scholarly journals Pharmacokinetics and Drug-Drug Interactions of Lopinavir-Ritonavir Administered with First- and Second-Line Antituberculosis Drugs in HIV-Infected Children Treated for Multidrug-Resistant Tuberculosis

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Louvina E. van der Laan ◽  
Anthony J. Garcia-Prats ◽  
H. Simon Schaaf ◽  
Tjokosela Tikiso ◽  
Lubbe Wiesner ◽  
...  

ABSTRACT Lopinavir-ritonavir forms the backbone of current first-line antiretroviral regimens in young HIV-infected children. As multidrug-resistant (MDR) tuberculosis (TB) frequently occurs in young children in high-burden TB settings, it is important to identify potential interactions between MDR-TB treatment and lopinavir-ritonavir. We describe the pharmacokinetics of and potential drug-drug interactions between lopinavir-ritonavir and drugs routinely used for MDR-TB treatment in HIV-infected children. A combined population pharmacokinetic model was developed to jointly describe the pharmacokinetics of lopinavir and ritonavir in 32 HIV-infected children (16 with MDR-TB receiving treatment with combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin and 16 without TB) who were established on a lopinavir-ritonavir-containing antiretroviral regimen. One-compartment models with first-order absorption and elimination for both lopinavir and ritonavir were combined into an integrated model. The dynamic inhibitory effect of the ritonavir concentration on lopinavir clearance was described using a maximum inhibition model. Even after adjustment for the effect of body weight with allometric scaling, a large variability in lopinavir and ritonavir exposure, together with strong correlations between the pharmacokinetic parameters of lopinavir and ritonavir, was detected. MDR-TB treatment did not have a significant effect on the bioavailability, clearance, or absorption rate constants of lopinavir or ritonavir. Most children (81% of children with MDR-TB, 88% of controls) achieved therapeutic lopinavir trough concentrations (>1 mg/liter). The coadministration of lopinavir-ritonavir with drugs routinely used for the treatment of MDR-TB was found to have no significant effect on the key pharmacokinetic parameters of lopinavir or ritonavir. These findings should be considered in the context of the large interpatient variability found in the present study and the study's modest sample size.

2021 ◽  
Vol 12 ◽  
Author(s):  
Louvina E. van der Laan ◽  
Anthony J. Garcia-Prats ◽  
H. Simon Schaaf ◽  
Jana L. Winckler ◽  
Heather Draper ◽  
...  

Given the high prevalence of multidrug-resistant (MDR)-TB in high HIV burden settings, it is important to identify potential drug-drug interactions between MDR-TB treatment and widely used nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-positive children. Population pharmacokinetic models were developed for lamivudine (n = 54) and abacavir (n = 50) in 54 HIV-positive children established on NRTIs; 27 with MDR-TB (combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, fluoroquinolones, and amikacin), and 27 controls without TB. Two-compartment models with first-order elimination and transit compartment absorption described both lamivudine and abacavir pharmacokinetics, respectively. Allometric scaling with body weight adjusted for the effect of body size. Clearance was predicted to reach half its mature value ∼2 (lamivudine) and ∼3 (abacavir) months after birth, with completion of maturation for both drugs at ∼2 years. No significant difference was found in key pharmacokinetic parameters of lamivudine and abacavir when co-administered with routine drugs used for MDR-TB in HIV-positive children.


2015 ◽  
Vol 59 (10) ◽  
pp. 6073-6079 ◽  
Author(s):  
Anthony J. Garcia-Prats ◽  
Heather R. Draper ◽  
Stephanie Thee ◽  
Kelly E. Dooley ◽  
Helen M. McIlleron ◽  
...  

ABSTRACTOfloxacin is widely used for the treatment of multidrug-resistant tuberculosis (MDR-TB). Data on its pharmacokinetics and safety in children are limited. It is not known whether the current internationally recommended pediatric dosage of 15 to 20 mg/kg of body weight achieves exposures reached in adults with tuberculosis after a standard 800-mg dose (adult median area under the concentration-time curve from 0 to 24 h [AUC0–24], 103 μg · h/ml). We assessed the pharmacokinetics and safety of ofloxacin in children <15 years old routinely receiving ofloxacin for MDR-TB treatment or preventive therapy. Plasma samples were collected predose and at 1, 2, 4, 8, and either 6 or 11 h after a 20-mg/kg dose. Pharmacokinetic parameters were calculated using noncompartmental analysis. Children with MDR-TB disease underwent long-term safety monitoring. Of 85 children (median age, 3.4 years), 11 (13%) were HIV infected, and of 79 children with evaluable data, 14 (18%) were underweight. The ofloxacin mean (range) maximum concentration (Cmax), AUC0–8, and half-life were 8.97 μg/ml (2.47 to 14.4), 44.2 μg · h/ml (12.1 to 75.8), and 3.49 h (1.89 to 6.95), respectively. The mean AUC0–24, estimated in 72 participants, was 66.7 μg · h/ml (range, 18.8 to 120.7). In multivariable analysis, AUC0–24was increased by 1.46 μg · h/ml for each 1-kg increase in body weight (95% confidence interval [CI], 0.44 to 2.47;P= 0.006); no other assessed variable contributed to the model. No grade 3 or 4 events at least possibly attributed to ofloxacin were observed. Ofloxacin was safe and well tolerated in children with MDR-TB, but exposures were well below reported adult values, suggesting that dosage modification may be required to optimize MDR-TB treatment regimens in children.


2021 ◽  
Author(s):  
Rika Yuliwulandari ◽  
Kinasih Prayuni ◽  
Intan Razari ◽  
Retno W Susilowati ◽  
Yenni Zulhamidah ◽  
...  

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N-acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.


2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Y. Hu ◽  
L. Xu ◽  
Y. L. He ◽  
Y. Pang ◽  
N. Lu ◽  
...  

This study aimed to investigate the prevalence of multidrug-resistant tuberculosis (MDR-TB) isolates resistant to the second-line antituberculosis drugs (SLDs) and its association with resistant-related gene mutations inMycobacterium tuberculosis(M.tb) isolates from Southwest of China. There were 81 isolates resistant to at least one of the SLDs among 156 MDR-TB isolates (81/156, 51.9%). The rates of general resistance to each of the drugs were as follows: OFX (66/156, 42.3%), KAN (26/156, 16.7%), CAP (13/156, 8.3%), PTO (11/156, 7.1%), PAS (22/156, 14.1%), and AMK (20/156, 12.8%). Therefore, the most predominant pattern was resistant to OFX compared with other SLDs (P<0.001). The results of sequencing showed that 80.2% OFX-resistant MDR-TB isolates containedgyrAmutation and 88.5% KAN-resistant isolates hadrrsmutations with the most frequent mutation being A1401G. These results suggest that improper use of SLDs especially OFX is a real threat to effective MDR-TB treatment not only in China but also in the whole world. Furthermore the tuberculosis control agencies should carry out SLDs susceptibility testing and rapid screening in a broader population of TB patients immediately and the SLDs should be strictly regulated by the administration in order to maintain their efficacy to treat MDR-TB.


2019 ◽  
Vol 12 (8) ◽  
pp. e230628 ◽  
Author(s):  
Christian Francisco ◽  
Mary Ann Lansang ◽  
Edsel Maurice Salvana ◽  
Katerina Leyritana

Tuberculosis (TB) is common among persons living with HIV. This public health concern is aggravated by infection with multidrug-resistant organisms and adverse effects of polypharmacy. There are few published cases of multidrug-resistant tuberculosis (MDR-TB) in multidrug-resistant HIV (MDR-HIV) infected patients. We report a case of a 29-year-old Filipino man with HIV on zidovudine (AZT)-containing antiretroviral therapy (ART) but was eventually shifted to tenofovir due to anaemia. He presented with left flank tenderness, which was found to be due to an MDR-TB psoas abscess, and for which second-line anti-TB treatment was started. HIV genotyping showed MDR-HIV infection susceptible only to AZT, protease inhibitors and integrase inhibitors. Subsequently, he developed neck abscess that grew Mycobacterium avium complex and was treated with ethambutol and azithromycin. ART regimen was revised to AZT plus lamivudine and lopinavir/ritonavir. Erythropoietin was administered for recurrent AZT-induced anaemia. Both abscesses resolved and no recurrence of anaemia was noted.


2019 ◽  
Vol 23 (10) ◽  
pp. 1050-1054
Author(s):  
L. Guglielmetti ◽  
J. Jaffré ◽  
C. Bernard ◽  
F. Brossier ◽  
N. El Helali ◽  
...  

SETTING: The World Health Organization (WHO) recommends that multidrug-resistant tuberculosis (MDR-TB) treatment should be managed in collaboration with multidisciplinary advisory committees (consilia). A formal national Consilium has been established in France since 2005 to provide a centralised advisory service for clinicians managing MDR-TB and extensively drug-resistant (XDR-TB) cases.OBJECTIVE: Review the activity of the French TB Consilium since its establishment.DESIGN: Retrospective description and analysis of the activity of the French TB Consilium.RESULTS: Between 2005 and 2016, 786 TB cases or contacts of TB cases were presented at the French TB Consilium, including respectively 42% and 79% of all the MDR-TB and XDR-TB cases notified in France during this period. Treatment regimens including bedaquiline and/or delamanid were recommended for 42% of the cases presented at the French TB Consilium since 2009. Patients were more likely to be presented at the French TB Consilium if they were born in the WHO Europe Region, had XDR-TB, were diagnosed in the Paris region, or had resistance to additional drugs than those defining XDR-TB.CONCLUSION: The French TB Consilium helped supervise appropriate management of MDR/XDR-TB cases and facilitated implementation of new drugs for MDR/XDR-TB treatment.


2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Ernest Peresu ◽  
J. Christo Heunis ◽  
N. Gladys Kigozi ◽  
Diana De Graeve

Abstract Background Eswatini is facing a critical shortage of human resources for health (HRH) and limited access to multidrug-resistant tuberculosis (MDR-TB) treatment in rural areas. This study assessed multiple stakeholders’ perceptions of task-shifting directly observed treatment (DOT) supervision and administration of intramuscular MDR-TB injections to lay health workers (LHWs). Methods A mixed methods study comprising a cross-sectional survey using a semi-structured questionnaire with community treatment supporters (CTSs) and a focus group discussion with key stakeholders including representatives from the Eswatini Ministry of Health (MOH), donor organisations, professional regulatory institutions, nursing academia, civil society and healthcare providers was conducted in May 2017. Descriptive statistics, thematic content analysis and data triangulation aided in the interpretation of results. Results A large majority of CTSs (n = 78; 95.1%) were female and 33 (40.2%) were older than 50 years. Most (n = 7; 70.0%) key stakeholders had over 10 years of work experience in policy-making, advocacy in the fields of HRH or day-to-day practice in MDR-TB management. Task-shifting of MDR-TB injection administration was implemented without national policy guidance and regulation. Stakeholders viewed the strategy to be driven by the prevailing shortage of professional frontline HRH and limited access to MDR-TB treatment. Task-shifting was perceived to improve medication adherence, and reduce stigma and transport-related MDR-TB treatment access barriers. Frontline healthcare workers and implementing donor partners fully supported task-shifting. Policy-makers and other stakeholders accepted task-shifting conditionally due to fears of poor standards of care related to perceived incompetence of CTSs. Appropriate compensation, adequate training and supervision, and non-financial incentives were suggested to retain CTSs. A holistic task-shifting policy and collaboration between the MOH, academia and nursing council in regulating the practice were recommended. Conclusions Stakeholders generally accepted the delegation of DOT supervision and administration of intramuscular MDR-TB injections to LHWs as a strategy to increase access to treatment, albeit with some apprehension. Findings from this study stress that task-shifting is not a panacea for HRH shortages, but a short-term solution that must form part of an overall simultaneous strategy to train, attract and retain adequate numbers of professional healthcare workers in Eswatini. To address some of the apprehension and ambivalence about expanding access to MDR-TB services through task-shifting, attention should be paid to important aspects such as competence-based training, certification and accreditation, adequate supportive on-the-job supervision, recognition, compensation, and expediting policy and regulatory support for LHWs.


2020 ◽  
Vol 24 (5) ◽  
pp. 485-491
Author(s):  
D. Butov ◽  
C. Lange ◽  
J. Heyckendorf ◽  
I. Kalmykova ◽  
T. Butova ◽  
...  

OBJECTIVE: To document the level of drug resistance in MDR-TB patients and to characterize management capacities for their medical care and MDR-TB treatment outcomes in the Kharkiv region of Ukraine. This area has one of the highest frequencies of MDR-TB worldwide.METHODS: A retrospective observational cohort study was performed on registry data from the regional anti-TB dispensary in Kharkiv. All microbiologically confirmed MDR-TB patients registered in 2014 were included. Diagnostic, treatment and post-treatment follow-up data were analysed.RESULTS: Of 169 patients with MDR-TB, 55.0% had pre-extensively drug-resistant (pre-XDR) or XDR resistant patterns. Rapid molecular diagnosis by GeneXpert and liquid M. tuberculosis cultures were only available for 66.9% and 56.8% of patients, respectively. Phenotypic drug-susceptibility testing (DST) for high priority TB drugs (bedaquiline, linezolid, clofazimine) were not available. DST for later generation fluroquinolones was available only in 53.2% of patients. 50.9% of patients had less than 4 drugs in the treatment regimen proven to be effective by DST. More than 23.1% of patients with MDR-TB failed their treatment and only 45.0% achieved a cure.CONCLUSION: The high prevalence of MDR-TB and poor MDR-TB treatment outcomes in the Kharkiv region, is associated with substantial shortages in rapid molecular and phenotypic DST, a lack of high priority MDR-TB drugs, poor treatment monitoring and follow-up capacities.


2019 ◽  
Author(s):  
Le Hong Van ◽  
Phan Trieu Phu ◽  
Dao Nguyen Vinh ◽  
Vo Thanh Son ◽  
Nguyen Thi Hanh ◽  
...  

Abstract Background: Multidrug resistant tuberculosis (MDR-TB) remains a serious public health problem with poor treatment outcome. Predictors of poor outcomes vary in different regions. Vietnam is among the 30 countries with high burden of MDR-TB. We aim to describe demographic characteristics and identify risk factors for poor outcome of MDR-TB in Ho Chi Minh City (HCMC), the most populous city in Vietnam. Methods: This retrospective study included 2,266 patients who initiated MDR-TB treatment from 2011 to 2015 in HCMC. Treatment outcomes were available in 2,240 patients. Data was collected from standardized paper-based treatment cards and electronic records. Kruskal Wallis test was used to diagnose the change of median of age and body mass index (BMI) over 5 years, and Wilcoxon test to compare median BMI of patients with and without diabetes mellitus. Chi squared test was used to compare categorical variables. Multivariate logistic regression on multiple imputation was used to identify risk factors for poor outcomes. Statistical analysis was performed using R program. Results: Among 2,266 eligible cases, 60.2% were failure of category I or II regimen, 57.7% were underweight, 30.2% had diabetes mellitus and 9.6% were HIV positive. Notification rate increased 24.7% from 2011 to 2015.Treatment success rate was 73.3%. Risk factors for poor treatment outcome included HIV co-infection (adjusted odds ratio (aOR): 2.94), advanced age (aOR: 1.45 for every increase of 5 years for patients 60 years or older), having history of MDR-TB treatment (aOR: 5.53), sputum smear grade scanty and 1+ (aOR: 1.47), smear grade 2+ or 3+ (aOR: 2.06), low BMI (aOR: 0.83 for every increase of 1kg/m2 of BMI for patients with BMI<21). Conclusion: Our study describes the increasing cases of MDR-TB in HCMC during 2011 to 2015. Patients with HIV, high smear grade, malnutrition and history of previous MDR-TB treatment should receive additional care. Keywords: multidrug resistant tuberculosis; retrospective; treatment outcome; risk factors; Vietnam


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Arnaud Iradukunda ◽  
Gabin-Pacifique Ndayishimiye ◽  
Darlene Sinarinzi ◽  
Emmanuel Nene Odjidja ◽  
Nestor Ntakaburimvo ◽  
...  

Abstract Background Despite the World Health Organization efforts to expand access to the tuberculosis treatment, multidrug resistant tuberculosis (MDR-TB) remains a major threat. MDR-TB represents a challenge for clinicians and staff operating in national tuberculosis (TB) programmes/centres. In sub-Saharan African countries including Burundi, MDR-TB coexists with high burden of other communicable and non-communicable diseases, creating a complex public health situation which is difficult to address. Tackling this will require targeted public health intervention based on evidence which well defines the at-risk population. In this study, using data from two referral anti-tuberculosis in Burundi, we model the key factors associated with MDR-TB in Burundi. Methods A case-control study was conducted from 1stAugust 2019 to 15th January 2020 in Kibumbu Sanatorium and Bujumbura anti-tuberculosis centres for cases and controls respectively. In all, 180 TB patients were selected, comprising of 60 cases and 120 controls using incidence density selection method. The associated factors were carried out by mixed effect logistic regression. Model performance was assessed by the Area under Curve (AUC). Model was internally validated via bootstrapping with 2000 replications. All analysis were done using R Statistical 3.5.0. Results MDR-TB was more identified among patients who lived in rural areas (51.3%), in patients’ residence (69.2%) and among those with a household size of six or more family members (59.5%). Most of the MDR-TB cases had already been under TB treatment (86.4%), had previous contact with an MDR-TR case (85.0%), consumed tobacco (55.5%) and were diabetic (66.6 %). HIV prevalence was 32.3 % in controls and 67.7 % among cases. After modelling using mixed effects, Residence of patients (aOR= 1.31, 95%C: 1.12-1.80), living in houses with more than 6 family members (aOR= 4.15, 95% C: 3.06-5.39), previous close contact with MDR-TB (aOR= 6.03, 95% C: 4.01-8.12), history of TB treatment (aOR= 2.16, 95% C: 1.06-3.42), tobacco consumption (aOR = 3.17 ,95% C: 2.06-5.45) and underlying diabetes’ ( aOR= 4.09,95% CI = 2.01-16.79) were significantly associated with MDR-TB. With 2000 stratified bootstrap replicates, the model had an excellent predictive performance, accurately predicting 88.15% (95% C: 82.06%-92.8%) of all observations. The coexistence of risk factors to the same patients increases the risk of MDR-TB occurrence. TB patients with no any risk factors had 17.6% of risk to become MDR-TB. That probability was respectively three times and five times higher among diabetic and close contact MDR-TB patients. Conclusion The relatively high TB’s prevalence and MDR-TB occurrence in Burundi raises a cause for concern especially in this context where there exist an equally high burden of chronic diseases including malnutrition. Targeting interventions based on these identified risk factors will allow judicious channel of resources and effective public health planning.


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