HIV/AIDS Tuberculosis Paediatrics
Conditions
Interventions
Twice daily DTG with Rifapicin
Not applicable
Sponsors
South African Medical Research Council
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Children <18 years with confirmed HIV-1 infection weighing 20-35kg ART-naive or experienced, with plans to use DTG for HIV treatment • Diagnosis of TB disease with clinician initiating rifampicin-containing first-line therapy • Parents/legal guardians/caregivers and children give informed written consent (or assent, where applicable) to be in the study • Girls who have reached menses must have a negative pregnancy test at screening and be willing to adhere to two effective methods of contraception (barrier and a non-barrier form of contraception during the study, starting at least 14 days prior to enrolment) if sexually active. The parents/caregivers will be counselled together with the child if the child tests positive in order to reduce any social harm which may arise.
Exclusion criteria
Exclusion criteria: • History or presence of known allergy or contraindications to DTG • Alanine aminotransferase (ALT) =5 times the upper limit of normal (ULN), OR ALT =3xULN and bilirubin =2xULN • Severe hepatic impairment or unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent jaundice), known biliary abnormalities (except for Gilbert's syndrome or asymptomatic gallstones) • Pregnancy or breastfeeding • A concurrent illness that could influence drug PK, i.e. severe diarrhoea, vomiting, renal or liver disease • Treatment with concomitant medications known to have interactions with DTG • Participants that are eligible for the study but refuse to give consent and/or assent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary Endpoint •Description of the pharmacokinetics (Ctrough, Cmax and AUC0-24h) of DTG 50mg twice daily in children (20-35kg) who are taking rifampicin-based regimen for the treatment of tuberculosis. Population plasma PK parameters of DTG in the presence or absence of RIF-based TB treatment, including absorption rate constant (ka), the volume of distribution (Vd), and oral clearance (Cl/F) and between-subject variability terms; post-hoc Bayesian predictions of secondary PK parameters of DTG including AUC and Cmin with HRZE dosing Secondary Endpoints •Pharmacokinetics of DTG Nonlinear mixed-effects models (NLMEM) will be used to describe the PK of DTG in an integrated model which will be used to estimate the primary PK parameters of DTG including ka, Vd, and CL. The effect of concomitant TB treatment, as well as other covariates on these parameters, will be evaluated in the model. The model can also be used to derive individual estimates of traditional (secondary) DTG PK measures such as Area Under the Curve (AUC), Cmax, Ctrough, tmax, half-life (t1/2). •Safety Subjects will be monitored clinically and biologically for safety. Biological monitoring will focus on liver function. Adverse Events and Serious Adverse Events will be graded following DAIDS grading tables (see Appendix B). •Efficacy Antiretroviral efficacy is based on HIV viral suppression. The cut-off value related to virological failure is defined as a viral load superior to 400 copies per mL, confirmed within a month. Viral load will be assessed as per the SOE (Table 2) The clinical outcome of the anti-TB treatment will be assessed retrospectively by a central panel who will review all cases for diagnostic accuracy and response to therapy. •Enzyme polymorphisms Enzyme polymorphism analysis will be conducted at a later stage from stored samples to determine the importance of polymorphisms in genes regulating anti-TB drug and antiretroviral concentrations and effects in the study population | — |
Secondary
| Measure | Time frame |
|---|---|
| • Pharmacokinetics of DTG Nonlinear mixed-effects models (NLMEM) will be used to describe the PK of DTG in an integrated model which will be used to estimate the primary PK parameters of DTG including ka, Vd, and CL. The effect of concomitant TB treatment, as well as other covariates on these parameters, will be evaluated in the model. The model can also be used to derive individual estimates of traditional (secondary) DTG PK measures such as Area Under the Curve (AUC), Cmax, Ctrough, tmax, half-life (t1/2). • Safety Subjects will be monitored clinically and biologically for safety. Biological monitoring will focus on liver function. Adverse Events and Serious Adverse Events will be graded following DAIDS grading tables (see Appendix B). • Efficacy Antiretroviral efficacy is based on HIV viral suppression. The cut-off value related to virological failure is defined as a viral load superior to 400 copies per mL, confirmed within a month. Viral load will be assessed as per the SOE (Table 2) The clinical outcome of the anti-TB treatment will be assessed retrospectively by a central panel who will review all cases for diagnostic accuracy and response to therapy. • Enzyme polymorphisms Enzyme polymorphism analysis will be conducted at a later stage from stored samples to determine the importance of polymorphisms in genes regulating anti-TB drug and antiretroviral concentrations and effects in the study population. | — |
Countries
South Africa
Contacts
Public ContactLeora Sewnarain
Clinical Research Coordinator
Outcome results
None listed