Clinical and Demographic Factors Associated With Kaposi Sarcoma-Associated Herpesvirus Shedding in Saliva or Cervical Secretions in a Cohort of Tanzanian Women.

Background: Reasons for the high prevalence of Kaposi sarcoma-associated herpesvirus (KSHV) in sub-Saharan Africa, and risk factors leading to viral reactivation and shedding, remain largely undefined. Preliminary studies have suggested that schistosome infection, which has been associated with impaired viral control, is associated with KSHV. In this study we sought to determine the relationship between active Schistosoma mansoni or Schistosoma haematobium infection and KSHV shedding. Methods: We quantified KSHV DNA in saliva and cervical swabs from 2 cohorts of women living in northwestern Tanzanian communities endemic for S mansoni or S haematobium by real-time polymerase chain reaction. χ2 and Fisher exact tests were used to determine differences in clinical and demographic factors between those who were and were not shedding KSHV. Results: Among 139 total women, 44.6% were KSHV seropositive. Six percent of those with S mansoni and 17.1% of those with S haematobium were actively shedding KSHV in saliva and none in cervical samples. Women from the S mansoni cohort who were shedding virus reported infertility more frequently (80% vs 19.5%, P = .009). There was no difference in frequency of KSHV salivary shedding between schistosome-infected and -uninfected women. Conclusions: In an area with high KSHV seroprevalence and endemic schistosome infections, we provide the first report with data demonstrating no association between schistosome infection and salivary or cervical herpesvirus shedding. KSHV salivary shedding was associated with infertility, a known effect of another herpesvirus, human herpesvirus 6.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.

BACKGROUND: The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE. METHODS: In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50. FINDINGS: Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines. INTERPRETATION: HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination. FUNDING: The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Prevalence of G6PD deficiency and submicroscopic malaria parasites carriage in malaria hotspot area in Northwest, Tanzania.

BACKGROUND: The use of primaquine for mass drug administration (MDA) is being considered as a key strategy for malaria elimination. In addition to being the only drug active against the dormant and relapsing forms of Plasmodium vivax, primaquine is the sole potent drug against mature/infectious Plasmodium falciparum gametocytes. It may prevent onward transmission and help contain the spread of artemisinin resistance. However, higher dose of primaquine is associated with the risk of acute haemolytic anaemia in individuals with a deficiency in glucose-6-phosphate dehydrogenase. In many P. falciparum endemic areas there is paucity of information about the distribution of individuals at risk of primaquine-induced haemolysis at higher dose 45 mg of primaquine. METHODS: A retrospective cross-sectional study was carried out using archived samples to establish the prevalence of G6PD deficiency in a malaria hotspot area in Misungwi district, located in Mwanza region, Tanzania. Blood samples collected from individuals recruited between August and November 2010 were genotyped for G6PD deficiency and submicroscopic parasites carriage using polymerase chain reaction. RESULTS: A total of 263 individuals aged between 0 and 87 were recruited. The overall prevalence of the X-linked G6PD A- mutation was 83.7% (220/263) wild type, 8% (21/263) heterozygous and 8.4% (22/263) homozygous or hemizygous. Although, assessment of the enzymatic activity to assign the phenotypes according to severity and clinical manifestation as per WHO was not carried out, the overall genotype and allele frequency for the G6PD deficiency was 16.4% and 13. 2%, respectively. There was no statistically significant difference in among the different G6PD genotypes (p > 0.05). Out of 248 samples analysed for submicroscopic parasites carriage, 58.1% (144/248) were P. falciparum positive by PCR. G6PD heterozygous deficiency were associated with carriage of submicroscopic P. falciparum (p = 0.029). CONCLUSIONS: This study showed that 16.4% of the population in this part of North-western Tanzania carry the G6PD A- mutation, within the range of 15-32% seen in other parts of Africa. G6PD gene mutation is widespread and heterogeneous across the study area where primaquine would be valuable for malaria control and elimination. The maps and population estimates presented here reflect potential risk of higher dose of primaquine being associated with the risk of acute haemolytic anaemia (AHA) in individuals with a deficiency in glucose-6-phosphate dehydrogenase and call further research on mapping of G6PD deficiency in Tanzania. Therefore, screening and education programmes for G6PD deficiency is warranted in a programme of malaria elimination using a higher primaquine dose.

Unmet need for modern contraception by HIV status: findings from community-based studies implemented before and after earlier ART initiation program in rural Tanzania.

BACKGROUND: Tanzania Health policy insists on the need to provide all women access to contraception despite HIV status. We used data from two HIV epidemiologic serological surveys carried out at different periods of ART provision in rural Tanzania to assess the level of unmet need for modern contraception by HIV status and associated factors. METHODS: We performed secondary data analysis of two surveys conducted at the Magu Health and Demographic Surveillance System site, in Mwanza, Tanzania. Information on unmet need for modern contraception was derived from fertility desire and contraception use. Unmet need, HIV status, and socioeconomic and demographic variables were analysed. The percentage of women with unmet needs for modern contraception by HIV status is presented for the 2012 and 2017 surveys. Bivariate and multivariate analyses using logistic regression were used to investigate associated factors showing adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs). RESULTS: Data from 3352 and 3196 women aged 15-49 years collected in the 2012 and 2017 surveys, respectively, were analysed. The percentages of women with unmet needs for modern contraception in the 2012 and 2017 surveys were 30.9% (95% CI 29.4-32.6) and 31.6% (95% CI 30.0-33.3), respectively. The unmet need for modern contraception was 26% lower in HIV-uninfected women in 2012 (aOR = 0.74; 95% CI 0.569-0.973); p = 0.031). Risk factors for unmet need for modern contraception in 2012 were HIV uninfected (adjusted OR = 0.74; 95% CI 0.569-0.973); p = 0.031), married marital status (adjusted OR = 0.768; 95% CI 0.743-0.794); p < 0.0001), higher education (adjusted OR = 0.768; 95% CI 0.743-0.794); p < 0.0001), and taking alcohol (adjusted OR = 0.768; 95% CI 0.743-0.794); p < 0.0001). Only two factors were associated with unmet need for modern contraception in 2017: married marital status (adjusted OR = 0.46; 95% CI 0.305-0.722); p = 0.001) and women who earned for their families (aOR = 0.66; 95% CI 0.494-0.887); p = 0.006). DISCUSSION: Nearly one-third of women had an unmet need for modern contraception, which was lower in HIV-uninfected women than in WLHIV-infected women. The study has identified women whose demand for contraception has not been met: WLHIV, post marital women, women with low education and women who were reported to earn money for their families. Family planning interventions should be tailored to these groups of women.

Fertility trends by HIV status in a health and demographic surveillance study in Magu District, Tanzania, 1994-2018.

BACKGROUND: Sub-Saharan Africa (SSA) has the highest fertility rates and highest HIV disease burden globally. However, it is not clear how the rapid expansion of anti-retroviral therapy (ART) for HIV has impacted the fertility gap between HIV-infected and uninfected women. We used data from a Health and Demographic Surveillance System (HDSS) in north-western Tanzania to explore trends in fertility rates and the relationship between HIV and fertility over the 25-year period. METHODS: From 1994 to 2018, births and population denominators from the HDSS population were used to obtain age-specific fertility rates (ASFRs) and total fertility rates (TFRs). HIV status was extracted from eight rounds of epidemiologic serological surveillances (1994-2017). Fertility rates by HIV status and in different levels of ART availability were compared over time. Independent risk factors for fertility changes were examined using Cox proportional hazard models. RESULTS: There were 24,662 births from 36,814 women (15-49) who contributed a total of 145,452.5 Person-Years of follow-ups. The TFR declined from 6.5 births per woman in 1994-1998 to 4.3 births per woman in 2014-2018. The number of births per woman was 40% lower in women living with HIV than in HIV-uninfected women (4.4 vs. 6.7), although this difference narrowed over time. The fertility rate in HIV-uninfected women was 36% lower in 2013-2018 than in 1994-1998(age-adjusted HR = 0.641; 95% CI 0.613-0.673). In contrast, the fertility rate in women living with HIV was relatively unchanged over the same follow up period (age-adjusted HR = 1.099; 95% CI 0.870-1.387). CONCLUSIONS: There was a notable fertility decline among women in the study area from 1994 to 2018. Fertility remained lower in women living with HIV than in HIV-uninfected women, but the difference continued to narrow over time. These results highlight the need for more research into fertility changes, fertility desire and family planning use in Tanzanian rural communities.

Effects of helminths and anthelmintic treatment on cardiometabolic diseases and risk factors: A systematic review.

BACKGROUND: Globally, helminth infections and cardiometabolic diseases often overlap in populations and individuals. Neither the causal relationship between helminth infections and cardiometabolic diseases nor the effect of helminth eradication on cardiometabolic risk have been reviewed systematically in a large number of human and animal studies. METHODS: We conducted a systematic review assessing the reported effects of helminth infections and anthelmintic treatment on the development and/or severity of cardiometabolic diseases and risk factors. The search was limited to the most prevalent human helminths worldwide. This study followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42021228610). Searches were performed on December 10, 2020 and rerun on March 2, 2022 using Ovid MEDLINE ALL (1946 to March 2, 2022), Web of Science, Cochrane Library, Global Index Medicus, and Ovid Embase (1974 to March 2, 2022). Randomized clinical trials, cohort, cross-sectional, case-control, and animal studies were included. Two reviewers performed screening independently. RESULTS: Eighty-four animal and human studies were included in the final analysis. Most studies reported on lipids (45), metabolic syndrome (38), and diabetes (30), with fewer on blood pressure (18), atherosclerotic cardiovascular disease (11), high-sensitivity C-reactive protein (hsCRP, 5), and non-atherosclerotic cardiovascular disease (4). Fifteen different helminth infections were represented. On average, helminth-infected participants had less dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. Eleven studies examined anthelmintic treatment, of which 9 (82%) reported post-treatment increases in dyslipidemia, metabolic syndrome, and diabetes or glucose levels. Results from animal and human studies were generally consistent. No consistent effects of helminth infections on blood pressure, hsCRP, or cardiac function were reported except some trends towards association of schistosome infection with lower blood pressure. The vast majority of evidence linking helminth infections to lower cardiometabolic diseases was reported in those with schistosome infections. CONCLUSIONS: Helminth infections may offer protection against dyslipidemia, metabolic syndrome, diabetes, and atherosclerotic cardiovascular disease. This protection may lessen after anthelmintic treatment. Our findings highlight the need for mechanistic trials to determine the pathways linking helminth infections with cardiometabolic diseases. Such studies could have implications for helminth eradication campaigns and could generate new strategies to address the global challenge of cardiometabolic diseases.

High Prevalence of Sexually Transmitted and Reproductive Tract Infections (STI/RTIs) among Patients Attending STI/Outpatient Department Clinics in Tanzania.

We determined the prevalence and reported risk factors associated with sexually transmitted and reproductive tract infections (STI/RTIs) among patients who presented with genital symptoms in STI/outpatient department (OPD) clinics in two regional referral hospitals and six health centres in six regions in Tanzania. Methods: The patients were consecutively recruited, and the data collection was conducted in eight health care facilities from 2014 to 2016. Genital swabs were collected for the detection of the aetiological pathogens of STI/RTIs. Results: A total of 1243 participants were recruited in the study; the majority (1073, 86%) were women. The overall median age was 27.8. The prevalence of Neisseria gonorrhoeae was 25.7% (319/1243), with proportions of 50.9 and 21.5% for men and women, respectively, of Chlamydia trachomatis 12.9% (160/1241) and Mycoplasma genitalium 4.7% (53/1134). Unmarried men were more often likely to be infected with gonococcal infections as compared to their women counterparts (57.9 vs. 24.1%) p < 0.001. The majority presented with genital discharge syndrome (GDS) 93.6% (1163/1243), genital ulcer disease (GUD) 13.0% (162/1243) and GDS + GUD 9.6% (119/1243). GDS was more common in the health centres, 96.1% (1195/1243), vs. the regional referral hospitals, 92.2% (1146/1243) (p = 0.01), but those reported to the regional referral hospitals were more likely to be infected with N. gonorrhoeae (OR = 2.5) and C. trachomatis (OR = 2.1) than those from the health centres (p < 0.001). The prevalence of bacterial vaginosis (BV) and vaginal candidiasis (VC) was 24.1 and 10.4%, respectively. Interestingly, unmarried and BV-positive women were less likely to be infected with VC (p = 0.03), though VC was strongly inversely associated with an N. gonorrhoeae infection (p < 0.001). High proportions of N. gonorrhoeae (51.1%) and C. trachomatis (23.3%) were found in the Dodoma and Dar es Salaam regions, respectively. M. genitalium (7.6%) was found to be the highest in Mwanza. Conclusion: We reported a high prevalence of STI/RTIs. The findings suggest that these infections are common and prevalent in STI/OPD clinics in six regions of Tanzania. We recommend surveillance to be conducted regularly to elucidate the true burden of emerging and classical STI/RTIs by employing modern and advanced laboratory techniques for the detection and monitoring of STI/RTIs in low- and high-risk populations, including the community settings.

Associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls: A cross-sectional study.

OBJECTIVES: This cross-sectional survey aimed to explore associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls. METHODS: Secondary schoolgirls aged 17-18 years from Mwanza, Tanzania, participated in structured face-to-face questionnaire-based interviews, conducted by nurses and clinicians. Age of menarche was evaluated in categories of 11-12, 13-14, 15-16 or ≥17 years. Primary outcome measures were self-reported early sexual debut (first vaginal sex at <16 years) and high-risk sexual behaviour, including non-use of condoms, having sex for gifts/money, having older sexual partners and/or other risky behaviours. RESULTS: Of 401 girls enrolled, 174 (43.4%) reported prior vaginal sex. Prevalence of early sexual debut was 14.2% but pressured/forced sex and risky sexual behaviours were common. Adjusted for potential confounding, younger age at menarche was associated with early sexual debut (adjusted odds ratio for linear trend: 1.88 per category, 95% confidence interval: 1.21-2.92, p = 0.005). This association remained after excluding girls with first sex at <8 years or experiencing pressure or force at first sex. Further, adjusted for potential confounding (including ever experiencing forced sex), early sexual debut was associated with high-risk sexual behaviour (adjusted odds ratio: 2.85, 95% confidence interval: 1.38-5.88, p = 0.004). CONCLUSIONS: Among urban Tanzanian school girls, younger age of menarche was associated with early sexual debut, and early sexual debut was associated with high-risk sexual behaviour. Researchers and public health professionals developing and delivering interventions aimed at preventing adverse sexual health outcomes should consider the impact of these early biological and sexual exposures.

Effects of Schistosoma mansoni and praziquantel treatment on the lower gastrointestinal mucosa: A cohort study in Tanzania.

Schistosomes infect over 200 million people worldwide, but few studies have characterized the effects of Schistosoma mansoni infection and effective treatment on the lower gastrointestinal mucosa. In this prospective cohort study, we compared the clinical findings on sigmoidoscopy and laboratory measures in Tanzanian adults with and without S. mansoni infection at baseline and 6 months after praziquantel treatment. Grading of the endoscopic findings was done using the Mayo Scoring System for Assessment of Ulcerative Colitis Activity. Schistosome infection was confirmed by stool microscopy and serum circulating anodic antigen (CAA). Baseline comparisons were performed in Stata using Fisher's exact and Wilcoxon rank-sum tests, and pre- and post-treatment comparisons using Wilcoxon matched-pairs signed-rank and McNemar's tests. We investigated the clinical characteristics of 48 individuals: 32 with and 16 without S. mansoni infection. Infected individuals had greater severity of sigmoid and rectal mucosal abnormalities and higher Mayo scores and serum eosinophils (all p < 0.05) than uninfected individuals at initial evaluation. At 6 months, 28 individuals completed repeat blood tests and sigmoidoscopy. Of these, 14 cleared their baseline infection (n = 7) or experienced a greater than 7-fold decrease in serum CAA (n = 7). Follow-up sigmoidoscopies revealed some improvements in sigmoid and rectal mucosal findings, although Mayo scores were not significantly lower. Both the median erythrocyte sedimentation rates (32.5→12.5 mm/hr) and percent of eosinophils (7.1→3.1%) decreased in this group from baseline to follow-up. S. mansoni infection was associated with mild-to-moderate lower gastrointestinal mucosal abnormalities that were grossly visible during sigmoidoscopy, and these improved partially 6 months after effective treatment with praziquantel. Additional studies, of longer duration and focused on both clinical and mucosal immunologic effects of S. mansoni, could provide additional insight.

Costs of delivering human papillomavirus vaccination using a one- or two-dose strategy in Tanzania.

OBJECTIVE: As part of the Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls (DoRIS; NCT02834637), the current study is one of the first to evaluate the financial and economic costs of the national rollout of an HPV vaccination program in school-aged girls in sub-Saharan Africa and the potential costs associated with a single dose HPV vaccine program, given recent evidence suggesting that a single dose may be as efficacious as a two-dose regimen. METHODS: The World Health Organization's (WHO) Cervical Cancer Prevention and Control Costing (C4P) micro-costing tool was used to estimate the total financial and economic costs of the national vaccination program from the perspective of the Tanzanian government. Cost data were collected in 2019 via surveys, workshops, and interviews with local stakeholders for vaccines and injection supplies, microplanning, training, sensitization, service delivery, supervision, and cold chain. The cost per two-dose and one-dose fully immunized girl (FIG) was calculated. RESULTS: The total financial and economic costs were US$10,117,455 and US$45,683,204, respectively, at a financial cost of $5.17 per two-dose FIG, and an economic cost of $23.34 per FIG. Vaccine and vaccine-related costs comprised the largest proportion of costs, followed by service delivery. In a one-dose scenario, the cost per FIG reduced to $2.51 (financial) and $12.18 (economic), with the largest reductions in vaccine and injection supply costs, and service delivery. CONCLUSIONS: The overall cost of Tanzania's HPV vaccination program was lower per vaccinee than costs estimated from previous demonstration projects in the region, especially in a single-dose scenario. Given the WHO Strategic Advisory Group of Experts on Immunization's recent recommendation to update dosing schedules to either one or two doses of the HPV vaccine, these data provide important baseline data for Tanzania and may serve as a guide for improving coverage going forward. The findings may also aid in the prioritization of funding for countries that have not yet added HPV vaccines to their routine immunizations.

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. METHODS: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. RESULTS: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. CONCLUSIONS: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Effectiveness of Cash Transfer Delivered Along With Combination HIV Prevention Interventions in Reducing the Risky Sexual Behavior of Adolescent Girls and Young Women in Tanzania: Cluster Randomized Controlled Trial.

BACKGROUND: Poverty and social inequality exacerbate HIV risk among adolescent girls and young women (AGYW) in sub-Saharan Africa. Cash transfers can influence the structural determinants of health, thereby reducing HIV risk. OBJECTIVE: This study assessed the effectiveness of cash transfer delivered along with combination HIV prevention (CHP) interventions in reducing the risky sexual behavior of AGYW in Tanzania. The incidence of herpes simplex virus type 2 (HSV-2) infection was used as a proxy for sexual risk behavior. METHODS: A cluster randomized controlled trial was conducted in 15 matched pairs of communities (1:1 intervention to control) across 3 strata (urban, rural high-risk, and rural low-risk populations) of the Shinyanga Region, Tanzania. The target population was out-of-school AGYW aged 15-23 years who had completed 10-hour sessions of social and behavior change communication. Eligible communities were randomly assigned to receive CHP along with cash transfer quarterly (intervention group) or solely CHP interventions (control group) with no masking. Study recruitment and baseline survey were conducted between October 30, 2017 and December 1, 2017. Participants completed an audio computer-assisted self-interview, HIV counselling and testing, and HSV-2 testing at baseline and during follow-up visits at 6, 12, and 18 months after the baseline survey. A Cox proportional hazards model with random effects specified at the level of clusters (shared frailty) adjusted for matching pairs and other baseline imbalances was fitted to assess the effects of cash transfer on the incidence of HSV-2 infection (primary outcome). Secondary outcomes included HIV prevalence at follow-up, self-reported intergenerational sex, and self-reported compensated sex. All secondary outcomes were measured at each study visit. RESULTS: Of the 3026 AGYW enrolled in the trial (1482 in the intervention and 1544 in the control), 2720 AGYW (1373 in the intervention and 1347 in the control) were included in the final analysis. Overall, HSV-2 incidence was not significantly different at all follow-up points between the study arms in the adjusted analysis (hazard ratio 0.96, 95% CI 0.67-1.38; P=.83). However, HSV-2 incidence was significantly lower in the rural low-risk populations who received the cash transfer intervention (hazard ratio 0.45, 95% CI 0.29-0.71; P=.001), adjusted for potential confounders. CONCLUSIONS: Although this trial showed no significant impact of the cash transfer intervention on HSV-2 incidence among AGYW overall, the intervention significantly reduced HSV-2 incidence among AGYW in rural low-risk communities. Factors such as lesser poverty and more asset ownership in urban and rural high-risk communities may have undermined the impact of cash transfer. TRIAL REGISTRATION: ClinicalTrials.gov NCT03597243; https://clinicaltrials.gov/show/NCT03597243.

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.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). METHODS: In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. INTERPRETATION: One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. 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.

Primary resistance against integrase strand transfer inhibitors in integrase strand transfer inhibitor-naive patients failing first- and second-line ART in Tanzania.

INTRODUCTION: Sub-Saharan African countries are introducing integrase strand transfer inhibitors (INSTIs) in their ART programmes as the preferred first-line regimen, and dolutegravir is the INSTI of choice due to its potency, tolerability and high genetic barrier to resistance. Dolutegravir was introduced into the first-line ART regimen in Tanzania in 2019. However, there is a paucity of data on the occurrence of mutations in HIV lineages circulating in Tanzania. This study aimed to determine the prevalence of INSTI primary resistance mutations in Tanzanian patients exposed to ART but not INSTIs. METHODS: Plasma samples from 50 INSTI-naive patients failing first- or second-line ART [median (IQR) age: 40 (21.93-46.41) years; 68% women] were subjected to Sanger sequencing of the HIV integrase gene. Participants had been on ART for a median (IQR) duration of 7.32 (4.73-9.29) years, with 80% and 20% failing first- and second-line ART, respectively. RESULTS: No major INSTI mutations were found, but 2 (4%) participants had the accessory mutation T97A. Using the REGA HIV-1 subtyping tool, HIV subtype A1 (53.1%) was found to be dominant, followed by subtypes C (30.6%) and D (16.3%). CONCLUSIONS: This study found no current evidence for transmitted resistance against INSTIs among unexposed patients failing ART and supports the scale-up of INSTI-based regimens. However, the presence of accessory mutations calls for the surveillance of INSTI resistance mutations to ensure that the anticipated long-term desired outcomes are achieved.

The association of physical activity and cardiorespiratory fitness with ß-cell dysfunction, insulin resistance, and diabetes among adults in north-western Tanzania: A cross-sectional study.

Introduction: Research on the associations of physical activity and cardiorespiratory fitness with ß-cell dysfunction and insulin resistance among adults in Sub-Saharan Africa (SSA) is limited. We assessed the association of physical activity and cardiorespiratory fitness with ß-cell function, insulin resistance and diabetes among people living with HIV (PLWH) ART-naïve and HIV-uninfected Tanzanian adults. Method: In a cross-sectional study, we collected data on socio-demography, anthropometry, fat mass and fat free mass and C-reactive protein. Data on glucose and insulin collected during an oral glucose tolerance test were used to assess ß-cell dysfunction (defined as insulinogenic index <0.71 (mU/L)/(mmol/L), HOMA-ß index <38.3 (mU/L)/(mmol/L), and overall insulin release index <33.3 (mU/L)/(mmol/L)), oral disposition index <0.16 (mU/L)/(mg/dL)(mU/L)-1, insulin resistance (HOMA-IR index >1.9 (mU/L)/(mmol/L) and Matsuda index <7.2 (mU/L)/(mmol/L), prediabetes and diabetes which were the dependent variables. Physical activity energy expenditure (PAEE), sleeping heart rate (SHR), and maximum uptake of oxygen during exercise (VO2 max) were the independent variables and were assessed using a combined heart rate and accelerometer monitor. Logistic regressions were used to assess the associations. Results: Of 391 participants, 272 were PLWH and 119 HIV-uninfected. The mean age was 39 ( ± 10.5) years and 60% (n=235) were females. Compared to lower tertile, middle tertile of PAEE was associated with lower odds of abnormal insulinogenic index (OR=0.48, 95%CI: 0.27, 0.82). A 5 kj/kg/day increment of PAEE was associated with lower odds of abnormal HOMA-IR (OR=0.91, 95%CI: 0.84, 0.98), and reduced risk of pre-diabetes (RRR=0.98, 95%CI: 0.96, 0.99) and diabetes (RRR=0.92, 95%CI: 0.88, 0.96). An increment of 5 beats per min of SHR was associated with higher risk of diabetes (RRR=1.06, 95%CI: 1.01, 1.11). An increase of 5 mLO2/kg/min of VO2 max was associated with lower risk of pre-diabetes (RRR=0.91, 95%CI: 0.86, 0.97), but not diabetes. HIV status did not modify any of these associations (interaction, p>0.05). Conclusion: Among Tanzanian adults PLWH and HIV-uninfected individuals, low physical activity was associated with ß-cell dysfunction, insulin resistance and diabetes. Research is needed to assess if physical activity interventions can improve ß-cell function and insulin sensitivity to reduce risk of diabetes and delay progression of diabetes in SSA.

Antimicrobial Susceptibility Testing Patterns of Neisseria gonorrhoeae from Patients Attending Sexually Transmitted Infections Clinics in Six Regions in Tanzania.

Antimicrobial resistance (AMR) is global health threat that is on the increase, and it has been adversely affecting the proper management of sexually transmitted infections (STI). Data on antimicrobial susceptibility testing patterns of N. gonorrhoeae are limited in local settings. We determined in vitro antimicrobial susceptibility and phenotypic profiles of N. gonorrhoeae isolated from STI/Outpatient Department (OPD) clinics. Minimum Inhibitory Concentrations (MIC) (µg/mL) were determined using E-Test and agar dilution methods for previously and currently recommended antimicrobial agents. A total of 164 N. gonorrhoeae isolates from urethral discharge and endocervical swabs were tested. The prevalence of resistant N. gonorrhoeae to tetracycline, norfloxacin, penicillin and ciprofloxacin were 98.6%, 82.2%, 84.3% and 75.6%, respectively. None of the isolates was resistant to kanamycin. Penicillinase producing N. gonorrhoeae (PPNG) was found to be 73.7%, with 56.7% and 43.3% observed among isolates from women and men, respectively. Tetracycline resistant-N. gonorrhoeae (TRNG) was found to be 34.0%, and QRNG with HLR to ciprofloxacin was 79.9%. The overall MDR-NG was 79.9%, and XDR-NG was 3.6%. MIC50 and MIC90 were 4.0 and 8.0 and 2.0 and 4.0 µg/mL for ciprofloxacin and norfloxacin, respectively. Dendrograms showed that 44 phenotypic groups are associated with a high rate of AMR among high MDR-NG and moderate XDR-NG isolates. The predominant groups of quinolone-resistant N. gonorrhoeae (QRNG)+PPNG (34.7%) and QRNG+PPNG+TRNG (32.9%) were observed among the isolates having HLR to ciprofloxacin. We reported a high prevalence of AMR (>90%) to previously recommended antimicrobials used for the treatment of gonorrhoea. Multidrug resistant N. gonorrhoeae (MDR-NG) was highly reported, and extensively drug resistant (XDR-NG) has gradually increased to the currently recommended cephalosporins including ceftriaxone and cefixime. Heterogeneous groups of QRNG+PPNG+ and QRNG+PPNG+TRNG were highly resistant to penicillin, tetracycline, ciprofloxacin and norfloxacin. A surveillance program is imperative in the country to curb the spread of AMR.

Levels and correlates of physical activity and capacity among HIV-infected compared to HIV-uninfected individuals.

INTRODUCTION: In the HIV-infected individuals, physical activity improves physical strength, quality of life and reduces the risk of developing non-communicable diseases. In Sub-Saharan Africa, HIV-infected patients report being less active compared to HIV-uninfected individuals. We assessed the levels and correlates of objectively measured physical activity and capacity among HIV-infected antiretroviral therapy (ART)-naive individuals compared to HIV-uninfected individuals in Mwanza, Tanzania. METHOD: We conducted a cross-sectional study among newly diagnosed HIV-infected ART-naive individuals and HIV-uninfected individuals frequency-matched for age and sex. Socio-demographic data, anthropometrics, CD4 counts, haemoglobin level, and C-reactive protein (CRP) were collected. Physical activity energy expenditure (PAEE) was assessed as measure of physical activity whereas sleeping heart rate (SHR) and grip strength were assessed as measures of physical capacity. Multivariable linear regression was used to assess the correlates associated with physical activity and capacity. RESULTS: A total of 272 HIV-infected and 119 HIV-uninfected individuals, mean age 39 years and 60% women participated in the study. Compared to HIV-uninfected individuals, HIV-infected had poorer physical activity and capacity: lower PAEE (-7.3 kj/kg/day, 95% CI: -11.2, -3.3), elevated SHR (7.7 beats/min, 95%CI: 10.1, 5.3) and reduced grip strength (-4.7 kg, 95%CI: -6.8, -2.8). In HIV-infected individuals, low body mass index, moderate-severe anaemia, low CD4 counts and high CRP were associated with lower physical activity and capacity. In HIV-uninfected individuals, abdominal obesity and moderate anaemia were associated with lower physical activity and capacity. CONCLUSION: HIV-infected participants had lower levels of physical activity and capacity than HIV-uninfected participants. Correlates of physical activity and capacity differed by HIV status. Management of HIV and related conditions needs to be provided effectively in health care facilities. Interventions promoting physical activity in these populations will be of importance to improve their health and reduce the risk of non-communicable diseases.

No association between fertility desire and HIV infections among men and women: Findings from community-based studies before and after implementation of an early antiretroviral therapy (ART) initiation program in the rural district of North-western Tanzania.

Background: Fertility is associated with the desire to have children. The impacts of HIV and antiretroviral therapy (ART) on fertility are well known, but their impacts on the desire for children are less well known in Tanzania. We used data from two studies carried out at different periods of ART coverage in rural Tanzania to explore the relationship between HIV infection and fertility desires in men and women. Methods: We conducted secondary data analysis of the two community-based studies conducted in 2012 and 2017 in the Magu Health and Demographic system site, in Tanzania. Information on fertility desires, HIV status, and social-economic and demographic variables were analyzed. Fertility desire was defined as whether or not the participant wanted to bear a child in the next two years. The main analysis used log-binomial regression to assess the association between fertility desire and HIV infection. Results: In the 2012 study, 43% (95% CI 40.7-45.3) of men and 33.3% (95% CI 31.8 - 35.0) women wanted another child in the next two years. In 2017 the percentage rose to 55.7% (95% CI 53.6 - 57.8) in men and 41.5% (95% CI 39.8 - 43.1) in women. Although fertility desire in men and women were higher in HIV uninfected compared to HIV infected, age-adjusted analysis did not show a statistical significance difference in both studies (2012: PR=1.02, 95%CI 0.835 - 1.174, p<0.915 and 2017: PR = 0.90 95%CI 0.743 - 1.084 p= 0.262). Discussion: One-third of women and forty percent of men desired for fertility in 2012, while forty percent of women and nearly half of men desired for fertility in 2017. The data showed fertility desire, in 2012 and 2017 were not related to HIV infection in both periods of ART coverage.

Schistosoma mansoni Infection Is Associated With Increased Monocytes and Fewer Natural Killer T Cells in the Female Genital Tract.

Schistosoma mansoni infection may impair genital mucosal antiviral immunity, but immune cell populations have not been well characterized. We characterized mononuclear cells from cervical brushings of women with and without S mansoni infection. We observed lower frequencies of natural killer T cells and higher frequencies of CD14+ monocytes in infected women.