Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Hypertension and immune activation in antiretroviral therapy naïve people living with human immunodeficiency virus.

BACKGROUND: The pathogenesis of hypertension (HTN) in people living with HIV/AIDS (PLHIV) is complex and remains not fully understood. Chronic immune activation (IA) is postulated to be one of the culprits. This notion is derived from studies in HIV-uninfected populations and/or animals while data on HTN and how it relates to IA in PLHIV remains scarce. We determined the relationship between HTN and IA among antiretroviral therapy (ART) naïve PLHIV. METHODS: We analysed baseline data of 365 out of 430 clinical trial participants whose main aim was to investigate the effect of low-dose aspirin on HIV disease progression in PLHIV starting ART. Soluble CD14 (sCD14), T cells co-expressing CD38 and HLA-DR, and PD-1 were the IA and exhaustion markers, respectively studied and were analysed by flow cytometry. Mann-Whitney U-test was used for comparison of the markers by HTN status. A robust Poisson regression model was used to determine the predictors for HTN. RESULTS: A quarter of the 365 were hypertensive (25.3%, 95% CI 20.9-29.8%), and, had higher median (IQR) body mass index (kg/m2) (23.4 (19.6, 28.0) versus 21.9 (19.3, 25.1)) and lower median (IQR) estimated glomerular filtration rate (mL/min/1.73m2) (101.2 (79.4, 126.9) versus 113.6 (92.7, 138.8)) than normotensive participants (p < 0.05). Participants with HTN had higher median frequencies of all markers of IA and exhaustion but lower sCD14 (p > 0.05). None of these markers significantly predicted the occurrence of HTN. CONCLUSION: Studied markers of IA and exhaustion were higher in PLHIV with HTN than those without but were unpredictive of HTN. Larger multicentre studies with a wider range of markers are needed to confirm the role of IA in HIV-associated HTN.

Hypertension and traditional risk factors for cardiovascular diseases among treatment naïve HIV- infected adults initiating antiretroviral therapy in Urban Tanzania.

BACKGROUND: Cardiovascular diseases (CVDs) have become an important cause of ill health and death among people living with HIV and/or AIDS (PLHIV) in the antiretroviral therapy (ART) era. There is scarce data on the burden of hypertension (HTN) and risk factors for CVDs among PLHIV in developing countries, including Tanzania during the ART era. OBJECTIVE(S): To determine the prevalence of HTN and risk factors for CVDs among ART naïve PLHIV initiating ART. METHODS: We analysed baseline data of 430 clinical trial participants on the effect of low-dose aspirin on HIV disease progression among HIV-infected individuals initiating ART. HTN was the outcome CVD. Traditional risk factors for CVDs studied were age, alcohol consumption, cigarette smoking, individual and family history of CVDs, diabetes mellitus (DM), obesity/overweight, and dyslipidaemia. A generalized linear model (robust Poisson regression) was used to determine the predictors for HTN. RESULTS: The median (IQR) age was 37 (28, 45) years. Females were the majority contributing 64.9% of all participants. The prevalence of HTN was 24.8%. The most prevalent risk factors for CVDs were dyslipidaemia (88.3%), alcohol consumption (49.3%), and overweight or obesity (29.1%). Being overweight or obese predicted the occurrence of HTN, aPR 1.60 (95% CI 1.16-2.21) while WHO HIV clinical stage 3 was protective against HTN, aPR 0.42(95% CI 0.18-0.97). CONCLUSION: The prevalence of HTN and traditional risk factors for CVDs in the treatment naïve PLHIV initiating ART are significant. Identifying these risk factors and managing them at the time of ART initiation may lower future CVDs among PLHIV.

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.

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.

Population Pharmacokinetics of the Antimalarial Amodiaquine: a Pooled Analysis To Optimize Dosing.

Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where malaria is endemic. However, pediatric doses are largely based on a linear extrapolation from adult doses. We pooled data from previously published studies on the pharmacokinetics of amodiaquine, to optimize the dose across all age groups. Adults and children with uncomplicated malaria received daily weight-based doses of amodiaquine or artesunate-amodiaquine over 3 days. Plasma concentration-time profiles for both the parent drug and the metabolite were characterized using nonlinear mixed-effects modeling. Amodiaquine pharmacokinetics were adequately described by a two-compartment disposition model, with first-order elimination leading to the formation of desethylamodiaquine, which was best described by a three-compartment disposition model. Body size and age were the main covariates affecting amodiaquine clearance. After adjusting for the effect of weight, clearance rates for amodiaquine and desethylamodiaquine reached 50% of adult maturation at 2.8 months (95% confidence interval [CI], 1.5 to 3.7 months) and 3.9 months (95% CI, 2.6 to 5.3 months) after birth, assuming that the baby was born at term. Bioavailability was 22.4% (95% CI, 15.6 to 31.9%) lower at the start of treatment than during convalescence, which suggests a malaria disease effect. Neither the drug formulation nor the hemoglobin concentration had an effect on any pharmacokinetic parameters. Results from simulations showed that current manufacturer dosing recommendations resulted in low desethylamodiaquine exposure in patients weighing 8 kg, 15 to 17 kg, 33 to 35 kg, and >62 kg compared to that in a typical 50-kg patient. We propose possible optimized dosing regimens to achieve similar drug exposures among all age groups, which require further validation.

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.

Plasmodium falciparum variant erythrocyte surface antigens: a pilot study of antibody acquisition in recurrent natural infections.

BACKGROUND: During intra-erythrocytic replication Plasmodium falciparum escapes the human host immune system by switching expression of variant surface antigens (VSA). Piecemeal acquisition of variant specific antibody responses to these antigens as a result of exposure to multiple re-infections has been proposed to play a role in acquisition of naturally acquired immunity. METHODS: Immunofluorescence was used to explore the dynamics of anti-VSA IgG responses generated by children to (i) primary malaria episodes and (ii) recurrent P. falciparum infections. RESULTS: Consistent with previous studies on anti-VSA responses, sera from each child taken at the time of recovery from their respective primary infection tended to recognize their own secondary parasites poorly. Additionally, compared to patients with reinfections by parasites of new merozoite surface protein 2 (MSP2) genotypes, baseline sera sampled from patients with persistent infections (recrudescence) tended to have higher recognition of heterologous parasites. This is consistent with the prediction that anti-VSA IgG responses may play a role in promoting chronic asymptomatic infections. CONCLUSIONS: This pilot study validates the utility of recurrent natural malaria infections as a functional readout for examining the incremental acquisition of immunity to malaria.

Rationale and design of mDOT-HuA study: a randomized trial to assess the effect of mobile-directly observed therapy on adherence to hydroxyurea in adults with sickle cell anemia in Tanzania.

BACKGROUND: Hydroxyurea (HU) has been demonstrated to be efficacious in reducing complications in individuals with sickle cell anemia (SCA) but poor adherence is a barrier. Directly Observed Therapy (DOT) has been shown to improve adherence in various chronic diseases but there is limited data in adults with SCA. METHODS AND DESIGN: To examine the effect of mobile-directly observed therapy (mDOT) on adherence to HU (mDOT-HuA) in adults with SCA at Muhimbili National Hospital in Tanzania. The mDOT-HuA study is a single centre, prospective, randomized, open label clinical trial. One-hundred individuals with SCA with haemoglobin SS genotype, aged ≥18 years, living in Dar es Salaam, able and willing to record and submit videos electronically will be included. Participants will be divided into two treatment arms; 50 in the standard monitoring (SM) arm will receive mobile phones and fixed dose HU therapy with standard monitoring; 50 in the mDOT arm will receive mobile phones, fixed dose HU therapy with standard monitoring and a mobile directly observed web based medication adherence monitoring system. The primary outcome is the proportion of participants achieving ≥80 % HU adherence compared between the two arms as assessed through medication possession ratio at the end of 3 months of treatment. REDCap, an open source software application will be used to collect data using clinical research forms. The proportions of adherence in the two arms will be compared by Fisher's exact test. Analysis of outcomes will have performed by both the intention-to treat and per-protocol methods. DISCUSSION: Should this study become sucessful, it will have the potential for the development of novel strategies for improving HU adherence in SCA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02844673 , registered on 25tht July 2016 (retrospectively registered).

Adherence to artemether-lumefantrine drug combination: a rural community experience six years after change of malaria treatment policy in Tanzania.

BACKGROUND: Adherence to multidosing is challenging worldwide. This study assessed the extent of adherence to multidosing artemether-lumefantrine (ALu) in a rural community in Tanzania, six years after switching from single dose policy of sulphadoxine-pyrimethamine. METHODS: This study was a prospective observational, open label, non-randomized study involving 151 patients with uncomplicated malaria recruited at Fukayosi dispensary in Bagamoyo district in Tanzania. Patients treated with ALu were visited at home on day 3 for interview on drug intake, capillary blood sample collection for microscopy and ALu tablets count. Venous blood samples (2 ml) for determination of blood lumefantrine concentrations and blood slides for microscopy were collected on day-7. Kappa's coefficient was used to assess agreement between pill count and self-report. Adherence was categorized depending on the tablets remaining and what the patient reported. Only those with empty blister pack available but no tablet remaining and reported taking all six doses of ALu at a correct dose and correct time were regarded as definite adherent. The rest were either probable adherent or probable non-adherent. RESULTS: Only 14.9% of the patients were definite adherent the rest took the drug at incorrect time or did not finish the tablets. Out of 90 patients with analysed plasma samples for lumefantrine blood concentrations, 13/90 (14.4.0%) had lumefantrine concentrations <175 ng/ml. There was no difference in mean lumefantrine concentration in the patients who stated to have taken all doses as required (561.61 ng/ml 95% CI = 419.81-703.41) compared to those who stated to have not adhered well to drug intake (490.95 ng/ml, 95% CI = 404.18-577.7074 (p = 0.643). None of the patients had detectable parasites by microscopy on day-3 and day-7 regardless of adherence status and the level of day-7 blood lumefantrine. There was strong agreement between the self-reported responses on drug intake and pill-counts (kappa coefficient = 0.955). Age, sex, education and place where first dose was taken were associated with adherence. CONCLUSIONS: The overall adherence six years after the change of malaria treatment policy was low. It is, therefore, important to continuously monitor the level of adherence to treatment in order to get the current situation and institute corrective measures on time.

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.

Preparing Institutions to Implement Harmonized Medicine and Nursing Curricula Through the Use of Cross-Institutional Faculty Developers.

Background: Effective implementation of new curricula requires faculty to be knowledgeable about curriculum goals and have the appropriate pedagogical skills to implement the curriculum, even more so if the new curriculum is being deployed at multiple institutions. In this paper, we describe the process of creating a common faculty development program to train cross-institutional faculty developers to support the implementation of national harmonized medicine and nursing curricula. Methods: A five-step approach was used, including a cross-institutional needs assessment survey for faculty development needs, the development of a generic faculty development program, the identification and training of cross-institutional faculty educators, and the implementation of cross-institutional faculty capacity-building workshops. Results: A list of common cross-cutting faculty development needs for teaching and learning was identified from the needs assessment survey and used to develop an accredited, cross-institutional faculty development program for competency-based learning and assessment. A total of 24 cross-institutional faculty developers were identified and trained in 8 core learning and assessment workshops. A total of 18 cross-institutional and 71 institutional workshops were conducted, of which 1292 faculty members and 412 residents were trained, and three cross-institutional educational research projects were implemented. Conclusion: The success attained in this study shows that the use of cross-institutional faculty developers is a viable model and sustainable resource that can be used to support the implementation of harmonized national curricula.

Comparison of bioavailability between the most available generic tablet formulation containing artemether and lumefantrine on the Tanzanian market and the innovator's product.

BACKGROUND: Existence of anti-malarial generic drugs with low bioavailability marketed on sub-Saharan Africa raises a concern on patients achieving therapeutic concentrations after intake of such products. This work compared bioavailability of one generic tablet formulation with innovator's product. Both were fixed dose combination tablet formulations containing artemether and lumefantrine. METHODOLOGY: The study was conducted in Dar Es Salaam, Tanzania, in which a survey of the most abundant generic containing artemether-lumefantrine tablet formulation was carried out in retail pharmacies. The most widely available generic (Artefan®, Ajanta Pharma Ltd, Maharashtra, India) was sampled for bioavailability comparison with Coartem® (Novartis Pharma, Basel, Switzerland)--the innovator's product. A randomized, two-treatment cross-over study was conducted in 18 healthy Tanzanian black male volunteers. Each volunteer received Artefan® (test) and Coartem® (as reference) formulation separated by 42 days of drug-free washout period. Serial blood samples were collected up to 168 hours after oral administration of a single dose of each treatment. Quantitation of lumefantrine plasma levels was done using HPLC with UV detection. Bioequivalence of the two products was assessed in accordance with the US Food and Drug Authority (FDA) guidelines. RESULTS: The most widely available generic in pharmacies was Artefan® from India. All eighteen enrolled volunteers completed the study and both test and reference tablet formulations were well tolerated. It was possible to quantify lumefantrine alone, therefore, the pharmacokinetic parameters reported herein are for lumefantrine. The geometric mean ratios for Cmax, AUC0-t and AUC0-∞ were 84% in all cases and within FDA recommended bioequivalence limits of 80%-125%, but the 90% confidence intervals were outside FDA recommended limits (CI 49-143%, 53-137%, 52-135% respectively). There were no statistical significant differences between the two formulations with regard to PK parameters (P > 0.05). CONCLUSIONS: Although the ratios of AUCs and Cmax were within the acceptable FDA range, bioequivalence between Artefan® and Coartem® tablet formulations was not demonstrated due to failure to comply with the FDA 90% confidence interval criteria. Based on the observed total drug exposure (AUCs), Artefan® is likely to produce a similar therapeutic response as Coartem®.

Adherence to antiretroviral therapy among HIV infected children measured by caretaker report, medication return, and drug level in Dar Es Salaam, Tanzania.

BACKGROUND: Adherence to antiretroviral drugs in the treatment of paediatric HIV infection is complicated because of many factors including stigma and drug intake logistics. It is therefore important to identify children with non-adherence in order to intervene before they become at risk of developing treatment failure or drug resistance. The aim of this study was to determine the level of adherence to antiretroviral therapy (ART), measured by caretaker report, medication return and nevirapine plasma concentration. In addition, the association between level of adherence and patient's immune status was compared across the three methods of measuring adherence. METHODS: This was a descriptive cross-sectional study involving HIV infected children aged 2-14 years, on nevirapine- based antiretroviral treatment for at least six months, attending care and treatment clinic in three municipal hospitals in Dar- Es- Salaam City. Eligible patients and their accompanying caretakers were consecutively enrolled after obtaining written informed consent. Structured questionnaires were administered to caretakers to assess patient's adherence by caretaker report and medication return whereas a single blood sample for CD4 cell count/percent and determination of nevirapine plasma concentration was taken from patients on the day of assessment. RESULTS: A total of 300 patients and accompanying caretakers were enrolled and the mean patient age (SD) was 8 (3) years. Caretakers' report and medication return showed good adherence (98% and 97%) respectively. However, the level of adherence assessed by nevirapine plasma concentration (85%) was significantly lower than caretaker report and medication return (p < 0.001). The agreement between nevirapine plasma concentration and medication return and between nevirapine plasma concentration and caretaker report was weak (k = 0. 131) (k = 0. 09) respectively. Nevirapine plasma concentration below 3 µg/ml was associated with immunosuppression (p = 0. 021) whereas medication return (>5% of prescribed doses) and caretaker reported missing more than one dose within 72 hours prior to interview were not associated with immunosuppression (p = 0. 474), (p = 0. 569) respectively. CONCLUSION: Lower adherence level observed using nevirapine plasma concentration and its association with immunological response supports the validity of the method and indicates that adherence data obtained from caretaker report and medication return may overestimate the true adherence in paediatric antiretroviral therapy.

Factors influencing receipt of an antibiotic prescription among insured patients in Tanzania: a cross-sectional study.

OBJECTIVES: There are limited data on factors influencing antibiotic prescription among insured patients. We assessed for correlates of an antibiotic prescription among insured patients. DESIGN: A cross-sectional study. SETTING: The study was conducted at the National Health Insurance Fund offices, Dar es Salaam, Tanzania. DATA SOURCE: We captured data from the claim forms, containing inpatient and outpatient treatment information for insured patients, for the month of September 2019. OUTCOME VARIABLE: Receipt of an antibiotic prescription. EXPOSURE VARIABLES: Age, sex, diagnosis, prescriber qualification, health facility level, ownership and department were exposure variables. Predictors of receipt of an antibiotic prescription were determined by Poisson regression analysis. RESULTS: Of 993 analysed patients, the mean (±SD) age was 36.3 (±23.2) years, 581 (58.5%) were females and 535 (53.9%) were adults. The prevalence of antibiotic prescription was 46.4% (95% CI 42.8% to 50.0%). Strong predictors of an antibiotic prescription were being a child (1.7, 95% CI 1.3 to 2.2); acute upper respiratory tract infection (URTI) of multiple and unspecified sites (1.6, 95% CI 1.3 to 1.4); chronic rhinitis, nasopharyngitis and pharyngitis (4.0, 95% CI 2.4 to 6.4); being attended by a clinical officer (1.9, 95% CI 1.2 to 3.0); attending a health centre (1.5, 95% CI 1.1 to 2.0); attending a public facility (1.2, 95% CI 1.0 to 1.4) and visiting an inpatient department (2.0, 95% CI 1.2 to 3.4). CONCLUSIONS: Among insured patients, being a child, acute URTI, being attended by a clinical officer or dental therapist, being attended by an assistant medical/dental officer, attending a health centre or a district hospital, attending a public health facility and visiting an inpatient department predicted an antibiotic prescription. Incorporation of these findings in revisions or establishment of targeted antimicrobial stewardship programmes may lead to better antibiotic prescribing practices that are critical for combating antibiotic resistance.

The prevalence and pattern of antibiotic prescription among insured patients in Dar es Salaam Tanzania.

INTRODUCTION: high prevalence of antibiotic prescriptions may contribute to the problem of antibiotic resistance. Understanding the pattern of antibiotic prescriptions in a country may inform monitoring and stewardship activities, which are crucial in the fight against antibiotic resistance. We aimed to determine the prevalence and describe the pattern of antibiotic prescriptions among National Health Insurance Fund (NHIF) insured patients receiving treatment at health facilities in Ilala Municipality, Dar es Salaam, Tanzania. METHODS: a cross-sectional analysis of claim forms of NHIF insured patients. A data extraction form was used to capture data for September, 2019 submitted to the Ilala NHIF offices. RESULTS: among 993 insured patients (mean [±SD] age 36.3 [±23.2] years; 581 [58.5%] females; 535 [53.9%] adults) a total of 357 (46.4%, 95% CI, 42.8-50.0) received an antibiotic prescription. Of the 357 patients who received an antibiotic prescription, 71(19.9%) received more than one antibiotic prescription. The most common antibiotic prescribed was amoxicillin/clavulanate (17.1%) followed by amoxicillin (16.5%) whereas the most commonly prescribed antibiotic class was the penicillins (51.3%) followed by the nitroimidazoles (14.0%). Among patients who received more than one antibiotic, the most commonly co-prescribed antibiotics were Ampicillin/Cloxacillin plus Metronidazole (11.4%) followed by Amoxicillin plus Metronidazole (7.1%). According to 2019 WHO Access, Watch, Reserve (AWaRe) Classification of antibiotics, 60.8% of patients received the access antibiotics, 33.3% received the watch antibiotics whereas 17.4% of patients received antibiotics that were not recommended. No patient received an antibiotic from the reserve group. CONCLUSION: the prevalence of antibiotic prescriptions in Tanzania is high and some antibiotics not recommended by the WHO are still prescribed. We recommend revision of the current Tanzania treatment guideline on antibiotics to reflect WHO recommendations, and further research to address local factors influencing antibiotic prescriptions is warranted.

Effect of aspirin on HIV disease progression among HIV-infected individuals initiating antiretroviral therapy: study protocol for a randomised controlled trial.

INTRODUCTION: An increase in cardiovascular disease (CVD) among people living with HIV infection is linked to platelet and immune activation, a phenomenon unabolished by antiretroviral (ARV) drugs alone. In small studies, aspirin (acetylsalicylic acid [ASA]) has been shown to control immune activation, increase CD4+ count, halt HIV disease progression and reduce HIV viral load (HVL). We present a protocol for a larger ongoing randomised placebo controlled trial on the effect of an addition of ASA to ARV drugs on HIV disease progression. METHODS AND ANALYSIS: A single-centre phase IIA double-blind, parallel-group randomised controlled trial intends to recruit 454 consenting ARV drug-naïve, HIV-infected adults initiating ART. Participants are randomised in blocks of 10 in a 1:1 ratio to receive, in addition to ARV drugs, 75 mg ASA or placebo for 6 months. The primary outcome is the proportion of participants attaining HVL of <50 copies/mL by 8, 12 and 24 weeks. Secondary outcomes include proportions of participants with HVL of >1000 copies/mL at week 24, attaining a >30% rise of CD4 count from baseline value at week 12, experiencing adverse events, with normal levels of biomarkers of platelet and immune activation at weeks 12 and 24 and rates of morbidity and all-cause mortality. Intention-to-treat analysis will be done for all study outcomes. ETHICS AND DISSEMINATION: Ethical approval has been obtained from institutional and national ethics review committees. Findings will be submitted to peer-reviewed journals and presented in scientific conferences. TRIAL REGISTRATION NUMBER: PACTR202003522049711.

Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial.

BACKGROUND: Combination treatments, preferably containing an artemisinin derivative, are recommended to improve efficacy and prevent Plasmodium falciparum drug resistance. Our aim was to show non-inferiority of a new dispersible formulation of artemether-lumefantrine to the conventional crushed tablet in the treatment of young children with uncomplicated malaria. METHODS: We did a randomised non-inferiority study on children weighing 5-35 kg with uncomplicated P falciparum malaria in Benin, Kenya, Mali, Mozambique, and Tanzania. The primary outcome measure was PCR-corrected 28-day parasitological cure rate. We aimed to show non-inferiority (with a margin of -5%) of dispersible versus crushed tablet. We constructed an asymptotic one-sided 97.5% CI on the difference in cure rates. A computer-generated randomisation list was kept centrally and investigators were unaware of the study medication administered. We used a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00386763. FINDINGS: 899 children aged 12 years or younger were randomly assigned to either dispersible (n=447) or crushed tablets (n=452). More than 85% of patients in each treatment group completed the study. 812 children qualified for the modified intention-to-treat analysis (n=403 vs n=409). The PCR-corrected day-28 cure rate was 97.8% (95% CI 96.3-99.2) in the group on dispersible formulation and 98.5% (97.4-99.7) in the group on crushed formulation. The lower bound of the one-sided 97.5% CI was -2.7%. The most common drug-related adverse event was vomiting (n=33 [7%] and n=42 [9%], respectively). No signs of ototoxicity or relevant cardiotoxicity were seen. INTERPRETATION: A six-dose regimen of artemether-lumefantrine with the new dispersible formulation is as efficacious as the currently used crushed tablet in infants and children, and has a similar safety profile.

Chloroquine resistance before and after its withdrawal in Kenya.

BACKGROUND: The spread of resistance to chloroquine (CQ) led to its withdrawal from use in most countries in sub-Saharan Africa in the 1990s. In Malawi, this withdrawal was followed by a rapid reduction in the frequency of resistance to the point where the drug is now considered to be effective once again, just nine years after its withdrawal. In this report, the polymorphisms of markers associated with CQ-resistance against Plasmodium falciparum isolates from coastal Kenya (Kilifi) were investigated, from 1993, prior to the withdrawal of CQ, to 2006, seven years after its withdrawal. Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared. METHODS: Mutations associated with CQ resistance, at codons 76 of pfcrt, at 86 of pfmdr1, and at codons 51, 59 and 164 of dhfr were analysed using PCR-restriction enzyme methods. In total, 406, 240 and 323 isolates were genotyped for pfcrt-76, pfmdr1-86 and dhfr, respectively. RESULTS: From 1993 to 2006, the frequency of the pfcrt-76 mutant significantly decreased from around 95% to 60%, while the frequency of pfmdr1-86 did not decline, remaining around 75%. Though the frequency of dhfr mutants was already high (around 80%) at the start of the study, this frequency increased to above 95% during the study period. Mutation at codon 164 of dhfr was analysed in 2006 samples, and none of them had this mutation. CONCLUSION: In accord with the study in Malawi, a reduction in resistance to CQ following official withdrawal in 1999 was found, but unlike Malawi, the decline of resistance to CQ in Kilifi was much slower. It is estimated that, at current rates of decline, it will take 13 more years for the clinical efficacy of CQ to be restored in Kilifi. In addition, CQ resistance was declining before the drug's official withdrawal, suggesting that, prior to the official ban, the use of CQ had decreased, probably due to its poor clinical effectiveness.

Variability of efavirenz plasma concentrations among pediatric HIV patients treated with efavirenz based combination antiretroviral therapy in Dar es Salaam, Tanzania.

BACKGROUND: Children are subject to varying drug pharmacokinetics which influence plasma drug levels, and hence treatment outcomes especially for drugs like efavirenz whose plasma concentrations are directly related to treatment outcomes. This study is aimed at determining plasma efavirenz concentrations among Tanzanian pediatric HIV-1 patients on efavirenz-based combination antiretroviral therapy (cART) and relating it to clinical, immunological and virologic treatment responses. METHODS: A cross sectional study involving pediatric HIV patients aged 5-15 years on efavirenz-based cART for ≥ 6 months were recruited in Dar es Salaam. Data on demographics, cART regimens, efavirenz dose and time of the last dose were collected using structured questionnaires and checklists. Venous blood samples were drawn at 10-19 h post-dosing for efavirenz plasma analysis. RESULTS: A total of 145 children with a mean ± SD age of 10.83 ± 2.75 years, on cART for a mean ± SD of 3.7 ± 2.56 years were recruited. Median [IQR] efavirenz concentration was 2.56 [IQR = 1.5-4.6] µg/mL with wide inter-patient variability (CV 111%). Poor virologic response was observed in 70.8%, 20.8% and 15.9% of patients with efavirenz levels < 1 µg/mL, 1-4 µg/mL and > 4 µg/mL respectively. Patients with efavirenz levels of < 1 µg/mL were 11 times more likely to have detectable viral loads. Immunologically, 31.8% of children who had low levels (< 1 µg/mL) of efavirenz had a CD4 count of < 350 cells/µL. CONCLUSION: Wide inter-individual variability in efavirenz plasma concentrations is seen among Tanzanian children in routine clinical practice with many being outside the recommended therapeutic range. Virologic failure is very high in children with sub-therapeutic levels. Concentrations outside the therapeutic window suggest the need for dose adjustment on the basis of therapeutic drug monitoring to optimize treatment.