Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes

Study Overview
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Brief Summary
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Tuberculosis (TB) is a leading cause of death in HIV-infected individuals. There are insufficient data correlating concentrations of anti-TB drugs with treatment response. We hypothesize that sub-therapeutic concentrations of anti-TB drugs are associated with inadequate TB treatment response to Mycobacterium tuberculosis.

Detailed Description
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During the study periodic monitoring will be conducted to ensure that the protocol and Good Clinical Practices (GCPs) are being followed.The monitors may review source documents to confirm that the data recorded on CRFs is accurate. The study site may be subject to review by the Institutional Review Board (IRB) and/or appropriate regulatory authorities. A CRF will be completed for each included subject and will be signed by the investigator or by an authorized staff member to attest that the data is true. Any corrections to entries made in the CRFs, source documents must be dated, initialed and explained (if necessary) and should not obscure the original entry. Qualit assurance will as also be performed regularly on the CRFs. The primary end point will be analyzed using Time to event (cure, death, relapse etc)analysis and failure rates and hazard ratios will be calculated accordig to categorical drug concentrations with proposed cutt offs. Secondary end points will be analysed using time to event for occurence of toxicities which will also be corelated to the drug concentrations.

Official Title
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Evaluation of the Pharmacokinetics of Antituberculosis Drugs and Tuberculosis Treatment Outcomes in HIV-tuberculosis Co-infected Ugandan Adults

Conditions
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AIDS With Tuberculosis

Intervention / Treatment
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* Drug: Rifampicin, Isoniazid, Ethambutol, Pyrazinamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Evidence of a personally signed and dated informed consent Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Age of ≥18 years First episode of pulmonary TB i.e. proven or highly suspected TB considered for TB treatment qualifying for 6 months anti-Tb drugs regimen Confirmed HIV-1 infection Exclusion Criteria: Unable to provide informed consent Documented or highly suspected TB infection of any organs/systems other than the lung requiring TB treatment longer than 6 months Previously treated for a mycobacterial infection (TB or atypical mycobacterial infection, active or latent) Pregnancy or planned pregnancy within the next year Unwillingness to perform pregnancy test Decompensated liver disease and/or aminotransferases >5x ULN GFR < 50 ml/min Co-morbidities reducing life expectancy to <1 year (e.g. cancer) Patient wishes to take part in another interventional study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: anti-tuberculosis drugs<br>Rifampicin, Isoniazid, Ethambutol, Pyrazinamide tablets 3 to 5 tablets once daily for 2 months followed by Rifampicin, Isoniazid 3 to 5 tablets once daily for 4 months | Drug: Rifampicin, Isoniazid, Ethambutol, Pyrazinamide<br>* Rifampicin, Isoniazid, Ethambutol, Pyrazinamide: 3, 4 or 5 tablets daily for weight below 55kg, above 55kg or above 70kg respectively for first 2 months followed by Rifampicin, Isoniazid: 3, 4 or 5 tablets daily for patients' weight below 55kg, above 55kg or above 70kg respectively for 4 months<br>* Other names: and Montozid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| clinical outcome | To investigate the association between serum concentrations of antituberculosis drugs and tuberculosis treatment response in HIV-TB-co-infected individuals. | At the end of treatment (6 months after enrolmet) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | To investigate the steady-state pharmacokinetic parameters of anti-TB drugs at different time-points over the course of TB-treatment | At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation | 
| Number of adverse events | To assess the safety and tolerability of anti-TB drugs based on the WHO guidelines | 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation | 
| ART trough levels | To correlate the effect of anti-TB drugs on plasma concentrations of efavirenz or protease inhibitors and vice versa. | At 2 weeks, 8 weeks and 24 weeks after anti-tuberculosis drug initiation | 
| Isoniazid Cmax | To evaluate the effect of acetylator geno-and phenotype (NAT-2 gene) on isoniazid plasma concentrations and toxicity | At 2 weeks, 8 weeks and 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, Tuberculosis, Antituberculosis drugs