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

Primary Purpose

HIV Infection, Tuberculosis

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Standard-dose Lopinavir/Ritonavir

Double-dose Lopinavir/Ritonavir

Raltegravir

Isoniazid

Pyridoxine

Pyrazinamide

Ethambutol

Rifabutin

Rifampin

About this trial

This is an interventional treatment trial for HIV Infection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Hospital Nossa Senhora da Conceicao CRS (12201)
Instituto de Pesquisa Clinica Evandro Chagas (12101)
GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)
Les Centres GHESKIO CRS (30022)
Moi University Clinical Research Center CRS (12601)
Investigaciones Medicas en Salud (INMENSA) (11302)
Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)
Wits HIV CRS (11101)
Durban Adult HIV CRS (11201)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

A: Standard-dose LPV/r w/RBT

B: Double-dose LPV/r w/RIF

C: Standard-Dose LPV/r w/RBT + RAL

Arm Description

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).

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).

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Full Information

NCT ID

NCT01601626

First Posted

May 16, 2012

Last Updated

February 7, 2018

Sponsor

AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT01601626

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Terminated

Why Stopped

The study was stopped early due to feasibility concerns.

Study Start Date

July 13, 2013 (Actual)

Primary Completion Date

January 19, 2017 (Actual)

Study Completion Date

June 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

AIDS Clinical Trials Group

Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infection, Tuberculosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

71 (Actual)

8. Arms, Groups, and Interventions

Arm Title

A: Standard-dose LPV/r w/RBT

Arm Type

Experimental

Arm Description

Arm Title

B: Double-dose LPV/r w/RIF

Arm Type

Active Comparator

Arm Description

Arm Title

C: Standard-Dose LPV/r w/RBT + RAL

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Standard-dose Lopinavir/Ritonavir

Other Intervention Name(s)

LPV/RTV, LPV/r, Aluvia, Kaletra

Intervention Description

Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.

Intervention Type

Drug

Intervention Name(s)

Double-dose Lopinavir/Ritonavir

Other Intervention Name(s)

LPV/RTV, LPV/r, Aluvia, Kaletra

Intervention Description

Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.

Intervention Type

Drug

Intervention Name(s)

Raltegravir

Other Intervention Name(s)

RAL, Isentress

Intervention Description

One 400 mg tablet orally twice daily from entry to Week 72.

Intervention Type

Drug

Intervention Name(s)

Isoniazid

Other Intervention Name(s)

INH

Intervention Description

300 mg orally once daily from entry through Week 24.

Intervention Type

Drug

Intervention Name(s)

Pyridoxine

Other Intervention Name(s)

Vitamin B6

Intervention Description

25 mg orally once daily from entry to Week 24.

Intervention Type

Drug

Intervention Name(s)

Pyrazinamide

Other Intervention Name(s)

PZA

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Ethambutol

Other Intervention Name(s)

EMB

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

Rifabutin

Other Intervention Name(s)

RBT

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Rifampin

Other Intervention Name(s)

RIF

Intervention Description

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.

Primary Outcome Measure Information:

Title

Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.

Description

Time Frame

48 weeks

Secondary Outcome Measure Information:

Title

Percent of Participants Who Experienced Sputum Conversion at Week 8.

Description

Time Frame

8 weeks

Title

Percent of Participants Who Experienced TB Treatment Failure

Description

Time Frame

After 16 weeks and through week 72

Title

Percent of Participants Who Experienced TB Relapse/Recurrence

Description

Time Frame

At or after 24 weeks and through week 72

Title

Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance

Description

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.

Time Frame

At or after 24 weeks and through week 72

Title

Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48

Description

Time Frame

48 weeks

Title

Number of Participants Reporting a Grade 3 or 4 Sign or Symptom

Description

Time Frame

After randomization and through week 72

Title

Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality

Description

Time Frame

After randomization and through week 72

Title

Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity

Description

Time Frame

After randomization and through week 72

Title

Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity

Description

Time Frame

After randomization and through to the discontinuation of the last TB drug

Title

Percent of Participants Who Experienced HIV Virologic Failure

Description

Time Frame

At weeks 16, 24, 48, and 72

Title

Cumulative Probability of HIV Virologic Failure at Week 72

Description

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.

Time Frame

At weeks 16, 24, 48, and 72

Title

Number of Participants Who Experienced MTB IRIS

Description

Time Frame

After randomization and through week 72

Title

CD4 Count Change From Baseline to Week 8

Description

Time Frame

Baseline and 8 weeks

Title

CD4 Count Change From Baseline to Week 24

Description

Time Frame

Baseline and 24 weeks

Title

CD4 Count Change From Baseline to Week 48

Description

Time Frame

Baseline and 48 weeks

Title

CD4 Count Change From Baseline to Week 72

Description

Time Frame

Baseline and 72 weeks

Title

Percent of Participants Who Experienced a New AIDS-defining Illness

Description

Time Frame

After randomization and through week 72

Title

Percent of Participants Who Died

Description

Time Frame

After randomization and through week 72

Title

Percent of Participants Who Experienced a New AIDS-defining Illness or Died

Description

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.

Time Frame

After randomization and through week 72

Other Pre-specified Outcome Measures:

Title

LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C

Description

Describe LPV plasma pharmacokinetic (PK) characteristics (maximum concentration [Cmax] and minimum concentration [Cmin]) in participants enrolled in Arms A, B, and C, determined by non-compartmental analysis of 12-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous LPV dose and was used as the 12-hour LPV concentration. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose

Title

LPV AUC in Participants Enrolled in Arms A, B, and C

Description

Describe LPV plasma PK characteristics (area under the curve [AUC] between 0 and 12 hours) in participants enrolled in Arms A, B, and C, determined by non-compartmental analysis of 12-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous LPV dose and was used as the 12-hour LPV concentration. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose

Title

RBT Cmax and Cmin in Participants Enrolled in Arms A and C

Description

Describe RBT plasma PK characteristics (Cmax and Cmin) in participants enrolled in Arms A and C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 24 hours after the previous RBT dose. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose

Title

RBT AUC in Participants Enrolled in Arms A and C

Description

Describe RBT plasma PK characteristics (area under the curve [AUC] between 0 and 24 hours) in participants enrolled in Arms A and C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 24 hours after the previous RBT dose. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose

Title

RAL Cmax and Cmin in Participants Enrolled in Arm C

Description

Describe RAL plasma PK characteristics (Cmax and Cmin) in participants enrolled in Arm C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous RAL dose and was used as the 12-hour RAL concentration.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose

Title

RAL AUC in Participants Enrolled in Arm C

Description

Describe RAL plasma PK characteristics (area under the curve [AUC] between 0 and 24 hours) in participants enrolled in Arm C, determined by non-compartmental analysis of 24-hour PK sampling. The pre-dose concentration was determined using a sample drawn 12 hours after the previous RAL dose and was used as the 12-hour RAL concentration.

Time Frame

At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Constance A Benson, MD

Organizational Affiliation

University of California, San Diego

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Umesh Lalloo, MD, FRCP

Organizational Affiliation

Nelson R. Mandela School of Medicine

Official's Role

Study Chair

Facility Information:

Facility Name

Hospital Nossa Senhora da Conceicao CRS (12201)

City

Porto Alegre

State/Province

ZIP/Postal Code

9043010

Country

Brazil

Facility Name

Instituto de Pesquisa Clinica Evandro Chagas (12101)

City

Rio de Janeiro

ZIP/Postal Code

21045

Country

Brazil

Facility Name

GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)

City

Port Au Prince

Country

Haiti

Facility Name

Les Centres GHESKIO CRS (30022)

City

Port-au-Prince

ZIP/Postal Code

HT-6110

Country

Haiti

Facility Name

Moi University Clinical Research Center CRS (12601)

City

Eldoret

ZIP/Postal Code

30100

Country

Kenya

Facility Name

Investigaciones Medicas en Salud (INMENSA) (11302)

City

San Isidro

State/Province

Lima

Country

Peru

Facility Name

Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)

City

Lima

ZIP/Postal Code

18 PE

Country

Peru

Facility Name

Wits HIV CRS (11101)

City

Johannesburg

State/Province

Gauteng

Country

South Africa

Facility Name

Durban Adult HIV CRS (11201)

City

Durban

ZIP/Postal Code

4013 SF

Country

South Africa

12. IPD Sharing Statement

Links:

URL

https://rsc.tech-res.com/docs/default-source/safety/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf

Description

DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009

URL

https://rsc.tech-res.com/docs/default-source/safety/manual_for_expedited_reporting_aes_to_daids_v2.pdf

Description

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

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

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