-vaginal swabs using PCR testing among women in North-Western Tanzania: The ShWAB study.

BACKGROUND: Female Genital Schistosomiasis (FGS) is a neglected disease of the genital tract due to the inflammatory response to the presence of Schistosoma haematobium eggs in the genital tract. The WHO has prioritized the improvement of diagnostics for FGS and previous studies have explored the PCR-based detection of Schistosoma DNA on genital specimens, with encouraging results. This study aimed to determine the prevalence of FGS among women living in an endemic district in North-western Tanzania, using PCR on samples collected though cervical-vaginal swabs, and to compare the performance of self-collected and healthcare worker-collected (operator-collected) samples, and the acceptability of the different sampling methods. METHODS/PRINCIPAL FINDINGS: A cross-sectional study was conducted involving 211 women living in 2 villages in the Maswa district of North-western Tanzania. Urine, self-collected and operator-collected cervical-vaginal swabs were obtained from participants. A questionnaire was administered, focusing on the comfortability in undergoing different diagnostic procedures. Prevalence of urinary schistosomiasis, as assessed by eggs in urine, was 8.5% (95%CI 5.1-13.1). DNA was pre-isolated from genital swabs and transported at room temperature to Italy for molecular analysis. Prevalence of active schistosomiasis, urinary schistosomiasis, and FGS were 10.0% (95% CI 6.3-14.8), 8.5% (95%CI 5.1-13.1), and 4.7% (95%CI 2.3-8.5), respectively. When real-time PCR was performed after a pre-amplification step, the prevalence of active schistosomiasis increased to 10.4% (95%CI 6.7-15.4), and FGS to 5.2% (95%CI 2.6-9.1). Of note, more cases were detected by self-collected than operator-collected swabs. The vast majority of participants (95.3%) declared that they were comfortable/very comfortable about genital self-sampling, which was indicated as the preferred sampling method by 40.3% of participants. CONCLUSIONS/SIGNIFICANCE: The results of this study show that genital self-sampling followed by pre-amplified PCR on room temperature-stored DNA is a useful method from both technical and acceptability point of views. This encourages further studies to optimize samples processing, and identify the best operational flow to allow integration of FGS screening into women health programmes, such as HPV screening.

Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial.

BACKGROUND: An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls. METHODS: In this open-label, randomised, phase 3, non-inferiority trial, we enrolled healthy schoolgirls aged 9-14 years from Government schools in Mwanza, Tanzania. Eligible participants were randomly assigned to receive one, two, or three doses of either the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart) or the 9-valent vaccine (Gardasil-9, Sanofi Pasteur MSD, Lyon). The primary outcome was HPV 16 specific or HPV 18 specific seropositivity following one dose compared with two or three doses of the same HPV vaccine 24 months after vaccination. Safety was assessed as solicited adverse events up to 30 days after each dose and unsolicited adverse events up to 24 months after vaccination or to last study visit. The primary outcome was done in the per-protocol population, and safety was analysed in the total vaccinated population. This study was registered in ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility. 72 girls were excluded. 930 girls were enrolled and randomly assigned to receive one dose of Cervarix (155 participants), two doses of Cervarix (155 participants), three doses of Cervarix (155 participants), one dose of Gardasil-9 (155 participants), two doses of Gardasil-9 (155 participants), or three doses of Gardasil-9 (155 participants). 922 participants received all scheduled doses within the defined window (three withdrew, one was lost to follow-up, and one died before completion; two received their 6-month doses early, and one received the wrong valent vaccine in error; all 930 participants were included in the total vaccinated cohort). Retention at 24 months was 918 (99%) of 930 participants. In the according-to-protocol cohort, at 24 months, 99% of participants who received one dose of either HPV vaccine were seropositive for HPV 16 IgG antibodies, compared with 100% of participants who received two doses, and 100% of participants who received three doses. This met the prespecified non-inferiority criteria. Anti-HPV 18 seropositivity at 24 months did not meet non-inferiority criteria for one dose compared to two doses or three doses for either vaccine, although more than 98% of girls in all groups had HPV 18 antibodies. 53 serious adverse events (SAEs) were experienced by 42 (4·5%) of 930 girls, the most common of which was hospital admission for malaria. One girl died of malaria. Number of events was similar between groups and no SAEs were considered related to vaccination. INTERPRETATION: A single dose of the 2-valent or 9-valent HPV vaccine in girls aged 9-14 years induced robust immune responses up to 24 months, suggesting that this reduced dose regimen could be suitable for prevention of HPV infection among girls in the target age group for vaccination. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Efficacy and immunogenicity of a single dose of human papillomavirus vaccine compared to no vaccination or standard three and two-dose vaccination regimens: A systematic review of evidence from clinical trials.

OBJECTIVES: This study aimed to systematically review the literature on the efficacy and immunogenicity of single-dose HPV vaccination compared to no vaccination or multi-dose schedules among vaccine trial participants. METHODS: Medline, EMBASE, Global Health Database and Cochrane Central Register of Controlled Trials were searched for publications and conference abstracts (dated January 1999-August 2018) using MeSH and non-MeSH terms for human papillomavirus AND vaccines AND (immunogenicity OR efficacy/effectiveness) AND dosage. Search results were screened against pre-specified eligibility criteria. Data were extracted from included articles, and a narrative synthesis conducted on efficacy against HPV16/18 infection and humoral immunogenicity. RESULTS: Seven of 6,523 unique records identified were included in the review. Six were nested observational studies of participants randomised to receive two or three doses in three large HPV vaccine trials, in which some participants did not complete their allocated schedules. One small pilot study prospectively allocated participants to receive one or no vaccine dose. Frequency of HPV16/18 infection was low (e.g. <1% for 12-month-persistent infection) in all vaccinated participants up to seven years post vaccination and did not significantly differ by number of doses (p > 0.05 in all cases). Frequency of infection was significantly lower in one-dose recipients compared to unvaccinated controls (p < 0.01 for all infection endpoints in each study). HPV16/18 seropositivity rates were high in all HPV vaccine recipients (100% in three of four studies reporting this endpoint), though antibody levels were lower with one compared to two or three doses. CONCLUSIONS: This review supports the premise that one HPV vaccine dose may be as effective in preventing HPV infection as multi-dose schedules in healthy young women. However, it also highlights the paucity of available evidence from purpose-designed, prospectively-randomised trials. Results from ongoing clinical trials assessing the efficacy and immunogenicity of single-dose HPV vaccination compared to currently-recommended schedules are awaited.