Rifampin-Based Tuberculosis Treatment Versus Rifabutin-Based Tuberculosis Treatment in HIV

• Percent of participants who experienced mycobacterial culture conversion (Arm B vs Arm A and Arm B vs Arm C) [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
• Percent of participants who experienced TB treatment failure (Arm B vs Arm A and Arm B vs Arm C) [ Time Frame: At or after 24 weeks ] [ Designated as safety issue: No ]
• Percent of participants who experienced TB relapse/recurrence (Arm B vs Arm A and Arm B vs Arm C) [ Time Frame: Through 72 weeks ] [ Designated as safety issue: No ]
• Percent of participants whose HIV viral load was less than 50 copies/mL (Arm B vs Arm A and Arm B vs Arm C) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Percent of participants whose HIV viral load was less than 400 copies/mL (Arm A vs Arm C) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Percent of participants whose HIV viral load was less than 50 copies/mL (Arm A vs Arm C) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• Percent of participants reporting a grade 3 or 4 adverse event or laboratory abnormality recurrence [ Time Frame: Through 72 weeks ] [ Designated as safety issue: Yes ]
• Percent of participants who interrupted or discontinued at least one HIV drug due to toxicity [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• Percent of participants who interrupted or discontinued at least one TB drug due to toxicity [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• Percent of participants who experienced HIV virologic failure [ Time Frame: Through week 72 ] [ Designated as safety issue: No ]
• Percent of participants who experienced TB IRIS [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• CD4 count change from randomization [ Time Frame: Through week 72 ] [ Designated as safety issue: No ]
• Percent of participants who experienced a new AIDS-defining illness [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• Percent of participants who experienced death [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• Percent of participants who experienced a new AIDS-defining illness or death [ Time Frame: Through week 72 ] [ Designated as safety issue: Yes ]
• Time to HIV virologic failure [ Time Frame: Through week 72 ] [ Designated as safety issue: No ]

There is a rapidly-growing need to identify evidence-based, safe, and effective co-treatment regimens for HIV-related tuberculosis (TB) among patients who require protease inhibitor-based antiretroviral therapy. This study will compare three alternative co-treatment options among participants in high TB endemic resource-constrained settings, in which one co-treatment option explores if an additional anti-HIV drug needs to be used when patients are being treated with a protease inhibitor together with rifabutin-based anti-TB treatment.

Accrual will take place in two accrual periods. Accrual period 1 will enroll 60 participants who will undergo an initial dose-finding period before continuing regular study follow-up. Once the review of the dose-finding pharmacokinetic and safety data from accrual period 1 participants is completed, accrual period 2 will begin.

• HIV Infection
• Tuberculosis

• Drug: Lopinavir/Ritonavir
  Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
  Other Names:

  • LPV/RTV
  • Aluvia
  • Kaletra
• Drug: Lopinavir/Ritonavir
  Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
  Other Names:

  • LPV/RTV
  • Aluvia
  • Kaletra
• Drug: Raltegravir
  400 mg orally twice daily from entry to Week 72.
  Other Names:

  • RAL
  • Isentress
• Drug: Isoniazid
  300 mg orally once daily from entry through Week 24.
  Other Name: INH
• Drug: Pyridoxine
  25 mg orally once daily from entry to Week 24.
• Drug: Pyrazinamide
  20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
  Other Name: PZA
• Drug: Ethambutol
  15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants).
  Other Name: EMB
• Drug: Rifabutin
  300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24.
  Other Name: RBT
• Drug: Rifampin
  Weight-based dose; for weight < 45 kg: 450 mg orally once daily; for weight > 45 kg: 600 mg orally once daily, from entry to week 24.
  Other Name: RIF

• Experimental: A: Standard-dose LPV/r-based+2 NRTIs w/RBT-based TB Treatment
  Interventions:

  • Drug: Lopinavir/Ritonavir
  • Drug: Isoniazid
  • Drug: Pyrazinamide
  • Drug: Ethambutol
  • Drug: Rifabutin
• Active Comparator: B: Double-dose LPV/r + 2 NRTIs with RIF-based TB treatment
  Interventions:

  • Drug: Lopinavir/Ritonavir
  • Drug: Isoniazid
  • Drug: Pyridoxine
  • Drug: Pyrazinamide
  • Drug: Ethambutol
  • Drug: Rifampin
• Experimental: C: Standard-Dose LPV/r+ 2NRTIs+RAL w/RBT-based TB treatment
  Interventions:

  • Drug: Lopinavir/Ritonavir
  • Drug: Raltegravir
  • Drug: Isoniazid
  • Drug: Pyridoxine
  • Drug: Pyrazinamide
  • Drug: Ethambutol
  • Drug: Rifabutin

Inclusion Criteria:

• HIV-1 infection
• CD4+/CD8+ T-cell count obtained within 30 days prior to study entry
• Confirmed or probable pulmonary or extrapulmonary TB (more information on the criterion can be found in the protocol)
• Chest x-ray within 30 days prior to study entry.
• A PI-based antiretroviral (ART) regimen is required, as determined by the participant's primary clinician/clinical facility.
• Certain laboratory values obtained within 14 days prior to study entry (more information on the criterion can be found in the protocol)
• For females of reproductive potential, negative serum or urine pregnancy test within 7 days prior to study entry and 72 hours of starting study medications.
• Willing to use acceptable methods of contraception while on study drugs and for 6 weeks after stopping these drugs.
• Karnofsky performance score > 40 within 14 days prior to study entry, and likelihood of survival, in the opinion of the site investigator, for at least 6 months.
• Ability to swallow oral medications.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.

Exclusion Criteria:

• History of completed TB treatment and resolution of TB symptoms less than 1 year prior to the current TB episode at study entry, or incomplete treatment for a prior episode of TB (i.e., defaulted past TB treatment) at any time prior to the current TB episode.
• Documented multidrug-resistant tuberculosis (MDR TB) or extensively drug-resistant (XDR) TB.
• Participants infected with a rifamycin resistant strain of TB (more information on the criterion can be found in the protocol).
• Receipt of more than 28 cumulative days of anti-TB treatment for the current TB episode prior to study entry.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Active illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry, or that in the opinion of the site investigator, might otherwise interfere with adherence to study requirements.
• Pregnant or breastfeeding.
• Anticipated receipt of prohibited medications (more information on the criterion can be found in the protocol).
• Known intolerance/allergy/sensitivity or any hypersensitivity to components of study drugs or their formulations.
• History of close contact with known MDR or XDR TB patients at any time prior to study entry.