•In 2020, COVID-19 dislodged TB as the top infectious disease cause of mortality globally.•Globally, an estimated 10.0 million people developed active TB disease in 2019, with 1.4 million TB ...deaths.•The WHO regions of South-East Asia, Africa, and the Western Pacific had the most cases of TB.•Progress in achieving the United Nations (UN) General Assembly End TB targets remains slow.•TB services need to be ramped up, and underlying drivers of TB need be addressed.
The October 2020 Global TB report reviews TB control strategies and United Nations (UN) targets set in the political declaration at the September 2018 UN General Assembly high-level meeting on TB held in New York. Progress in TB care and prevention has been very slow. In 2019, TB remained the most common cause of death from a single infectious pathogen. Globally, an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV. Adults accounted for 88% and children for 12% of people with TB. The WHO regions of South-East Asia (44%), Africa (25%), and the Western Pacific (18%) had the most people with TB. Eight countries accounted for two thirds of the global total: India (26%), Indonesia (8.5%), China (8.4%), the Philippines (6.0%), Pakistan (5.7%), Nigeria (4.4%), Bangladesh (3.6%) and South Africa (3.6%). Only 30% of the 3.5 million five-year target for children treated for TB was met. Major advances have been development of new all oral regimens for MDRTB and new regimens for preventive therapy. In 2020, the COVID-19 pandemic dislodged TB from the top infectious disease cause of mortality globally. Notably, global TB control efforts were not on track even before the advent of the COVID-19 pandemic. Many challenges remain to improve sub-optimal TB treatment and prevention services. Tuberculosis screening and diagnostic test services need to be ramped up. The major drivers of TB remain undernutrition, poverty, diabetes, tobacco smoking, and household air pollution and these need be addressed to achieve the WHO 2035 TB care and prevention targets. National programs need to include interventions for post-tuberculosis holistic wellbeing. From first detection of COVID-19 global coordination and political will with huge financial investments have led to the development of effective vaccines against SARS-CoV2 infection. The world now needs to similarly focus on development of new vaccines for TB utilizing new technological methods.
Unfavorable treatment outcomes for tuberculosis (TB) treatment might result from altered plasma exposure to antitubercular drugs in TB patients. The present study investigated the distribution of the ...N-Acetyltransferase 2 (NAT2) genotype, isoniazid acetylation status, genotype-phenotype concordance of NAT2, and isoniazid plasma exposure among Ethiopian tuberculosis patients. Blood samples were collected from newly diagnosed TB patients receiving a fixed dose combination of first-line antitubercular drugs daily. Genotyping of NAT2 was done using TaqMan drug metabolism assay. Isoniazid and its metabolite concentration were determined using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 120 patients (63 male and 57 female) were enrolled in this study. The mean daily dose of isoniazid was 4.71 mg/kg. The frequency of slow, intermediate, and fast NAT2 acetylators genotypes were 74.2%, 22.4%, and 3.3% respectively. The overall median isoniazid maximum plasma concentration (C
) was 4.77 µg/mL and the AUC
was 11.21 µg.h/mL. The median C
in slow, intermediate, and fast acetylators were 5.65, 3.44, and 2.47 μg/mL, respectively. The median AUC
hour in slow, intermediate, and fast acetylators were 13.1, 6.086, and 3.73 mg•h/L, respectively. The majority (87.5%) of the study participants achieved isoniazid C
of above 3 µg/mL, which is considered a lower limit for a favorable treatment outcome. There is 85% concordance between the NAT2 genotype and acetylation phenotypes. NAT2 genotype, female sex, and dose were independent predictors of C
and AUC
(p < 0.001). Our finding revealed that there is a high frequency of slow NAT2 genotypes. The plasma C
of isoniazid was higher in the female and slow acetylators genotype group. The overall target plasma isoniazid concentrations in Ethiopian tuberculosis patients were achieved in the majority of the patients. Therefore, it is important to monitor adverse drug reactions and the use of a higher dose of isoniazid should be closely monitored.
Efavirenz is metabolized by CYP2B6, an inducible enzyme whose expression is regulated by the constitutive androstane receptor and pregnane X receptor nuclear receptors. CAR and PXR are encoded by ...genetically polymorphic NR1I2 and NR1I3, respectively. We examined the impact of NR1I2 and NR1I3 genotype on plasma EFV concentration and CYP2B6 enzyme activity among TB-HIV co-infected patients in Ethiopia. Treatment-naïve HIV patients with TB co-infection (n = 80) were enrolled and received first-line EFV-based antiretroviral and rifampicin-based anti-TB therapy. Plasma EFV and 8-hydroxy-EFV concentrations at the 4th and 16th week of EFV treatment were determined using LC/MS/MS. EFV/8-hydroxy-EFVmetabolic ratio was used as CYP2B6 metabolic activity index. In multivariate regression analysis, NR1I3 rs3003596C or NR1I2 rs2472677T variant allele carriers had significantly lower plasma EFV concentrations than non-carriers. Patients with NR1I2 rs3814057C/C genotype or NR1I3 rs3003596C allele carriers had significantly lower mean log EFV MR. Among CYP2B6*6 allele carriers, patients with NR1I3 rs2502815T/T or NR1I2 rs3814057C/C genotype had significantly lower mean log EFV MR. In conclusion, genetic variants in NR1I2 and NR1I3 genes influence plasma EFV exposure and CYP2B6 enzyme activity in TB-HIV co-infected patients on drug treatment.
Background Despite the reported success in reducing morbidity, praziquantel alone is insufficient for the control and elimination of schistosomiasis, partly due to its poor efficacy against the ...juvenile worms. Artemisinin derivatives are effective against juvenile worms but are less effective against adult worms. We compared the safety and efficacy of praziquantel and Dihydroartemisinin-piperaquine combination against the standard praziquantel alone for treatment of intestinal schistosomiasis. Methods In this randomized, open-label, non-inferiority trial, 639 Schistosoma mansoni infected children were enrolled and randomized to receive either praziquantel alone or praziquantel plus Dihydroartemisinin-piperaquine combination. Two stool samples were collected on consecutive days at baseline, 3 and 8 weeks post-treatment and analyzed using thick smear Kato Katz method. Efficacy was assessed by cure and egg reduction rates at 3 and 8 weeks post-treatment. Adverse events were assessed within four hours of drugs intake. The primary outcome was cure rates at 8 weeks of post-treatment. Secondary outcomes were egg reduction rates at 8 weeks of post-treatment and treatment-associated adverse events. Results At 3 weeks of post-treatment, cure rates were 88.3% (263/298, 95% CI = 84.1%- 91.4%) and 81.2% (277/341, 95% CI = 76.7%- 85.0%) for the combination therapy and praziquantel alone, respectively (p 0.01, odds ratio (OR) = 1.74, 95% CI of OR = 1.11 to 2.69). At 8 weeks, there was a significant drop in the cure rates in praziquantel alone group to 63.9% (218/341, 95% CI = 58.7%- 68.8%) compared to 81.9% (244/298, 95% CI = 77.1%- 85.8%) in the combination therapy group (p 0.0001, OR = 2.55, 95%CI of OR = 1.75 to 3.69). Egg reduction rates at 8 weeks post-treatment were significantly higher in the combination therapy group 93.6% (95% CI = 90.8%- 96.4%) compared to 87.9% (95% CI = 84.4%- 91.4%) in the praziquantel only group (p = 0.01). On both Univariate and Multivariate regression analysis, type of treatment received was a significant predictor of cure at week 8 post-treatment. Overall, 30.8% (95% CI = 27.2%- 34.4%) of the study participants experienced mild and transient treatment-associated adverse events, post-treatment abdominal pain (27.1%) being the most common adverse event observed. There was no significant difference in the overall occurrence of adverse events between the two treatment groups. Conclusion Praziquantel and Dihydroartemisinin piperaquine combination therapy is safe, and more efficacious compared to praziquantel alone for the treatment of intestinal schistosomiasis. Further studies are needed to explore if the combination therapy can be considered as an option for mass drug administration to control and eventually eliminate schistosomiasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Schistosomiasis is a neglected tropical disease that continues to cause morbidity and mortality in Sub Saharan Africa. Due to its endemicity, co-infection with malaria is common. The diseases cause ...anaemia and impaired nutritional status among children. We investigated the prevalence of intestinal schistosomiasis and its association with malaria, anaemia and nutritional status among school children.
This was a cross sectional survey among 830 children in Nyamikoma village along Lake Victoria in Tanzania. A pre-tested questionnaire was used to collect socio-demographic data, history of drug use, and clinical data. Two faecal samples were collected on two consecutive days and analyzed using thick smears Kato Katz method. Diagnosis of malaria was done by malaria rapid diagnostic test, and haemoglobin concentration was determined using HemoCue. Nutritional status was assessed by anthropometric measurements.
The overall prevalence of intestinal schistosomiasis was 90.6% (95% CI = 88.6% - 92.6%). Intensity of infection was light 24.1% (200/830), moderate 38.4% (319/830) and heavy 28.1% (233/830). Pre-adolescents (≤12 years) were more infected with intestinal schistosomiasis (93.2%) than adolescents (>12 years) (84.7%) (p < 0.001). Prevalence of malaria was 1.7% (14/824), and that of intestinal schistosomiasis-malaria co-infection was 1.6% (13/824). The overall prevalence of anaemia was 24.6% (95%CI = 18.7% - 30.5%). Severe anaemia was found in 2.3% (19/824) of study participants. The prevalence of stunting and wasting were 29.0% and 11.3%, respectively. On both univariate and multivariate regression analysis, only lower age was significantly associated intestinal schistosomiasis infection, but not anemia, malaria, stunting or wasting. However among those infected, a negative binomial regression analysis indicated independent significant association of male sex, loose stool consistency, and stunting with high eggs count/gram of stool.
Despite several rounds of annual mass praziquantel administration, intestinal schistosomiasis is highly prevalent among school children particularly in younger children living in the study area. Biannual targeted mass praziquantel treatments or alternative regimens may be considered in future in the study area to redress the situation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Praziquantel pharmacokinetics studies in schistosomiasis infected children are scarce partly due to the challenges/complexity of intensive blood sampling in the target population. This study ...was aimed to investigate the optimal single sampling time-point for monitoring praziquantel exposure. This was intensive pharmacokinetic study conducted among 32
Schistosoma mansoni
infected children treated with an oral standard single-dose 40 mg/kg praziquantel. Plasma samples were collected at 0, 1, 2, 4, 6 and 8 h post-praziquantel administration. Quantification of praziquantel and its enantiomers (
R-
and
S-
praziquantel) concentrations was done by Liquid chromatography-tandem mass spectrometer (LC–MS/MS). The correlation between area under the plasma concentration–time curve from 0 to 8 h (AUC
8
) and plasma concentrations at each specific sampling time-point was determined by Pearson’s correlation coefficient (r
2
). The median age (range) of the study population was 12.5 years (10–17). The study participants were 17 males and 15 females. Both total praziquantel and its enantiomers (
R-
and
S-
praziquantel) displayed a wide inter-individual pharmacokinetic variability. Regression analysis indicated that, plasma concentrations collected at 4 h post-dose had a significantly highest correlation with the AUC
8
for both total praziquantel (r
2
= 0.81, p < 0.001) and
S-
praziquantel (r
2
= 0.84, p < 0.001) than any other sampling time-point; while for
R-
praziquantel, plasma concentrations collected at 6 h sampling time-point had a significantly highest correlation with the AUC
8
(r
2
= 0.79, p < 0.001) than any other sampling time-point. Four hours sampling time-point post-praziquantel administration is ideal optimal single sampling time-point for therapeutic monitoring of total praziquantel exposure while 6 h sampling time-point is suitable for monitoring of a pharmacologically active
R-
praziquantel enantiomer.
Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug ...administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.
We investigated prevalence and predictors of glucose metabolism disorders (GMDs) among People Living with HIV (PLWH) on efavirenz- and atazanavir/ritonavir-based combination antiretroviral therapy ...(cART).
This cross-sectional study involved adult PLWH on efavirenz- (n = 240) and atazanavir/ritonavir-based (n = 111) cART. The prevalence of GMDs was determined by fasting serum glucose, insulin, and homeostasis model assessment. A logistic regression model was used to determine predictors.
The overall prevalence of GMDs for all regimens was 27.6% (97/351) 95% CI 23.0-32.6% s, with 31.1% (75/240) 95% CI 25.4-37.5% for efavirenz-based and 19.8% (22/111) 95% CI 12.9-28.5%) for atazanavir/ritonavir-based cART group. The prevalence of impaired fasting glycemia was significantly higher (p = 0.026) in the efavirenz- (15.4%) (37/240); 95%CI (11.1-20.6%) than atazanavir/ritonavir-based (7.2%) (8/111), (95%CI (3.2-13.7%) cART. However, no significant difference was observed in the prevalence of diabetes mellitus and insulin resistance between the two regimens. Age ≥46 years old and specific type of ARV contained in cART, such as TDF, were independent predictors of GMD in both groups. Whereas the male gender and BMI category were predictors of GMDs among EFV-based cART group, AZT- and ABC- containing regimens and triglyceride levels were predictors in the ATV/r-based group.
GMDs were highly prevalent among adults on EFV- than ATV/r-based cARTs. Age ≥46 years and TDF-containing cARTs are common predictors in both regimens. Close monitoring for impaired fasting glucose during long-term EFV-based cART is recommended for early diagnosis of type-2 diabetes and management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
School-based mass drug administration (MDA) of Praziquantel (PZQ) is the global intervention strategy for elimination of schistosomiasis. Genetic variations in drug metabolizing enzymes and ...transporter proteins influences drug exposure and treatment outcomes, but data on PZQ pharmacokinetics and safety outcomes are scarce. We investigated the effect of pharmacogenetics variations on PZQ plasma concentrations and safety outcomes among 462 Rwandan schoolchildren who received single dose PZQ and albendazole in MDA. Genotyping for common functional variant alleles CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3) and CYP2J2*7 were done. Plasma concentration of PZQ, cis-4-OH-PZQ and trans-4-OH-PZQ were measured using LC/MS/MS. Active safety monitoring was done on days 1, 2, and 7 post-MDA. CYP2C9 and CYP2C19 genotypes were significantly associated with PZQ plasma concentrations and its cis- and trans-4-OH-PZQ/PZQ metabolic ratios (MR). CYP2C9*2 and CYP2C9*3 carriers had significantly higher PZQ concentration (p = 0.02), lower trans-4-OH-PZQ/PZQ (p < 0.001), and cis-4-OH-PZQ/PZQ (p = 0.02) MR. CYP2C19 (*2, *3) carriers had significantly higher plasma PZQ concentration than CYP2C19 *1/*1 and CYP2C19 *17 carriers (*1/*17 or *17/*17) (p < 0.001). CYP3A4 was significantly associated with cis-4-OH-PZQ MR (p = 0.04). Lower cis-4-OH-PZQ/PZQ MR (p < 0.0001) was a predictor of MDA-associated adverse events, but no significant association with genotypes were found. In conclusion, CYP2C9 and CYP2C19 genotypes significantly influence the plasma PZQ concentration and its MR. Lower cis-4-OH-PZQ/PZQ MR is significant predictor of adverse events following MDA.
•MDR-TB agents exhibit overlapping enzyme inhibition that might affect ART outcomes.•Clofazimine, a core MDR-TB drug, could be responsible for most DDIs with ARVs.•Rifampicin enhances clofazimine ...against M. tuberculosis.•Rifampicin inductive effect may be important during MDR-TB HIV co-treatment.•Plausible biological explanations for MDR-TB and HIV drug–drug interactions exist.
HIV-positive TB co-infected patients are at increased risk of multidrug-resistant (MDR)-TB compared to HIV-negative patients. Co-treatment of MDR-TB and HIV is common particularly in Sub-Saharan Africa where the co-morbidity is endemic. We discuss potential cellular metabolic pathway–mediated drug–drug interactions and the possible effect on HIV treatment outcomes of commonly prescribed antiretroviral therapy.
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