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

• Proportion of patients with expected Cmax of rifampin. [ Time Frame: Weeks 1 and 10-12: rifampin time points at hours 0, 2, 4, 6 and 8. ] [ Designated as safety issue: No ]
  Expected maximum concentration of rifampin is 8-24 mcg/mL
• Proportion of patients with expected pre dose concentration of lopinavir. [ Time Frame: Weeks 2 and 10-12: lopinavir time points at hours 0, 2, 4, 6 and 8. ] [ Designated as safety issue: Yes ]
  The expected pre dose concentration of lopinavir is >1.0 mcg/mL.

• Proportion of patients with successful treatment of HIV therapy. [ Time Frame: 10-12 weeks ] [ Designated as safety issue: Yes ]
  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.
• Proportion of patients with expected AUC of rifampin [ Time Frame: 10-12 weeks ] [ Designated as safety issue: No ]
  The expected AUC of rifampin is 44-70 mcg•h/mL
• Proportion of patient with success of tuberculosis therapy [ Time Frame: 10-12 weeks ] [ Designated as safety issue: No ]
  Success of treatment using criteria established by the Brazilian National Ttuberculosis Program.
• Proportion of patients with expected Cmax and AUC of lopinavir [ Time Frame: 10-12 weeks ] [ Designated as safety issue: No ]
  The expected Cmax of lopinavir is 6-14 mcg/mL. The expected AUC lopinavir is 56-130 µg•h/mL

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

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: After enrollment the subject will have a baseline rifampin PK will be done. They 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 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.

• AIDS
• Tuberculosis

• Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, Maartens G, McIlleron HM. Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):566-9.
• la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother. 2004 May;48(5):1553-60.

Inclusion Criteria:

• Be protease inhibitor naïve,defined as no prior PI use longer than 2 weeks.
• Be at least 18 years of age and able to give informed consent.
• Diagnosed with tuberculosis 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.
• HIV positive with documentation present in source document.
• Have a CD4 cell count greater than 50 cells/mm3

Exclusion Criteria:

• Non-compliance with DOTPlus.
• History of being treated for tuberculosis in the prior 2 years unless there is DST 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/mm3 or less
• Hepatitis B or C infection
• Alcohol or illicit drug use, which in the investigators opinion may affect participation in study.