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

Study Overview
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Brief Summary
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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 (PI)-based antiretroviral therapy (ART). This study compared 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 PI together with rifabutin-based anti-TB treatment.

Detailed Description
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Rifampin (RIF), the cornerstone of TB treatment, has very problematic drug-drug interactions with PIs. The use of relatively high doses of ritonavir appear necessary to overcome this interaction, but it is unclear whether the co-treatment regimen of RIF-based TB treatment and double-dose PI-based ART will be safe and tolerable for patients with HIV-related TB and effective in treating both HIV and TB. The study proposed to determine if, for HIV-1-infected participants with active TB who require PI-based ART, a standard-dose lopinavir/ritonavir (LPV/r) regimen, with or without raltegravir (RAL), coupled with rifabutin (RBT)-based TB treatment is superior to a double-dose LPV/r regimen coupled with RIF-based TB treatment. At study entry, participants were randomized (1:1:1) to receive standard-dose LPV/r-based HIV treatment plus RBT-based TB treatment (Arm A), double-dose LPV/r-based HIV treatment plus RIF-based TB treatment (Arm B), or standard-dose LPV/r-based HIV treatment plus RAL plus RBT-based TB treatment (Arm C). Accrual was planned to take place in two accrual periods. Accrual period 1 would enroll 60 participants who would undergo an initial dose-finding period before continuing regular study follow-up. Once the review of the dose-finding pharmacokinetic (PK) and safety data from accrual period 1 participants was completed, accrual period 2 was planned to open to accrual. Study duration was 72 weeks. Visits occurred at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 72. The key evaluations included physical examination, clinical assessments, TB evaluations including chest x-ray, acid-fast bacilli (AFB) smear, mycobacterial culture, and drug susceptibility testing, CD4 cell count, HIV viral load, hematology, chemistry, and pregnancy testing in women of reproductive potential. Sputum, serum, and urine were stored for use in future analyses. An intensive PK visit occurred at day 12. PK blood draws in participants in Arms A and C were at RBT pre-dose and at 2, 4, 5, 6, and 24 hours RBT post-dose. PK blood draws in participants in Arm B were at LPV/r pre-dose and at 2, 4, 5, and 6 hours LPV/r post-dose. The target sample size was 471 participants, but the study was terminated after 71 participants due to feasibility concerns. The 71 participants were followed for the planned 72 weeks. Because of the limited sample size, formal statistical comparisons were not undertaken as originally planned.

Official Title
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A Randomized, Phase 2b Study of a Double-Dose Lopinavir/Ritonavir-Based Antiretroviral Regimen With Rifampin-Based Tuberculosis Treatment Versus a Standard-Dose Lopinavir/Ritonavir-Based Antiretroviral Regimen With Rifabutin-Based Tuberculosis Treatment With or Without Raltegravir in HIV-1-Infected Persons Requiring Treatment for Active TB and HIV

Conditions
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HIV Infection, Tuberculosis

Intervention / Treatment
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* Drug: Standard-dose Lopinavir/Ritonavir
* Drug: Double-dose Lopinavir/Ritonavir
* Drug: Raltegravir
* Drug: Isoniazid
* Drug: Pyridoxine
* Drug: Pyrazinamide
* Drug: Ethambutol
* Drug: Rifabutin
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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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 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 tuberculosis (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

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Standard-dose LPV/r w/RBT<br>ART: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors. Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily. After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs). | Drug: Standard-dose Lopinavir/Ritonavir<br>* Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.<br>* Other names: Kaletra;Drug: Isoniazid<br>* 300 mg orally once daily from entry through Week 24.<br>* Other names: INH;Drug: Pyridoxine<br>* 25 mg orally once daily from entry to Week 24.<br>* Other names: Vitamin B6;Drug: Pyrazinamide<br>* 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).<br>* Other names: PZA;Drug: Ethambutol<br>* 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).<br>* Other names: EMB;Drug: Rifabutin<br>* 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.<br>* Other names: RBT;|
| Active Comparator: B: Double-dose LPV/r w/RIF<br>ART: lopinavir 800 mg/ritonavir 200 mg twice daily + two nucleoside reverse transcriptase inhibitors. Anti-TB therapy: isoniazid 300 mg, weight-based dosing for rifampin, ethambutol, and pyrazinamide, and pyridoxine 25 mg daily. After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs). | Drug: Double-dose Lopinavir/Ritonavir<br>* Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.<br>* Other names: Kaletra;Drug: Isoniazid<br>* 300 mg orally once daily from entry through Week 24.<br>* Other names: INH;Drug: Pyridoxine<br>* 25 mg orally once daily from entry to Week 24.<br>* Other names: Vitamin B6;Drug: Pyrazinamide<br>* 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).<br>* Other names: PZA;Drug: Ethambutol<br>* 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).<br>* Other names: EMB;Drug: Rifampin<br>* 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.<br>* Other names: RIF;|
| Experimental: C: Standard-Dose LPV/r w/RBT + RAL<br>ART: lopinavir 400 mg/ritonavir 100 mg twice daily + raltegravir 400 mg twice daily + two nucleoside reverse transcriptase inhibitors. Anti-TB therapy: isoniazid 300 mg, rifabutin 300 mg, weight-based dosing for ethambutol and pyrazinamide, and pyridoxine 25 mg daily. After completion of TB treatment through week 72: lopinavir 400 mg/ritonavir 100 mg twice daily + two nucleoside reverse transcriptase inhibitors (NRTIs). | Drug: Standard-dose Lopinavir/Ritonavir<br>* Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.<br>* Other names: Kaletra;Drug: Raltegravir<br>* One 400 mg tablet orally twice daily from entry to Week 72.<br>* Other names: Isentress;Drug: Isoniazid<br>* 300 mg orally once daily from entry through Week 24.<br>* Other names: INH;Drug: Pyridoxine<br>* 25 mg orally once daily from entry to Week 24.<br>* Other names: Vitamin B6;Drug: Pyrazinamide<br>* 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).<br>* Other names: PZA;Drug: Ethambutol<br>* 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).<br>* Other names: EMB;Drug: Rifabutin<br>* 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.<br>* Other names: RBT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. | The percent of participants whose HIV viral load was less than 400 copies/mL at week 48 was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. Participants who were lost-to-follow-up or dead by week 48 or had missing results at week 48 were coded as having HIV viral load greater than 400 copies/mL. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants Who Experienced Sputum Conversion at Week 8. | Sputum conversion was defined as culture MTB-negative at week 8 or AFB smear negative at week 8 (and culture contaminated or missing at week 8); there were no Xpert MTB/RIF results at week 8. The percent of participants experienced sputum conversion at week 8 was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | 8 weeks | 
| Percent of Participants Who Experienced TB Treatment Failure | TB treatment failure was defined as having a MTB-positive culture after 16 weeks of TB treatment for a participant who was documented to be taking TB medications. The percent of participants who experienced TB treatment failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After 16 weeks and through week 72 | 
| Percent of Participants Who Experienced TB Relapse/Recurrence | TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The percent of participants who experienced TB relapse/recurrence was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | At or after 24 weeks and through week 72 | 
| Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance | TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The drug resistance was determined based on phenotypic methods. The percent of participants who experienced TB relapse/recurrence and who had TB drug resistance was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | At or after 24 weeks and through week 72 | 
| Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48 | The percent of participants whose HIV viral load was less than 50 copies/mL at week 48 was calculated with an associated standard error. Participants who were lost-to-follow-up or dead by week 48 or had missing RNA at week 48 were coded as having HIV viral load greater than 50 copies/mL. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | 48 weeks | 
| Number of Participants Reporting a Grade 3 or 4 Sign or Symptom | The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) sign or symptom were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality | The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) laboratory abnormality were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity | The percent of participants who interrupted or discontinued at least one HIV drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity | The percent of participants who interrupted or discontinued at least one TB drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through to the discontinuation of the last TB drug | 
| Percent of Participants Who Experienced HIV Virologic Failure | Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. Participants who were missing data due to being lost-to-follow-up or dead were coded as virologic failures. The percent of participants who experienced HIV virologic failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | At weeks 16, 24, 48, and 72 | 
| Cumulative Probability of HIV Virologic Failure at Week 72 | Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. The percent of participants with HIV virologic failure at week 72 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | At weeks 16, 24, 48, and 72 | 
| Number of Participants Who Experienced MTB IRIS | The number of participants who experienced MTB immune reconstitution inflammatory syndrome (IRIS) was summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| CD4 Count Change From Baseline to Week 8 | The difference in CD4 count from baseline to week 8 was calculated as the CD4 count at week 8 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | Baseline and 8 weeks | 
| CD4 Count Change From Baseline to Week 24 | The difference in CD4 count from baseline to week 24 was calculated as the CD4 count at week 24 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | Baseline and 24 weeks | 
| CD4 Count Change From Baseline to Week 48 | The difference in CD4 count from baseline to week 48 was calculated as the CD4 count at week 48 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | Baseline and 48 weeks | 
| CD4 Count Change From Baseline to Week 72 | The difference in CD4 count from baseline to week 72 was calculated as the CD4 count at week 72 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | Baseline and 72 weeks | 
| Percent of Participants Who Experienced a New AIDS-defining Illness | New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| Percent of Participants Who Died | The percent of participants who died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 | 
| Percent of Participants Who Experienced a New AIDS-defining Illness or Died | New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness or died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size. | After randomization and through week 72 |