Comparison between interventional versus medical therapy in patients with rheumatic mitral valve stenosis in Tanzania.

BACKGROUND: Rheumatic heart disease remains the most common cardiovascular disease in children and young adults. The outcome of interventional versus medical therapy on the long term is not fully elucidated yet. This study provides contemporary data on the clinical profile, treatment and follow up of patients with rheumatic mitral stenosis (MS) in Tanzania. METHODS: Patients' medical information, investigations and treatment data were recorded in this prospective cohort study. They were followed up for 6-24 months to determine the long-term outcome. Interventional therapy was defined as a combination of surgery and percutaneous balloon mitral valvuloplasty. Kaplan-Meier curves and Cox proportional hazards model were used in analyses. p-Value < 0.05 was considered statistically significant. RESULTS: We enrolled 290 consecutive patients. Interventions were done in half of the patients. Median follow up was 23.5 months. Mortality was higher in the medical than interventional treatment (10.4% vs. 4%, log-rank p = 0.001). Median age was 36 years, females (68.3%) and low income (55.5%). Multivalvular disease was found in 116 (40%) patients, atrial fibrillation (31.4%), stroke/transient ischaemic attack (18.9%) and heart failure class III-IV (44.1%). Median (IQR) duration of disease was 3 (4) years, secondary prophylaxis (27.7%) and oral anticoagulants use (62.3%). In multivariable analysis, the risk of death among patients on medical was 3.07 times higher than those on interventional treatment (crude HR 3.07, 95% CI 1.43-6.56, p = 0.004), 2.44 times higher among patients with arrhythmias versus without arrhythmias (crude HR 2.44, 95% CI 1.19-4.49, p = 0.015) and 2.13 times higher among patients with multivalvular than single valve disease (crude HR 2.13, 95% CI 1.09-4.16, p = 0.026). CONCLUSIONS: Intervention is carrying low mortality compared to medical treatment. Arrhythmias and multivalvular disease are associated with a high mortality. Rheumatic MS is more prevalent in young people, females and individuals with low income. There is a late hospital presentation and a low use of both secondary prophylactic antibiotics and anticoagulants.

Establishment of clinical pharmacy services: evidence-based information from stakeholders.

High morbidity and mortality related to the use of drugs resulted in demand for clinical pharmacy services (CPS) globally. In developed countries, the evolution of pharmacists' role in direct patient care started in the 1960s. The participation of pharmacists in CPS has resulted in positive clinical, economic, and humanistic outcomes. In developing countries, efforts have started to ensure pharmacists are engaged in the provision of CPS. However, the efforts are hampered by poorly defined pharmacist career paths, financial constraints, and a lack of political willingness. In Tanzania, efforts started in 2008, in which CPS was introduced into the Bachelor of Pharmacy curriculum, followed by the initiation of a postgraduate program on hospital and clinical pharmacy in 2013. A regulation was released by the Tanzania Ministry of Health in 2020 to enforce pharmacists' engagement in providing CPS. In 2021, a project was launched in the country, aiming to strengthen the provision of CPS in public and faith-based hospitals by training on-job pharmacists. The project was implemented in phases, including stakeholders' engagement, baseline survey, training, and supportive supervision of the trained pharmacists. Therefore, this commentary aims to share what we experienced during project implementation, the achievements, challenges, and key lessons learned.

Sub-clinical rheumatic heart disease (RHD) detected by hand-held echocardiogram in children participating in a school-based RHD prevention program in Tanzania.

BACKGROUND: Rheumatic Heart Disease (RHD) continues to cause suffering and premature deaths in many sub-Saharan Africa (SSA) countries, where the disease is still endemic. RHD is largely preventable and determining its community burden is an important critical step in any RHD prevention program. METHODS: We conducted a cross-sectional study of 5-16 years old pupils from 11 primary schools participating in an RHD prevention program in 4 districts in Tanzania, between 2018 and 2019. At the school, all children were invited to participate after receiving consent from their parents/guardians. Participating children filled a questionnaire and were auscultated for cardiac murmurs. Echocardiographic screening was done by two experienced cardiologists, using a hand-held machine (V-Scan, GE®). All positive screening tests were stored for further examination by the same two cardiologists to reach to a consensus of definite, borderline or no RHD, using a modified World Heart Federation (WHF) criterion. RESULTS: Of the 6895 children invited, 4738 (68.7%) were screened and 4436 (64.3%) had complete data. The mean (SD) age was 10.04 (2.43) years, and 2422 (54.6%) were girls. Fifty three (1.2%) children were found to have a murmur. The proportion of children with trace or mild valvular regurgitation, sub-valvular/chordal thickening and valvular thickening/deformity were 8.3%, 1.3%, and 1.0%, respectively. Sub-clinical RHD was found in 95 children (59 definite and 36 borderline), giving a prevalence of 2.1%, [95% CI 1.7% - 2.6%]. Sub-clinical RHD was independently associated with female sex (aOR 1.83, 95% CI 1.18-2.85, p = 0.007), older age groups (aOR 1.73, 95% CI 1.10-2.72, p = 0.018 for age group 11-14 years; and aOR 3.02 95% CI 1.01-9.05, p = 0.048 for age group 15-16 years), as well as presence of a cardiac murmur, aOR 5.63 95% CI 2.31-13.69, p < 0.0001. None of the studied socio- or economic factors was associated with the presence of sub-clinical RHD in this study. CONCLUSION: The prevalence of sub-clinical RHD among primary school children in Tanzania is 2.1%, similar to previous reports in SSA. Efforts to prevent and control RHD in our communities are highly warranted.

Effectiveness of antenatal dexamethasone in reducing respiratory distress syndrome and mortality in preterm neonates: a nested case control study.

BACKGROUND: Respiratory distress syndrome (RDS) is a significant cause of preterm neonatal morbidity and mortality globally. Measures like the use of antenatal corticosteroids (ACS) and immediate resuscitation of the newborn after birth are taken to abate preterm related complications. Most studies that evidenced the benefit of ACS were done in high resource settings. Therefore, this study was conducted to assess the effectiveness of ACS in reducing RDS and neonatal mortality in preterm neonates in resource-limited settings. METHODS: A three months prospective nested case-control study (1:2 unmatched) was conducted at Muhimbili National Hospital and Amana regional referral hospital in Dar es salaam, Tanzania. Neonates delivered at 28 to 34 gestational weeks were enrolled and followed up until discharge. Data analysis was done using the statistical package of social sciences version 23. Logistic regression analysis was used to determine the effect of ACS on the RDS and mortality in the cohort, controlling for important maternal and neonatal variables. All tests were considered statistically significant at p < 0.05. RESULTS: Out of 330 preterm neonates enrolled, 110 were cases and 220 were controls. The median gestational age at delivery was 30 weeks and 6 days (IQR 4.68) among cases and 33 weeks (IQR 3) among controls. One-minute APGAR score of < 7 (AOR: 3.11; 95% CI 1.54-6.30), and neonatal birth weight (AOR: 0.998; 95% CI 0.997-0.999) were significantly associated with RDS. No significant association was observed between ACS exposure and RDS occurrence (AOR: 1.65; 95% CI 0.86 - 3.15). The overall mortality rate was 9 per 1000 neonates. Neonatal mortality occurred only among cases whereby, a unit increase in gestational age was associated with a 30% reduction in neonatal mortality (Adjusted hazard ratio, AHR: 0.70, 95% CI: 0.5-0.92, p = 0.011). CONCLUSION: Decrease in gestational age, one minute APGAR score of < 7 and decreasing birth weight were associated with RDS among preterm neonates. ACS was not associated with reduced RDS occurrence and neonatal mortality rates. Moreover, increase in gestation age was the only factor found to be protective against preterm neonatal mortality.

Advances in training of the specialized human resources for health in Tanzania: the case of Muhimbili University of Health and Allied Sciences.

BACKGROUND: Increasing the number of specialized human resources for health is paramount to attainment of the United Nations sustainable development goals. Higher learning institutions in low-and middle-income countries must address this necessity. Here, we describe the 5-years trends in accreditation of the clinical and non-clinical postgraduate (PG) programmes, student admission and graduation at the Muhimbili University of Health and Allied Sciences (MUHAS) in Tanzania, highlighting successes, challenges and opportunities for improvement. METHODS: This was a retrospective longitudinal study describing trends in PG training at MUHAS between 2015 and 2016 and 2019-2020. Major interventions in the reporting period included university-wide short course training programme to faculty on curricula development and initiation of online application system. Data were collected through a review of secondary data from various university records and was analyzed descriptively. Primary outcomes were the number of accredited PG programmes, number of PG applicants as well as proportions of applicants selected, applicants registered (enrolled) and students graduated, with a focus on gender and internationalization (students who are not from Tanzania). RESULTS: The number of PG programmes increased from 60 in 2015-2016 to 77 in 2019-2020, including programmes in rare fields such as cardiothoracic surgery, cardiothoracic anesthesia and critical care. The number of PG applications, selected applicants, registered applicants and PG students graduating at the university over the past five academic years had steadily increased by 79, 81, 50 and 79%, respectively. The average proportions of PG students who applied, were selected and registered as well as graduated at the university over the past five years by gender and internationalization has remained stably at 60% vs. 40% (male vs. female) and 90% vs. 10% (Tanzanian vs. international), respectively. In total, the university graduated 1348 specialized healthcare workers in the five years period, including 45 super-specialists in critical fields, through a steady increase from 200 graduates in 2015-2016 to 357 graduates in 2019-2020. Major challenges encountered include inadequate sponsorship, limited number of academic staff and limited physical infrastructure for teaching. CONCLUSION: Despite challenges encountered, MUHAS has made significant advances over the past five years in training of specialized and super-specialized healthcare workforce by increasing the number of programmes, enrollment and graduates whilst maintaining a narrow gender gap and international relevance. MUHAS will continue to be the pillar in training of the specialized human resources for health and is thus poised to contribute to timely attainment of the health-related United Nations sustainable development goals in Tanzania and beyond, particularly within the Sub-Saharan Africa region.

Pregnancy Increases CYP3A Enzymes Activity as Measured by the 4ß-Hydroxycholesterol/Cholesterol Ratio.

Changes in cortisol and other hormones during pregnancy may alter CYP3A enzymes activity, but data from sub-Saharan Africa are sparse. We investigated the effect of pregnancy and CYP3A5 genotypes on CYP3A enzymes activity using the plasma 4ß-hydroxycholesterol (4ß-OHC)/cholesterol (Chol) ratio, a known endogenous biomarker. Tanzanian pregnant women (n = 110) and non-pregnant women (n = 59) controls were enrolled. Plasma 4ß-OHC and Chol were determined in the second and third trimesters for pregnant women and once for non-pregnant women using gas chromatography−mass spectrometry. Genotyping for CYP3A5 (*3, *6, *7) was performed. Wilcoxon Signed-Rank Test and Mann−Whitney U test were used to compare the median 4ß-OHC/Chol ratio between trimesters in pregnant women and between pregnant and non-pregnant women. Repeated-measure ANOVA was used to evaluate the effect of the CYP3A5 genotypes on the 4ß-OHC/Chol ratio in pregnant women. No significant effect of the pregnancy status or the CYP3A5 genotype on the cholesterol level was observed. The plasma 4ß-OHC/Chol ratio significantly increased by 7.3% from the second trimester to the third trimester (p = 0.02). Pregnant women had a significantly higher mean 4ß-OHC/Chol ratio than non-pregnant women, (p < 0.001). In non-pregnant women, the mean 4ß-OHC/Chol ratio was significantly lower in carriers of defective CYP3A5 alleles (*3, *6 or *7) as compared to women with the CYP3A5*1/*1 genotypes (p = 0.002). Pregnancy increases CYP3A enzymes activity in a gestational-stage manner. The CYP3A5 genotype predicts CYP3A enzymes activity in the black Tanzanian population, but not during pregnancy-mediated CYP3A enzyme induction.

Usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with artemether-lumefantrine in Tanzania.

BACKGROUND: Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatment outcomes and a cut-off of ≥ 200 ng/ml is associated with day 28 cure rate in the general population. However, day 7 lumefantrine plasma concentration can be affected by age, the extent of fever, baseline parasitaemia, and bodyweight. Therefore, this study assessed the usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with generic or innovator drug-containing artemether-lumefantrine (ALu) in Tanzania. METHODS: This study was nested in an equivalence prospective study that aimed at determining the effectiveness of a generic ALu (Artefan®) in comparison with the innovator's product (Coartem®). Children with uncomplicated malaria aged 6-59 months were recruited and randomized to receive either generic or innovator's product. Children were treated with ALu as per World Health Organization recommendations. The clinical and parasitological outcomes were assessed after 28 days of follow up. PCR was performed to distinguish recrudescence and re-infections among children with recurrent malaria. Analysis of day 7 lumefantrine plasma concentration was carried out using a high-performance liquid chromatographic method with UV detection. RESULTS: The PCR corrected cure rates were 98.7% for children treated with generic and 98.6% for those treated with the innovator product (p = 1.00). The geometric mean (± SD) of day 7 plasma lumefantrine concentration was 159.3 (± 2.4) ng/ml for the generic and 164 (± 2.5) ng/ml for the innovator groups, p = 0.87. Geometric mean (± SD) day 7 lumefantrine plasma concentration between cured and recurrent malaria was not statistically different in both treatment arms [158.5 (± 2.4) vs 100.0 (± 1.5) ng/ml, (p = 0.28) for generic arm and 158.5 (± 2.3) vs 251.2 (± 4.2) ng/ml, (p = 0.24) for innovator arm]. Nutritional status was found to be a determinant of recurrent malaria (adjusted hazardous ratio (95% confidence interval) = 3(1.1-8.2), p = 0.029. CONCLUSION: Using the recommended cut-off point of ≥ 200 ng/ml, day 7 plasma lumefantrine concentration failed to predict malaria treatment outcome in children treated with ALu in Tanzania. Further studies are recommended to establish the day 7 plasma lumefantrine concentration cut-off point to predict malaria treatment outcome in children.

Effect of sulfadoxine-pyrimethamine doses for prevention of malaria during pregnancy in hypoendemic area in Tanzania.

BACKGROUND: Malaria in pregnancy increases the risk of deleterious maternal and birth outcomes. The use of ≥ 3 doses of sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria (IPTp-SP) is recommended for preventing the consequences of malaria during pregnancy. This study assessed the effect of IPTp-SP for prevention of malaria during pregnancy in low transmission settings. METHODS: A cross-sectional study that involved consecutively selected 1161 pregnant women was conducted at Mwananyamala regional referral hospital in Dar es Salaam. Assessment of the uptake of IPTp-SP was done by extracting information from antenatal clinic cards. Maternal venous blood, cord blood, placental blood and placental biopsy were collected for assessment of anaemia and malaria. High performance liquid chromatography with ultraviolet detection (HPLC-UV) was used to detect and quantify sulfadoxine (SDX). Dried blood spots (DBS) of placental blood were collected for determination of sub-microscopic malaria using polymerase chain reaction (PCR). RESULTS: In total, 397 (34.2%) pregnant women reported to have used sub-optimal doses (≤ 2) while 764 (65.8%) used optimal doses (≥ 3) of IPTp-SP at the time of delivery. The prevalence of placental malaria as determined by histology was 3.6%. Submicroscopic placental malaria was detected in 1.4% of the study participants. Women with peripheral malaria had six times risk of maternal anaemia than those who were malaria negative (aOR, 5.83; 95% CI 1.10-30.92; p = 0.04). The geometric mean plasma SDX concentration was 10.76 ± 2.51 µg/mL. Sub-optimal IPTp-SP dose was not associated with placental malaria, premature delivery and fetal anaemia. The use of ≤ 2 doses of IPTp-SP increased the risk of maternal anaemia by 1.36-fold compared to ≥ 3 doses (aOR, 1.36; 95% CI 1.04-1.79; p = 0.02). CONCLUSION: The use of < 2 doses of IPTp-SP increased the risk of maternal anaemia. However, sub-optimal doses (≤ 2 doses) were not associated with increased the risk of malaria parasitaemia, fetal anaemia and preterm delivery among pregnant women in low malaria transmission setting. The use of optimal doses (≥ 3 doses) of IPTp-SP and complementary interventions should continue even in areas with low malaria transmission.

Pregnancy and CYP3A5 Genotype Affect Day 7 Plasma Lumefantrine Concentrations.

Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated Plasmodium falciparum malaria were enrolled. Patients were treated with ALu and followed up for 28 days. CYP3A4, CYP3A5, and ABCB1 genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), P < 0.003]. Pregnancy, low body weight, and CYP3A5*1/*1 genotype were significantly associated with low day 7 LF plasma concentration (P < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, P < 0.001). In conclusion, pregnancy, low body weight, and CYP3A5*1 allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and CYP3A5*1/*1 genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.

Comparison of malaria treatment outcome of generic and innovator's anti-malarial drugs containing artemether-lumefantrine combination in the management of uncomplicated malaria amongst Tanzanian children.

BACKGROUND: In 2006, artemether-lumefantrine (ALU), specifically Coartem® (Novartis Pharma AG, Basel Switzerland), was approved as the first-line drug for treatment of uncomplicated malaria in Tanzania. Due to poor availability and affordability of the innovator's product, the government of Tanzania in 2013 prequalified the use of generic anti-malarial drugs, whereby Artefan® (Ajanta, Pharma Ltd, India) was the first to be approved. METHODS: This was an equivalence prospective study that aimed to determine the effectiveness of anti-malarial generic Artefan® in comparison with innovator's product Coartem®. Patients aged 6 to 59 months with uncomplicated malaria were recruited and randomized to either receive Artefan® or Coartem® as a control. Participants were required to revisit clinic five times as follow up to monitor treatment outcome as per World Health Organization recommendations. On each visit, thick and thin blood smears, dried blood spot (DBS), haemoglobin concentrations and auxiliary temperature were performed and documented. RESULTS: Out of 230 recruited participants, 200 met inclusion criteria and were randomized equally to receive Artefan® and Coartem®. The overall PCR uncorrected cure rate were 80% for Artefan® and 75% for Coartem® (p = 0.44). Adequate clinical and parasitological response were 82.1% for Artefan® and 74.7% for Coartem®, and there was no early treatment failure (ETF) observed in both arms of treatment. Both drugs showed excellent early parasite clearance, whereby no participants had peripheral parasitaemia on day 3. Late clinical failures (LCF) were 3.6% for Artefan® and 1.3% for Coartem® (p = 0.31), and late parasitological failure (LPF) were 15.4% for Artefan® and 22.7% for Coartem® (p = 0.32). Mean haemoglobin (g/dl) concentrations observed on day 28 were higher compared to day 0 for both drugs, although not statistically significant. Only one (1.3%) participant on Artefan® had temperature ≥ 37.5 °C on day 3. CONCLUSION: The findings of this study indicate that both Artefan® and Coartem® are equivalent and effective in the management of uncomplicated malaria amongst children in the Coast part of Tanzania.

Diagnostic performance of CareStart™ malaria HRP2/pLDH test in comparison with standard microscopy for detection of uncomplicated malaria infection among symptomatic patients, Eastern Coast of Tanzania.

BACKGROUND: CareStart™ malaria HRP2/pLDH (Pf/pan) combo test is one of the several rapid diagnostic tests (RDT) approved for diagnosis of malaria at the point of care in Tanzania. However, there are limited studies on the diagnostic performance of RDT after wide scale use in primary health care facilities in Tanzania. Therefore, this study was carried out to determine the diagnostic performance of RDT when compared with blood smear (BS) microscopy as a reference standard. METHODS: A cross-sectional study was conducted between March and August 2019 at Kibiti Health Centre, Pwani region, Tanzania. Blood samples for malaria tests were collected from patients with malaria symptoms. Diagnostic performance parameters of RDT, i.e. sensitivity, specificity, positive and negative likelihood ratios (LR+/-), diagnostic accuracy and predictive values were determined using contingency table. An agreement between RDT and microscopy was statistically determined by Cohen's kappa test. RESULTS: Of 980 patients screened, 567 (57.9%) were found to be malaria positive by RDT, whereas 510 patients (52%) were positive by microscopy. Of the 510 microscopy-positive patients, 487 (95.5%) were infected with Plasmodium falciparum. The geometric mean parasite density was 2921parasites/µl, whereas majority (68.6%) of patients had parasite density greater than 10,000/µl. The sensitivity, specificity, positive and negative predictive values of CareStart™ were 99.8%, 87.6%, 89.8%, and 99.8%, respectively. The LR+ and LR- were 8.0 and 0.002, respectively. The diagnostic accuracy was 0.5. There was a strong agreement between the results obtained using CareStart™ and BS microscopy (kappa = 0.863, P < 0.0001). CONCLUSION: CareStart™ malaria HRP2/pLDH (Pf/pan) had high sensitivity and strong agreement with microscopy results. However, moderate specificity of RDT resulted in a substantial number of patients with false positive malaria test. Wherever available, microscopy should be used to confirm RDT test results.

Adverse birth outcomes among mothers who received intermittent preventive treatment with Sulphadoxine-Pyrimethamine in the low malaria transmission region.

BACKGROUND: Malaria in pregnancy increases the risk of adverse birth outcomes such as low birth weight (LBW), maternal and foetal anemia. In Tanzania, some areas have attained low malaria transmission. However, data on the burden of preterm delivery, LBW, maternal and foetal anemia following substantial reduction of malaria transmission in recent years is still scarce in these settings. METHODS: A study involving 631 pregnant women was conducted at Mwananyamala referral hospital in Dar es Salaam from April to August, 2018. Study enrollment was done prior to delivery. Structured interview and antenatal clinic cards were used to obtain data including the use of intermittent preventive therapy in pregnancy using sulfadoxine-pyrimethamine (IPTp-SP). Infants birth weights were recorded, maternal venous and cord blood were taken for testing of malaria and determination of haemoglobin (Hb) levels. Chi-square test and regression analysis were done to identify risk factors for preterm delivery, LBW, maternal and foetal anemia. RESULTS: The prevalence of malaria among mothers who used at least one dose of IPTp-SP was 0.6% (4/631). Fourteen mothers (2.2%) did not use IPTp-SP and had no malaria infection. The prevalence of maternal anemia, LBW, foetal anemia and preterm delivery was 40.6, 6.5, 5.9 and 9.2% respectively. Participants who were malaria positive had 11 times more risk of LBW compared to those who were negative (AOR, 11; 95%, CI 1.07-132.2; p = 0.04). The risk of delivering babies with LBW was 1.12 times high among mothers who were ≤ 36 weeks of gestation (AOR, 1.12; 95% CI, 0.06-0.25; p = < 0.001). The use of ≥3 doses of IPTp-SP was associated with 83% decrease in risk of LBW compared to those who did not use any dose of IPTp-SP (AOR, 0.17; 95% CI, 0.03-0.88; p = 0.05). Severe anaemia at delivery was associated with seven times increased risk of preterm delivery compared to non-anemic participants (AOR, 6.5; 95% CI, 1.49-28.16; p = 0.013). CONCLUSION: Despite the reduced malaria transmission and use of IPTp-SP, prevalence of preterm delivery, maternal anemia, LBW and foetal anemia is still high in Tanzania. The recommended ≥3 doses of IPTp-SP should continue be provided even in areas with substantial reduction of malaria.

A pilot study of a non-invasive oral nitrate stable isotopic method suggests that arginine and citrulline supplementation increases whole-body NO production in Tanzanian children with sickle cell disease.

BACKGROUND: Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell disease (SCD). We designed a nested pilot study to be conducted within a clinical trial testing the effects of a daily ready-to-use supplementary food (RUSF) fortified with arginine (Arg) and citrulline (Citr) vs. non-fortified RUSF in children with SCD. The pilot study evaluated 1) the feasibility of a non-invasive stable isotope method to measure whole-body NO production and 2) whether Arg+Citr supplementation was associated with increased whole-body NO production. SUBJECTS: Twenty-nine children (70% male, 9-11years, weight 16.3-31.3 kg) with SCD. METHODS: Sixteen children received RUSF+Arg/Citr (Arg, 0.2  g/kg/day; Citr, 0.1  g/kg/day) in combination with daily chloroquine (50 mg) and thirteen received the base RUSF in combination with weekly chloroquine (150 mg). Plasma amino acids were assessed using ion-exchange elution (Biochrom-30, Biochrom, UK) and whole-body NO production was measured using a non-invasive stable isotopic method. RESULTS: The RUSF+Arg/Citr intervention increased plasma arginine (P = .02) and ornithine (P = .003) and decreased the ratio of asymmetric dimethylarginine to arginine (P = .01), compared to the base RUSF. A significant increase in whole-body NO production was observed in the RUSF-Arg/Citr group compared to baseline (weight-adjusted systemic NO synthesis 3.38 ± 2.29 µmol/kg/hr vs 2.35 ± 1.13 µmol/kg/hr, P = .04). No significant changes were detected in the base RUSF group (weight-adjusted systemic NO synthesis 2.64 ± 1.14 µmol/kg/hr vs 2.53 ± 1.12 µmol/kg/hr, P = .80). CONCLUSIONS: The non-invasive stable isotopic method was acceptable and the results provided supporting evidence that Arg/Citr supplementation may increase systemic NO synthesis in children with SCD.

Effect of pharmacogenetics on plasma lumefantrine pharmacokinetics and malaria treatment outcome in pregnant women.

BACKGROUND: Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women. METHODS: Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol. RESULTS: In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4-17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018). CONCLUSIONS: Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women.

Malaria prevalence, severity and treatment outcome in relation to day 7 lumefantrine plasma concentration in pregnant women.

BACKGROUND: Day 7 plasma concentrations of lumefantrine (LF) can serve as a marker to predict malaria treatment outcome in different study populations. Two main cut-off points (175 and 280 ng/ml) are used to indicate plasma concentrations of LF, below which treatment failure is anticipated. However, there is limited data on the cumulative risk of recurrent parasitaemia (RP) in relation to day 7 LF plasma concentrations in pregnant women. This study describes the prevalence, severity, factors influencing treatment outcome of malaria in pregnancy and day 7 LF plasma concentration therapeutic cut-off points that predicts treatment outcome in pregnant women. METHODS: This was a one-arm prospective cohort study whereby 89 pregnant women with uncomplicated Plasmodium falciparum malaria receiving artemether-lumefantrine (ALu) participated in pharmacokinetics and pharmacodynamics study. Blood samples were collected on days 0, 2, 7, 14, 21 and 28 for malaria parasite quantification. LF plasma concentrations were determined on day 7. The primary outcome measure was an adequate clinical and parasitological response (ACPR) after treatment with ALu. RESULTS: The prevalence of malaria in pregnant women was 8.1 % (95 % CI 6.85-9.35) of whom 3.4 % (95 % CI 1.49-8.51) had severe malaria. The overall PCR-uncorrected treatment failure rate was 11.7 % (95 % CI 0.54-13.46 %). Low baseline hemoglobin (<10 g/dl) and day 7 LF concentration <600 ng/ml were significant predictors of RP. The median day 7 LF concentration was significantly lower in pregnant women with RP (270 ng/ml) than those with ACPR (705 ng/ml) (p = 0.016). The relative risk of RP was 4.8 folds higher (p = 0.034) when cut-off of <280 ng/ml was compared to ≥280 ng/ml and 7.8-folds higher (p = 0.022) when cut-off of <600 ng/ml was compared to ≥600 ng/ml. The cut-off value of 175 ng/ml was not associated with the risk of RP (p = 0.399). CONCLUSIONS: Pregnant women with day 7 LF concentration <600 ng/ml are at high risk of RP than those with ≥600 ng/ml. To achieve effective therapeutic outcome, higher day 7 venous plasma LF concentration ≥600 ng/ml is required for pregnant patients than the previously suggested cut-off value of 175 or 280 ng/ml for non-pregnant adult patients.

The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment.

BACKGROUND: HIV-malaria co-infected patients in most parts of sub-Saharan Africa are treated with both artemether-lumefantrine (AL) and efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART). EFV, NVP, artemether and lumefantrine are substrates, inhibitors or inducers of CYP3A4 and CYP2B6, creating a potential for drug-drug interactions. The effect of EFV and/or NVP on lumefantrine pharmacokinetic profile among HIV-malaria co-infected patients on ART and treated with AL was investigated. Optimal lumefantrine dosage regimen for patients on EFV-based ART was determined by population pharmacokinetics and simulation. METHODS: This was a non-randomized, open label, parallel, prospective cohort study in which 128, 66 and 75 HIV-malaria co-infected patients on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) and ART naïve (control-am) were enrolled, respectively. Patients were treated with AL and contributed sparse venous plasma samples. Pharmacokinetic analysis of lumefantrine was done using non-linear mixed effect modelling. RESULTS: Of the evaluated models, a two-compartment pharmacokinetic model with first order absorption and lag-time described well lumefantrine plasma concentrations time profile. Patients in the EFV-arm but not in the NVP-arm had significantly lower lumefantrine bioavailability compared to that in the control-arm. Equally, 32% of patients in the EFV-arm had day-7 lumefantrine plasma concentrations below 280 ng/ml compared to only 4% in the control-arm and 3% in the NVP-arm. Upon post hoc simulation of lumefantrine exposure, patients in the EFV-arm had lower exposure (median (IQR)) compared to that in the control-arm; AUC0-inf; was 303,130 (211,080-431,962) versus 784,830 (547,405-1,116,250); day-7 lumefantrine plasma concentrations was: 335.5 (215.8-519.5) versus 858.7 (562.3-1,333.8), respectively. The predictive model through simulation of lumefantrine exposure at different dosage regimen scenarios for patients on EFV-based ART, suggest that AL taken twice daily for five days using the current dose could improve lumefantrine exposure and consequently malaria treatment outcomes. CONCLUSIONS: Co-treatment of AL with EFV-based ART but not NVP-based ART significantly reduces lumefantrine bioavailability and consequently total exposure. To ensure adequate lumefantrine exposure and malaria treatment success in HIV-malaria co-infected patients on EFV-based ART, an extension of the duration of AL treatment to five days using the current dose is proposed.

Outcome of artemether-lumefantrine treatment for uncomplicated malaria in HIV-infected adult patients on anti-retroviral therapy.

BACKGROUND: Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risks of acquiring malaria. The majority of antiretroviral (ART) and anti-malarial drugs are metabolized by the CYP450 system, creating a chance of drug-drug interaction upon co-administration. Limited data are available on the effectiveness of the artemether-lumefantrine combination (AL) when co-administered with non-nucleoside reverse transcriptase inhibitors (NNRTIs). The aim of this study was to compare anti-malarial treatment responses between HIV-1 infected patients on either nevirapine- or efavirenz-based treatment and those not yet on ART (control-arm) with uncomplicated falciparum malaria, treated with AL. METHOD: This was a prospective, non-randomized, open-label study conducted in Bagamoyo district, with three arms of HIV-infected adults: efavirenz-based treatment arm (EFV-arm) n = 66, nevirapine-based treatment arm (NVP-arm) n = 128, and control-arm n = 75, with uncomplicated malaria. All patients were treated with AL and followed up for 28 days. The primary outcome measure was an adequate clinical and parasitological response (ACPR) after treatment with AL by day 28. RESULTS: Day 28 ACPR was 97.6%, 82.5% and 94.5% for the NVP-arm, EFV-arm and control-arm, respectively. No early treatment or late parasitological failure was reported. The cumulative risk of recurrent parasitaemia was >19-fold higher in the EFV-arm than in the control-arm (Hazard ratio [HR], 19.11 [95% confidence interval {CI}, 10.5-34.5]; P < 0.01). The cumulative risk of recurrent parasitaemia in the NVP-arm was not significantly higher than in the control-arm ([HR], 2.44 [95% {CI}, 0.79-7.6]; P = 0.53). The median (IQR) day 7 plasma concentrations of lumefantrine for the three arms were: 1,125 ng/m (638.8-1913), 300.4 ng/ml (220.8-343.1) and 970 ng/ml (562.1-1729) for the NVP-arm, the EFV-arm and the control-arm, respectively (P < 0.001). In all three arms, the reported adverse events were mostly mild. CONCLUSION: After 28 days of follow-up, AL was statistically safe and effective in the treatment of uncomplicated malaria in the NVP-arm. The results of this study also provide an indication of the possible impact of EFV on the performance of AL and the likelihood of it affecting uncomplicated falciparum malaria treatment outcome.

Pharmacokinetics of piperaquine and its association with intermittent malaria preventive therapy outcomes during pregnancy.

BACKGROUND: Dihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). We investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy. METHODS: Malaria-free (mRDT) pregnant women (n = 400) who received monthly IPTp-DHP were enrolled and followed till delivery. Day 7 Plasma piperaquine concentrations were determined after each IPTp dose using UPLC/MS/MS. IPTp outcomes (symptomatic malaria and parasitemia during pregnancy, placental malaria, and maternal malaria at delivery) were monitored. Linear mixed model and Cox regression were used to assess predictors of day 7 piperaquine concentration and treatment outcome, respectively. RESULTS: The incidences of symptomatic malaria and parasitemia during pregnancy per 100 person-year at risk were 2 and 33, respectively. The prevalence of histopathologically confirmed placental malaria and maternal malaria at delivery were 3% and 9.8%, respectively. Repeated monthly IPTp-DHP resulted in significantly increased day 7 plasma piperaquine concentration (p < 0.001). Following the 1st, 2nd, and 3rd monthly IPTp-DHP doses, the proportions of women with day 7 piperaquine concentration below the therapeutic threshold (< 30 ng/mL) were 6.1%, 4.1% and 3.6%, respectively. Factors such as maternal age, body weight and trimester were not significant predictors of day 7 piperaquine concentration. However, having a low day 7 piperaquine plasma concentration (< 30 ng/mL) was significantly associated with a higher risk of parasitemia during pregnancy (p = 0.004). CONCLUSION: Lower day 7 piperaquine plasma concentration is a risk factor for parasitemia during pregnancy. Single plasma sampling at day 7 can be used to monitor piperaquine effectiveness during IPTp-DHP. TRIAL REGISTRATION: Registered 09/12/2016, PACTR201612001901313.

Efficacy of ivermectin and albendazole combination in suppressing transmission of lymphatic filariasis following mass administration in Tanzania: a prospective cohort study.

BACKGROUND: Preventive chemotherapy with ivermectin and albendazole (IA) in mass drug administration (MDA) programs for all at-risk populations is the core public health intervention to eliminate lymphatic filariasis (LF). Achieving this goal depends on drug effectiveness in reducing parasite reservoirs in the community to halt transmission. We assessed the efficacy of ivermectin and albendazole in clearing microfilariae and circulating filarial antigens (CFA) following MDA. METHODS: This community-based prospective study was conducted in Mkinga district, Tanga region, Tanzania, from November 2018 to June 2019. A total of 4115 MDA-eligible individuals were screened for CFA using Filarial test strips. CFA positives were re-examined for microfilariae by microscopy. CFA and microfilariae positive individuals were enrolled and received IA through MDA campaign. The status of microfilariae and CFA was monitored before MDA, and on day 7 and six-month following MDA. The primary efficacy outcomes were the clearance rates of microfilariae on day 7 and six-months, and CFA at 6 months of post-MDA. The McNemar test assessed the proportions of microfilariae positive pre- and post-MDA, while Chi-square tests were utilized to examine factors associated with CFA status six months post-MDA. RESULTS: Out of 4115 individuals screened, 239 (5.8%) tested positive for CFA, of whom 11 (4.6%) were also positive for microfilariae. Out of the ten microfilariae-positive individuals available for follow-up on day 7, nine tested negative, yielding a microfilariae clearance rate of 90% [95% confidence interval (CI): 59.6-98.2%]. Participants who tested negative for microfilariae on day 7 remained free of microfilariae six months after MDA. However, those who did not clear microfilariae on day-7 remained positive six-months post-MDA. The McNemar test revealed a significant improvement in microfilariae clearance on day 7 following MDA (P = 0.02). Out of 183 CFA-positive individuals who were available at 6-month follow-up, 160 (87.4%) remained CFA positive, while 23 became CFA negative. The CFA clearance rate at 6 months post-MDA was 12.6% (95% CI: 8.5-8.5%). There was no significant association of variability in ivermectin plasma exposure, measured by maximum concentration or area under the curve, and the clearance status of microfilariae or CFA post-MDA. CONCLUSIONS: Preventive chemotherapy with IA effectively clears microfilariae within a week. However, it is less effective in clearing CFA at six months of post-MDA. The low clearance rate for filarial antigenemia underscores the need for alternative drug combinations and additional preventive measures to achieve LF elimination by 2030.

Characterization of Non-Ischemic Dilated Cardiomyopathy in a Native Tanzanian Cohort: MOYO Study.

Background: Non-ischemic dilated cardiomyopathy (NIDCM) is a common cause of heart failure with progressive tendency. The disease occurs in one in every 2,500 individuals in the developed world, with high morbidity and mortality. However, detailed data on the role of NIDCM in heart failure in Tanzania is lacking. Aim: To characterize NIDCM in a Tanzanian cohort with respect to demographics, clinical profile, imaging findings and management. Methods: Characterization of non-ischemic dilated cardioMyOpathY in a native Tanzanian cOhort (MOYO) is a prospective cohort study of NIDCM patients seen at the Jakaya Kikwete Cardiac Institute. Patients aged ≥18 years with a clinical diagnosis of heart failure, an ejection fraction of ≤45% on echocardiography and no evidence of ischemia were enrolled. Clinical data, echocardiography, electrocardiography (ECG), coronary angiography and stress ECG information were collected from February 2020 to March 2022. Results: Of 402 patients, n = 220 (54.7%) were males with a median (IQR) age of 55.0 (41.0, 66.0) years. Causes of NIDCM were presumably hypertensive n = 218 (54.2%), idiopathic n = 116 (28.9%), PPCM n = 45 (11.2%), alcoholic n = 10 (2.5%) and other causes n = 13 (3.2%). The most common presenting symptoms were dyspnea n = 342 (85.1%), with the majority of patients presenting with New York Heart Association (NYHA) Class III n = 195 (48.5%). The mean (SD) left ventricular ejection fraction (LVEF) was 29.4% (±7.7), and severe systolic dysfunction (LVEF <30%) was common n = 208 (51.7%). Compared with other forms of DCM, idiopathic DCM patients were significantly younger, had more advanced NYHA class (p < 0.001) and presented more often with left bundle branch block on ECG (p = 0.0042). There was suboptimal use of novel guidelines recommended medications ARNI n = 10 (2.5%) and SGLT2 2-inhibitors n = 2 (0.5%). Conclusions: In our Tanzanian cohort, the majority of patients with NIDCM have an identified underlying cause, and they present at late stages of the disease. Patients with idiopathic DCM are younger with more severe disease compared to other forms of NIDCM.