ObjectivesThere are limited data on factors influencing antibiotic prescription among insured pat... more ObjectivesThere are limited data on factors influencing antibiotic prescription among insured patients. We assessed for correlates of an antibiotic prescription among insured patients.DesignA cross-sectional study.SettingThe study was conducted at the National Health Insurance Fund offices, Dar es Salaam, Tanzania.Data sourceWe captured data from the claim forms, containing inpatient and outpatient treatment information for insured patients, for the month of September 2019.Outcome variableReceipt of an antibiotic prescription.Exposure variablesAge, 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.ResultsOf 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 ...
Background: Febrile malaria is the most common clinical manifestation of P. falciparum infection,... more Background: Febrile malaria is the most common clinical manifestation of P. falciparum infection, and is often the primary endpoint in clinical trials and epidemiological studies. Subjective and objective fevers are both used to define the endpoint, but have not been carefully compared, and the relative incidence of clinical malaria by active and passive case detection is unknown. Methods: We analyzed data from cohorts under active and passive surveillance, including 19,462 presentations with fever and 5,551 blood tests for asymptomatic parasitaemia. A logistic regression model was used to calculate Malaria Attributable Fractions (MAFs) for various case definitions. Incidences of febrile malaria by active and passive surveillance were compared in a subset of children matched for age and location. Results: Active surveillance identified three times the incidence of clinical malaria as passive surveillance in a subset of children matched for age and location. Objective fever (temperature$37.5uC) gave consistently higher MAFs than case definitions based on subjective fever. Conclusion: The endpoints from active and passive surveillance have high specificity, but the incidence of endpoints is lower on passive surveillance. Subjective fever had low specificity and should not be used in primary endpoint. Passive surveillance will reduce the power of clinical trials but may cost-effectively deliver acceptable sensitivity in studies of large populations.
IntroductionAn increase in cardiovascular disease (CVD) among people living with HIV infection is... more IntroductionAn 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 analysisA 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 includ...
Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where mal... more 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
Background Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatm... more 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 c...
Background: Children are subject to varying drug pharmacokinetics which influence plasma drug lev... more 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.
The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as co... more The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/ Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes. Efavirenz (EFV), a potent non-nucleoside reverse transcriptase inhibitor (NNRTI), is part of the first-line anti-retroviral combination therapies (cART) for HIV/AIDS in resource-limited countries. Tanzania is one of the resource-limited countries, greatly affected by the HIV epidemic with prevalence of 5% among adults aged 15-64 years. The burden of tuberculosis (TB) in Tanzania is also rising particularly among people living with HIV; HIV/ TB co-infection accounted for 34% of the newly diagnosed cases of TB in 2016. Recent treatment guidelines recommend EFV containing ART as the default first-line regimens both in HIV-infected adults and children above 3 years of age 1. It is also the default first-line ART regimen for HIV/TB co-treatment 1-3. The levels of EFV plasma exposure have been related to HIV treatment outcomes. In a study by Marzolin et al., EFV levels below 1 μg/mL were associated with virological failure while levels above 4 μg/ml were associated with neuropsychiatric symptoms 4. Efavirenz exhibits prolonged autoinduction leading to sub-therapeutic plasma levels in some patients after long-term treatment 5. Furthermore metabolic disorders including, maldistribution, hyperlipemia, glucose
Background: In 2006, artemether-lumefantrine (ALU), specifically Coartem ® (Novartis Pharma AG, B... more 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 antimalarial 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.
Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell dise... more 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. Twenty-nine children (70% male, 9-11years, weight 16.3-31.3 kg) with SCD. 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-inv...
Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailabi... more Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailability are implicated in morbidity related to sickle-cell disease. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses that: (1) supplementary arginine, citrulline, and daily chloroquine increase bioavailable arginine and flow-mediated dilatation (FMD; maximal diameter change; FMD%), a measure of nitric oxide-dependent endothelial function; and (2) protein energy supplementation in the form of ready-to-use supplementary food (RUSF) improves the height-for-age and body-mass index-for-age Z-scores in children with sickle-cell disease. We performed a double-blind, random order crossover trial with two 4-month intervention periods (each followed by 4-month washout periods) in Muhimbili National Hospital in Dar-es-Salaam, Tanzania. We enrolled 119 children from the Muhimbili Sickle Cohort who were aged 8-12 years, naive to hydroxyurea, and had d...
During intra-erythrocytic replication Plasmodium falciparum escapes the human host immune system ... more 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. 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. 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 pa...
Hydroxyurea (HU) has been demonstrated to be efficacious in reducing complications in individuals... more 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. 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 monitori...
To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects... more To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4β-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4β-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. A one-compartment, enzyme turnover model described 4β-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative st...
We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the... more We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8-hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*...
We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz aut... more We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure cont...
The American journal of tropical medicine and hygiene, 2007
Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. Th... more Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. The factors contributing to the acidosis were assessed in 62 children with severe falciparum malaria (cases) and in 29 control children who had recently recovered from mild or moderate malaria. The acidosis was largely caused by the accumulation of both lactic and 3-hydroxybutyric acids. The determinants of oxygen release to the tissues were also examined; although there was no difference between cases and controls in respect of 2,3-bisphosphoglycerate and mean corpuscular hemoglobin concentration, there was a marked increase in P(50) in the cases, caused by pyrexia, low pH, and base deficit. There was substantial relative or actual hypoglycemia in many cases. The relationship of these observations to therapeutic strategy is discussed.
Background: Adherence to multidosing is challenging worldwide. This study assessed the extent of ... more 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.
The American journal of tropical medicine and hygiene, 2014
Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria i... more Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal…
ObjectivesThere are limited data on factors influencing antibiotic prescription among insured pat... more ObjectivesThere are limited data on factors influencing antibiotic prescription among insured patients. We assessed for correlates of an antibiotic prescription among insured patients.DesignA cross-sectional study.SettingThe study was conducted at the National Health Insurance Fund offices, Dar es Salaam, Tanzania.Data sourceWe captured data from the claim forms, containing inpatient and outpatient treatment information for insured patients, for the month of September 2019.Outcome variableReceipt of an antibiotic prescription.Exposure variablesAge, 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.ResultsOf 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 ...
Background: Febrile malaria is the most common clinical manifestation of P. falciparum infection,... more Background: Febrile malaria is the most common clinical manifestation of P. falciparum infection, and is often the primary endpoint in clinical trials and epidemiological studies. Subjective and objective fevers are both used to define the endpoint, but have not been carefully compared, and the relative incidence of clinical malaria by active and passive case detection is unknown. Methods: We analyzed data from cohorts under active and passive surveillance, including 19,462 presentations with fever and 5,551 blood tests for asymptomatic parasitaemia. A logistic regression model was used to calculate Malaria Attributable Fractions (MAFs) for various case definitions. Incidences of febrile malaria by active and passive surveillance were compared in a subset of children matched for age and location. Results: Active surveillance identified three times the incidence of clinical malaria as passive surveillance in a subset of children matched for age and location. Objective fever (temperature$37.5uC) gave consistently higher MAFs than case definitions based on subjective fever. Conclusion: The endpoints from active and passive surveillance have high specificity, but the incidence of endpoints is lower on passive surveillance. Subjective fever had low specificity and should not be used in primary endpoint. Passive surveillance will reduce the power of clinical trials but may cost-effectively deliver acceptable sensitivity in studies of large populations.
IntroductionAn increase in cardiovascular disease (CVD) among people living with HIV infection is... more IntroductionAn 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 analysisA 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 includ...
Amodiaquine plus artesunate is the recommended antimalarial treatment in many countries where mal... more 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
Background Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatm... more 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 c...
Background: Children are subject to varying drug pharmacokinetics which influence plasma drug lev... more 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.
The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as co... more The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/ Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes. Efavirenz (EFV), a potent non-nucleoside reverse transcriptase inhibitor (NNRTI), is part of the first-line anti-retroviral combination therapies (cART) for HIV/AIDS in resource-limited countries. Tanzania is one of the resource-limited countries, greatly affected by the HIV epidemic with prevalence of 5% among adults aged 15-64 years. The burden of tuberculosis (TB) in Tanzania is also rising particularly among people living with HIV; HIV/ TB co-infection accounted for 34% of the newly diagnosed cases of TB in 2016. Recent treatment guidelines recommend EFV containing ART as the default first-line regimens both in HIV-infected adults and children above 3 years of age 1. It is also the default first-line ART regimen for HIV/TB co-treatment 1-3. The levels of EFV plasma exposure have been related to HIV treatment outcomes. In a study by Marzolin et al., EFV levels below 1 μg/mL were associated with virological failure while levels above 4 μg/ml were associated with neuropsychiatric symptoms 4. Efavirenz exhibits prolonged autoinduction leading to sub-therapeutic plasma levels in some patients after long-term treatment 5. Furthermore metabolic disorders including, maldistribution, hyperlipemia, glucose
Background: In 2006, artemether-lumefantrine (ALU), specifically Coartem ® (Novartis Pharma AG, B... more 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 antimalarial 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.
Low bioavailability of nitric oxide (NO) is implicated in the pathophysiology of sickle cell dise... more 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. Twenty-nine children (70% male, 9-11years, weight 16.3-31.3 kg) with SCD. 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-inv...
Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailabi... more Sickle-cell disease increases the risk of malnutrition. Low arginine and nitric oxide bioavailability are implicated in morbidity related to sickle-cell disease. Simple interventions are required, especially in low-income settings. We aimed to test the hypotheses that: (1) supplementary arginine, citrulline, and daily chloroquine increase bioavailable arginine and flow-mediated dilatation (FMD; maximal diameter change; FMD%), a measure of nitric oxide-dependent endothelial function; and (2) protein energy supplementation in the form of ready-to-use supplementary food (RUSF) improves the height-for-age and body-mass index-for-age Z-scores in children with sickle-cell disease. We performed a double-blind, random order crossover trial with two 4-month intervention periods (each followed by 4-month washout periods) in Muhimbili National Hospital in Dar-es-Salaam, Tanzania. We enrolled 119 children from the Muhimbili Sickle Cohort who were aged 8-12 years, naive to hydroxyurea, and had d...
During intra-erythrocytic replication Plasmodium falciparum escapes the human host immune system ... more 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. 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. 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 pa...
Hydroxyurea (HU) has been demonstrated to be efficacious in reducing complications in individuals... more 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. 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 monitori...
To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects... more To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4β-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4β-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. A one-compartment, enzyme turnover model described 4β-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative st...
We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the... more We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8-hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*...
We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz aut... more We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure cont...
The American journal of tropical medicine and hygiene, 2007
Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. Th... more Metabolic acidosis is a common complication of severe malaria caused by Plasmodium falciparum. The factors contributing to the acidosis were assessed in 62 children with severe falciparum malaria (cases) and in 29 control children who had recently recovered from mild or moderate malaria. The acidosis was largely caused by the accumulation of both lactic and 3-hydroxybutyric acids. The determinants of oxygen release to the tissues were also examined; although there was no difference between cases and controls in respect of 2,3-bisphosphoglycerate and mean corpuscular hemoglobin concentration, there was a marked increase in P(50) in the cases, caused by pyrexia, low pH, and base deficit. There was substantial relative or actual hypoglycemia in many cases. The relationship of these observations to therapeutic strategy is discussed.
Background: Adherence to multidosing is challenging worldwide. This study assessed the extent of ... more 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.
The American journal of tropical medicine and hygiene, 2014
Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria i... more Controlled human malaria infection (CHMI) by mosquito bite has been used to assess anti-malaria interventions in > 1,500 volunteers since development of methods for infecting mosquitoes by feeding on Plasmodium falciparum (Pf) gametocyte cultures. Such CHMIs have never been used in Africa. Aseptic, purified, cryopreserved Pf sporozoites, PfSPZ Challenge, were used to infect Dutch volunteers by intradermal injection. We conducted a double-blind, placebo-controlled trial to assess safety and infectivity of PfSPZ Challenge in adult male Tanzanians. Volunteers were injected intradermally with 10,000 (N = 12) or 25,000 (N = 12) PfSPZ or normal…
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Papers by Philip Sasi