Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir Given With Rifampin

Study Overview
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Brief Summary
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The object of this study is to evaluate the pharmacokinetic interactions, short term safety and efficacy of standard dose lopinavir/ritonavir 200mg/50 (two tablets twice daily) given with ritonavir 100 mg three tablets twice daily given in combination with rifampin in HIV-infected persons with tuberculosis

Detailed Description
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This will be an open label non-randomized pharmacokinetic study of 10-12 HIV-infected patients co-infected with Mycobacterium tuberculosis. Enrollment: Potential subjects with active tuberculosis who have tolerated a rifampin containing regimen for at least 2 weeks. Potential subjects will be referred from the surrounding communities to Laboratorio de Pesquisa Clinica em Micobacterioses(LAPCLINTB) Visit 1: Subjects will then be started on lopinavir/ritonavir containing HAART regimen with standard twice daily dosing. Ritonavir 100 mg capsules will be added to the regimen and the dose escalated until the patient is taking 3 capsules twice daily. The time between enrollment and visit 1 will be determined by the treating physician. Visit 2: They will return about 1 week after dose escalation has been completed to sample lopinavir and rifampin concentrations. Visit 3: Subject will return in 2 weeks to have repeat to review results of lopinavir concentrations and response to therapy. Ritonavir will be adjusted as needed. Visit 4: Subject will then return in 4 weeks for last visit for evaluation. Lopinavir and rifampin PK will be done.

Official Title
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A Pharmacokinetic Study of Super-boosted Lopinavir/Ritonavir in Combination With Rifampin in HIV-1-infected Patients With Tuberculosis.

Conditions
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AIDS, Tuberculosis

Intervention / Treatment
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* Drug: Lopinavir/ritonavir and ritonavir


Participation Criteria
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Eligibility Criteria
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Antiretroviral naive If not antiretroviral naïve they must meet the following criteria: Taking Kaletra containing regimen with suppressed viral load. Taking an NNRTI or integrase containing regimen without prior history of use of PI for more than 2 weeks Taking an NNRTI or integrase containing regimen with prior exposure to PI greater than 2 weeks. It must be clearly stated in the source document that PI was switched to another agent for convenience. Taking another PI containing regimens with suppressed viral load. It must be clearly stated in source document that if another PI was used for greater than 2 weeks the regimen was switched to another agent for convenience. Subjects with prior history of PI use may be enrolled, if there is a genotype showing no resistance to Kaletra Other Inclusion criteria Be at least 18 years of age and able to give informed consent. Diagnosed with TB by criteria per Brazilian Ministry of Health Have a good clinical response to TB. Tolerating tuberculosis therapy containing rifampin for the 2 weeks prior to screening,except for persons taking protease inhibitors at time of diagnosis of TB.,. Subjects taking protease inhibitors will be screened and initiate visit 1 within 3 days of starting TB medication HIV positive with documentation present in source document. Have a CD4 cell count greater than 50 cells/mm3if not taking ART. Persons with cd4 < 50 may be enrolled, if it is felt that in the best interest of the patient, that enrollment in the study will allow for quicker initiation of antiretroviral therapy than referral to another treatment center. Exclusion Criteria: Non-compliance with DOTPlus. Alternatively DOT can be done by telephoning patient on a daily basis 5 times a week and having patient annotate taking drug in a log which would be reviewed by clinic staff History of being treated for tuberculosis in the prior 2 years unless there is DST, including PCR testing, showing sensitivity to rifamycin. Known hypersensitivity to rifampin or rifabutin. Liver enzymes greater than 2 times ULN. Bilirubin greater than 2 times ULN. Serum creatinine greater than 3 times ULN. Hemoglobin less than 7.0 gms even if receiving erythropoietin. Absolute neutrophil count less than 750 cells/mm3 even if receiving G-CSF. Fasting triglycerides greater than 400 mg/dL. Fasting cholesterol > 1.6 upper limits of normal. GI intolerance of tuberculosis medications requiring discontinuation of tuberculosis medications. Fasting glucose greater 150 mg/dL. Pregnant women. Use of one of the prohibited medications Any condition that the investigators feel could compromise the use of the current medication. Have a CD4 cell count of 50 cells/mm3or less Hepatitis B or C infection Alcohol or illicit drug use, which in the investigators opinion may affect participation in study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: Lopinavir/ritonavir and ritonavir<br>Two tablets of twice daily of Lopinavir/ritonavir 200 mg/50mg with 3 tablets of ritonavir 100 mg of twice daily given with rifampin 600 mg daily. | Drug: Lopinavir/ritonavir and ritonavir<br>* Two tablets twice daily of Lopinavir/ritonavir 200 mg/50mg with 3 capsules of ritonavir 100 mg twice daily given with rifampin 600 mg daily<br>* Other names: Norvir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with expected pre dose concentration of lopinavir. | The expected pre dose concentration of lopinavir is >1.0 mcg/mL. | Weeks 2 and 8: lopinavir time points at hours 0, 2, 4, 6 and 8. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with successful treatment of HIV therapy. | HIV failure will be defined as failure to drop the viral load by 0.5 log 10 copies/mL drop by week 4 of treatment and a viral load drop >1 log 10 copies/ml by week 8. | Approximately 10-12 weeks | 
| Proportion of patients with expected AUC of rifampin | The expected AUC of rifampin is 44-70 mcg•h/mL | Approximatley 10-12 weeks | 
| Proportion of patient with success of tuberculosis therapy | Success of treatment using criteria established by the Brazilian National Ttuberculosis Program. | Approximatly 10-12 weeks | 
| Proportion of patients with expected Cmax and AUC of lopinavir | The expected Cmax of lopinavir is 6-14 mcg/mL. The expected AUC lopinavir is 56-130 µg•h/mL | 10-12 weeks | 
| Proportion of patients with expected Cmax of rifampin. | Expected maximum concentration of rifampin is 8-24 mcg/mL | Weeks 2 and 8: rifampin time points at hours 0, 2, 4, 6 and 8. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, AIDS, Tuberculosis, Rifampin, Lopinavir, Pharmacokinetic