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

• Sponsor: AIDS Clinical Trials Group (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01601626
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 71
• Locations: 9
• Arms: 3
• Actual Duration (Months): 47.5
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Infection; Tuberculosis	Drug: Standard-dose Lopinavir/Ritonavir; Drug: Double-dose Lopinavir/Ritonavir; Drug: Raltegravir; Drug: Isoniazid; Drug: Pyridoxine; Drug: Pyrazinamide; Drug: Ethambutol; Drug: Rifabutin; Drug: Rifampin	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jul 13, 2013
• Actual Primary Completion Date: Jan 19, 2017
• Actual Study Completion Date: Jun 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A: Standard-dose LPV/r w/RBT 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; Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.; Other Names: LPV/RTV LPV/r Aluvia Kaletra ; Drug: Isoniazid; 300 mg orally once daily from entry through Week 24.; Other Names: INH ; Drug: Pyridoxine; 25 mg orally once daily from entry to Week 24.; Other Names: Vitamin B6 ; 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 Names: 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 Names: 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 Names: RBT
Active Comparator: B: Double-dose LPV/r w/RIF 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; Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.; Other Names: LPV/RTV LPV/r Aluvia Kaletra ; Drug: Isoniazid; 300 mg orally once daily from entry through Week 24.; Other Names: INH ; Drug: Pyridoxine; 25 mg orally once daily from entry to Week 24.; Other Names: Vitamin B6 ; 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 Names: 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 Names: EMB ; 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 Names: RIF
Experimental: C: Standard-Dose LPV/r w/RBT + RAL 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; Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.; Other Names: LPV/RTV LPV/r Aluvia Kaletra ; Drug: Raltegravir; One 400 mg tablet 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 Names: INH ; Drug: Pyridoxine; 25 mg orally once daily from entry to Week 24.; Other Names: Vitamin B6 ; 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 Names: 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 Names: 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 Names: RBT

Outcome Measures

Primary Outcome Measures

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

   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

1. Percent of Participants Who Experienced Sputum Conversion at Week 8. [8 weeks]

   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.

2. Percent of Participants Who Experienced TB Treatment Failure [After 16 weeks and through week 72]

   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.

3. Percent of Participants Who Experienced TB Relapse/Recurrence [At or after 24 weeks and through week 72]

   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.

4. Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance [At or after 24 weeks and through week 72]

   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.

5. Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48 [48 weeks]

   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.

6. Number of Participants Reporting a Grade 3 or 4 Sign or Symptom [After randomization and through week 72]

   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.

7. Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality [After randomization and through week 72]

   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.

8. Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity [After randomization and through week 72]

   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.

9. Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity [After randomization and through to the discontinuation of the last TB drug]

   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.

10. Percent of Participants Who Experienced HIV Virologic Failure [At weeks 16, 24, 48, and 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. 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.

11. Cumulative Probability of HIV Virologic Failure at Week 72 [At weeks 16, 24, 48, and 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.

12. Number of Participants Who Experienced MTB IRIS [After randomization and through week 72]

    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.

13. CD4 Count Change From Baseline to Week 8 [Baseline and 8 weeks]

    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.

14. CD4 Count Change From Baseline to Week 24 [Baseline and 24 weeks]

    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.

15. CD4 Count Change From Baseline to Week 48 [Baseline and 48 weeks]

    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.

16. CD4 Count Change From Baseline to Week 72 [Baseline and 72 weeks]

    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.

17. Percent of Participants Who Experienced a New AIDS-defining Illness [After randomization and through week 72]

    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.

18. Percent of Participants Who Died [After randomization and through week 72]

    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.

19. Percent of Participants Who Experienced a New AIDS-defining Illness or Died [After randomization and through week 72]

    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.

Other Outcome Measures

1. LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C [At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose]

   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.

2. LPV AUC in Participants Enrolled in Arms A, B, and C [At 2 weeks: pre-dose and at 2, 4, 5, and 6 hours post-dose]

   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.

3. RBT Cmax and Cmin in Participants Enrolled in Arms A and C [At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose]

   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.

4. RBT AUC in Participants Enrolled in Arms A and C [At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose]

   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.

5. RAL Cmax and Cmin in Participants Enrolled in Arm C [At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose]

   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.

6. RAL AUC in Participants Enrolled in Arm C [At 2 weeks: pre-dose and at 2, 4, 5, 6, and 24 hours post-dose]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Nossa Senhora da Conceicao CRS (12201)	Porto Alegre	RS	Brazil	9043010
2	Instituto de Pesquisa Clinica Evandro Chagas (12101)	Rio de Janeiro		Brazil	21045
3	GHESKIO Institute of Infectious Diseases and Reproductive Health (GHESKIO - IMIS) CRS (31730)	Port Au Prince		Haiti
4	Les Centres GHESKIO CRS (30022)	Port-au-Prince		Haiti	HT-6110
5	Moi University Clinical Research Center CRS (12601)	Eldoret		Kenya	30100
6	Investigaciones Medicas en Salud (INMENSA) (11302)	San Isidro	Lima	Peru
7	Asociacion Civil Impacta Salud y Educacion - Miraf CRS (11301)	Lima		Peru	18 PE
8	Wits HIV CRS (11101)	Johannesburg	Gauteng	South Africa
9	Durban Adult HIV CRS (11201)	Durban		South Africa	4013 SF

Sponsors and Collaborators

• AIDS Clinical Trials Group
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Constance A Benson, MD, University of California, San Diego
• Study Chair: Umesh Lalloo, MD, FRCP, Nelson R. Mandela School of Medicine

Study Documents (Full-Text)

• Statistical Analysis Plan: Primary Analysis - Jul 14, 2017
• Statistical Analysis Plan: PK and Safety Interim Analysis - Oct 7, 2016
• Study Protocol and Informed Consent Form - Jan 31, 2012

More Information

Additional Information:

• DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004; Clarification, August 2009
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

Publications

None provided.

• Responsible Party: AIDS Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT01601626
• Other Study ID Numbers: ACTG A5290; 1U01AI068636
• First Posted: May 18, 2012
• Last Update Posted: Feb 13, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Tuberculosis; Pyridoxine; Vitamin B 6; Ritonavir; Lopinavir; Raltegravir Potassium; Rifampin; Isoniazid; Pyrazinamide; Ethambutol; Rifabutin

Study Results

Participant Flow

Recruitment Details	Study participants were recruited at 9 sites from 5 countries (2 each from Brazil, Haiti, Peru, and South Africa and 1 from Kenya) between July 2013 and February 2016.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Period Title: Overall Study
STARTED	24	24	23
COMPLETED	21	19	21
NOT COMPLETED	3	5	2

Baseline Characteristics

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT	Total
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.	Total of all reporting groups
Overall Participants	24	24	23	71
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	42	35	38	37
Sex: Female, Male (Count of Participants)
Female	13 54.2%	9 37.5%	15 65.2%	37 52.1%
Male	11 45.8%	15 62.5%	8 34.8%	34 47.9%
Race/Ethnicity, Customized (Count of Participants)
Black of African Origin	7 29.2%	8 33.3%	6 26.1%	21 29.6%
Black African	8 33.3%	6 25%	4 17.4%	18 25.4%
White	4 16.7%	2 8.3%	6 26.1%	12 16.9%
Mixed Black	3 12.5%	5 20.8%	3 13%	11 15.5%
Mestizo	2 8.3%	2 8.3%	2 8.7%	6 8.5%
Mixed, of Predominantly African Ancestry	0 0%	0 0%	1 4.3%	1 1.4%
Other	0 0%	1 4.2%	1 4.3%	2 2.8%
Region of Enrollment (participants) [Number]
Haiti	6 25%	6 25%	6 26.1%	18 25.4%
Brazil	8 33.3%	10 41.7%	10 43.5%	28 39.4%
South Africa	4 16.7%	3 12.5%	3 13%	10 14.1%
Kenya	4 16.7%	3 12.5%	2 8.7%	9 12.7%
Peru	2 8.3%	2 8.3%	2 8.7%	6 8.5%
Qualitative HIV RNA (Count of Participants)
Less than 40 copies/mL	4 16.7%	2 8.3%	3 13%	9 12.7%
Greater than or equal to 40 copies/mL	20 83.3%	22 91.7%	20 87%	62 87.3%
Quantitative HIV RNA (log10 copies/mL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [log10 copies/mL]	4.7	4.8	4.2	4.6
CD4 Cell Count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	128	117	158	130
Tuberculosis (TB) Diagnosis Certainty (Count of Participants)
Confirmed Pulmonary TB	13 54.2%	8 33.3%	6 26.1%	27 38%
Confirmed Extrapulmonary TB	1 4.2%	1 4.2%	3 13%	5 7%
Confirmed Pulmonary and Extrapulmonary TB	1 4.2%	0 0%	0 0%	1 1.4%
Probable Pulmonary TB	9 37.5%	15 62.5%	13 56.5%	37 52.1%
Probable Extrapulmonary TB	0 0%	0 0%	1 4.3%	1 1.4%
Acid Fast Bacilli (AFB) Smear (Count of Participants)
Positive	11 45.8%	8 33.3%	6 26.1%	25 35.2%
Negative	10 41.7%	14 58.3%	16 69.6%	40 56.3%
No Results Available	3 12.5%	2 8.3%	1 4.3%	6 8.5%
Mycobacteria Tuberculosis (MTB) Culture (Count of Participants)
MTB-Positive	13 54.2%	8 33.3%	9 39.1%	30 42.3%
MTB-Negative	6 25%	13 54.2%	13 56.5%	32 45.1%
No Results Available	5 20.8%	3 12.5%	1 4.3%	9 12.7%
Body Mass Index (BMI) (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	19.9	20.4	18.9	19.6

Outcome Measures

1. Primary Outcome

Title	Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48.
Description	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.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	58.3 242.9%	66.7 277.9%	60.9 264.8%

2. Secondary Outcome

Title	Percent of Participants Who Experienced Sputum Conversion at Week 8.
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Participants who were either culture MTB-positive at entry; AFB smear positive at entry (and culture MTB-negative, contaminated, or missing at entry); or Xpert MTB/RIF positive at entry (and culture or smear negative, contaminated, or missing at entry) were included in the analysis.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	16	11	10
Number (95% Confidence Interval) [percentage of participants]	87.5 364.6%	81.8 340.8%	70.0 304.3%

3. Secondary Outcome

Title	Percent of Participants Who Experienced TB Treatment Failure
Description	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.
Time Frame	After 16 weeks and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	0.0 0%	0.0 0%

4. Secondary Outcome

Title	Percent of Participants Who Experienced TB Relapse/Recurrence
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 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.
Time Frame	At or after 24 weeks and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	4.2 17.5%	4.3 18.7%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All participants who experienced TB relapse/recurrence were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	0	1	1
Number (95% Confidence Interval) [participants]	0 0%	0 0%

6. Secondary Outcome

Title	Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48
Description	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.
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	45.8 190.8%	54.2 225.8%	56.5 245.7%

7. Secondary Outcome

Title	Number of Participants Reporting a Grade 3 or 4 Sign or Symptom
Description	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.
Time Frame	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Count of Participants [Participants]	7 29.2%	5 20.8%	5 21.7%

8. Secondary Outcome

Title	Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality
Description	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.
Time Frame	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Count of Participants [Participants]	6 25%	3 12.5%	5 21.7%

9. Secondary Outcome

Title	Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity
Description	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.
Time Frame	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	20.8 86.7%	16.7 69.6%	21.7 94.3%

10. Secondary Outcome

Title	Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity
Description	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.
Time Frame	After randomization and through to the discontinuation of the last TB drug

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	20.8 86.7%	8.3 34.6%	13.0 56.5%

11. Secondary Outcome

Title	Percent of Participants Who Experienced HIV Virologic Failure
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. 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.
Time Frame	At weeks 16, 24, 48, and 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	29.2 121.7%	50.0 208.3%	30.4 132.2%

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [cumulative events per 100 participants]	29.2 121.7%	50.0 208.3%	30.4 132.2%

13. Secondary Outcome

Title	Number of Participants Who Experienced MTB IRIS
Description	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.
Time Frame	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Count of Participants [Participants]	1 4.2%	2 8.3%	3 13%

14. Secondary Outcome

Title	CD4 Count Change From Baseline to Week 8
Description	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.
Time Frame	Baseline and 8 weeks

Outcome Measure Data

Analysis Population Description

Participants who had CD4 cell count data available at baseline and week 8 were included in the analysis.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	22	24	22
Median (Inter-Quartile Range) [cells/mm^3]	7	26	37

15. Secondary Outcome

Title	CD4 Count Change From Baseline to Week 24
Description	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.
Time Frame	Baseline and 24 weeks

Outcome Measure Data

Analysis Population Description

Participants who had CD4 cell count data available at baseline and week 24 were included in the analysis.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	21	23	18
Median (Inter-Quartile Range) [cells/mm^3]	20	56	13

16. Secondary Outcome

Title	CD4 Count Change From Baseline to Week 48
Description	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.
Time Frame	Baseline and 48 weeks

Outcome Measure Data

Analysis Population Description

Participants who had CD4 cell count data available at baseline and week 48 were included in the analysis.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	20	20	18
Median (Inter-Quartile Range) [cells/mm^3]	99	119	74

17. Secondary Outcome

Title	CD4 Count Change From Baseline to Week 72
Description	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.
Time Frame	Baseline and 72 weeks

Outcome Measure Data

Analysis Population Description

Participants who had CD4 cell count data available at baseline and week 72 were included in the analysis.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	20	19	20
Median (Inter-Quartile Range) [cells/mm^3]	126	212	54

18. Secondary Outcome

Title	Percent of Participants Who Experienced a New AIDS-defining Illness
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 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	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	4.2 17.5%	0.0 0%

19. Secondary Outcome

Title	Percent of Participants Who Died
Description	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.
Time Frame	After randomization and through week 72

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	4.2 17.5%	4.7 19.6%	4.3 18.7%

20. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized participants were included.

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	24	24	23
Number (95% Confidence Interval) [percentage of participants]	4.2 17.5%	8.3 34.6%	4.3 18.7%

21. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, and the LPV concentration at the pre-dose draw was above the assay's lower limit of quantification (20 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	19	17	14
Maximum Concentration (Cmax)	18531	18138	16802
Minimum Concentration (Cmin)	9920	8033	8548

22. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, and the LPV concentration at the pre-dose draw was above the assay's lower limit of quantification (20 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	19	17	14
Median (Inter-Quartile Range) [hours*ng/mL]	159796	161772	149247

23. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, followed the protocol-required RBT dosing schedule, and the RBT concentration at the pre-dose draw was above the assay's lower limit of quantification (75 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	18	0	11
Maximum Concentration (Cmax)	461	349
Minimum Concentration (Cmin)	161	115

24. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, followed the protocol-required RBT dosing schedule, and the RBT concentration at the pre-dose draw was above the assay's lower limit of quantification (75 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	18	0	11
Median (Inter-Quartile Range) [hours*ng/mL]	7374	5516

25. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, and the RAL concentration at the pre-dose draw was above the assay's lower limit of quantification (5 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	0	0	16
Maximum Concentration (Cmax)	2830
Minimum Concentration (Cmin)	166

26. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

Participants were included in this analysis if they completed the PK visit, did not miss any doses of any study-required medications on the day prior to the PK visit, and the RAL concentration at the pre-dose draw was above the assay's lower limit of quantification (5 ng/mL).

Arm/Group Title	A: Standard-dose LPV/r w/RBT	B: Double-dose LPV/r w/RIF	C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.	ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.	ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
Measure Participants	0	0	16
Median (Inter-Quartile Range) [hours*ng/mL]	11338

Adverse Events

Time Frame	From study entry to either premature study discontinuation or study completion at Week 72.
Adverse Event Reporting Description	The study protocol required reporting of all new diagnoses; all new Grade 2 (moderate) or higher TB-related signs and symptoms, all new signs and symptoms Grade 3 (severe) or higher; all new all Grade 3 or higher laboratory values; and all signs, symptoms, and laboratory values that led to a change in treatment, regardless of grade. The DAIDS AE Grading Table (V1.0) and EAE Manual (V2.0) were used. All randomized participants who initiated study treatment were included.
Arm/Group Title	A: Standard-dose LPV/r w/RBT		B: Double-dose LPV/r w/RIF		C: Standard-Dose LPV/r + RAL w/RBT
Arm/Group Description	ART: standard-dose LPV/r twice daily + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + two NRTIs.		ART: double-dose LPV/r twice daily + 2 NRTIs. Anti-TB therapy: isoniazid, rifampin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + 2 NRTIs.		ART: standard-dose LPV/r twice daily + RAL + two NRTIs. Anti-TB therapy: isoniazid, rifabutin, ethambutol, pyrazinamide, and pyridoxine daily. After completion of TB treatment through week 72: standard-dose LPV/r twice daily + RAL + two NRTIs.
All Cause Mortality
	A: Standard-dose LPV/r w/RBT		B: Double-dose LPV/r w/RIF		C: Standard-Dose LPV/r + RAL w/RBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)		1/24 (4.2%)		1/23 (4.3%)
Serious Adverse Events
	A: Standard-dose LPV/r w/RBT		B: Double-dose LPV/r w/RIF		C: Standard-Dose LPV/r + RAL w/RBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)		5/24 (20.8%)		5/23 (21.7%)
Blood and lymphatic system disorders
Anaemia	1/24 (4.2%)		1/24 (4.2%)		0/23 (0%)
Pancytopenia	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Thrombocytopenia	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Cardiac disorders
Cardiac failure congestive	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Eye disorders
Iridocyclitis	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Gastrointestinal disorders
Abdominal pain upper	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Gastrointestinal disorder	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Infections and infestations
Acute hepatitis B	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Disseminated tuberculosis	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Gastroenteritis	1/24 (4.2%)		1/24 (4.2%)		0/23 (0%)
Pneumonia	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Pneumonia bacterial	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Rhodococcus infection	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Sepsis	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Tuberculosis gastrointestinal	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Injury, poisoning and procedural complications
Accidental overdose	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Head injury	0/24 (0%)		1/24 (4.2%)		0/23 (0%)
Metabolism and nutrition disorders
Lactic acidosis	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Nervous system disorders
Seizure	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Renal and urinary disorders
Acute kidney injury	1/24 (4.2%)		0/24 (0%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/24 (0%)		0/24 (0%)		1/23 (4.3%)
Other (Not Including Serious) Adverse Events
	A: Standard-dose LPV/r w/RBT		B: Double-dose LPV/r w/RIF		C: Standard-Dose LPV/r + RAL w/RBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/24 (100%)		23/24 (95.8%)		23/23 (100%)
Blood and lymphatic system disorders
Anaemia	3/24 (12.5%)		1/24 (4.2%)		0/23 (0%)
Lymphadenopathy	1/24 (4.2%)		2/24 (8.3%)		2/23 (8.7%)
Cardiac disorders
Tachycardia	1/24 (4.2%)		2/24 (8.3%)		3/23 (13%)
Eye disorders
Eye pain	3/24 (12.5%)		0/24 (0%)		0/23 (0%)
Ocular hyperaemia	3/24 (12.5%)		0/24 (0%)		0/23 (0%)
Uveitis	2/24 (8.3%)		0/24 (0%)		0/23 (0%)
Visual acuity reduced	2/24 (8.3%)		0/24 (0%)		0/23 (0%)
Gastrointestinal disorders
Abdominal pain	3/24 (12.5%)		1/24 (4.2%)		2/23 (8.7%)
Dyspepsia	0/24 (0%)		0/24 (0%)		2/23 (8.7%)
Dysphagia	1/24 (4.2%)		2/24 (8.3%)		0/23 (0%)
Nausea	0/24 (0%)		1/24 (4.2%)		2/23 (8.7%)
Oral disorder	3/24 (12.5%)		0/24 (0%)		2/23 (8.7%)
Vomiting	2/24 (8.3%)		2/24 (8.3%)		2/23 (8.7%)
General disorders
Asthenia	2/24 (8.3%)		1/24 (4.2%)		1/23 (4.3%)
Chest pain	2/24 (8.3%)		1/24 (4.2%)		1/23 (4.3%)
Fatigue	2/24 (8.3%)		0/24 (0%)		2/23 (8.7%)
Pyrexia	3/24 (12.5%)		6/24 (25%)		3/23 (13%)
Infections and infestations
Immune reconstitution inflammatory syndrome associated tuberculosis	1/24 (4.2%)		2/24 (8.3%)		4/23 (17.4%)
Oral candidiasis	3/24 (12.5%)		3/24 (12.5%)		2/23 (8.7%)
Pneumonia bacterial	2/24 (8.3%)		1/24 (4.2%)		1/23 (4.3%)
Pulmonary tuberculosis	0/24 (0%)		2/24 (8.3%)		0/23 (0%)
Purulent discharge	0/24 (0%)		2/24 (8.3%)		0/23 (0%)
Investigations
Alanine aminotransferase increased	2/24 (8.3%)		3/24 (12.5%)		4/23 (17.4%)
Aspartate aminotransferase increased	7/24 (29.2%)		7/24 (29.2%)		9/23 (39.1%)
Blood albumin decreased	15/24 (62.5%)		15/24 (62.5%)		14/23 (60.9%)
Blood alkaline phosphatase increased	6/24 (25%)		8/24 (33.3%)		6/23 (26.1%)
Blood bicarbonate decreased	3/24 (12.5%)		2/24 (8.3%)		3/23 (13%)
Blood bilirubin increased	2/24 (8.3%)		2/24 (8.3%)		1/23 (4.3%)
Blood creatinine increased	3/24 (12.5%)		1/24 (4.2%)		1/23 (4.3%)
Blood potassium decreased	0/24 (0%)		3/24 (12.5%)		1/23 (4.3%)
Blood potassium increased	0/24 (0%)		1/24 (4.2%)		3/23 (13%)
Blood sodium decreased	8/24 (33.3%)		8/24 (33.3%)		11/23 (47.8%)
Blood sodium increased	3/24 (12.5%)		5/24 (20.8%)		4/23 (17.4%)
Haemoglobin decreased	14/24 (58.3%)		9/24 (37.5%)		7/23 (30.4%)
Neutrophil count decreased	3/24 (12.5%)		1/24 (4.2%)		3/23 (13%)
Weight decreased	2/24 (8.3%)		3/24 (12.5%)		3/23 (13%)
White blood cell count decreased	1/24 (4.2%)		1/24 (4.2%)		3/23 (13%)
Metabolism and nutrition disorders
Decreased appetite	2/24 (8.3%)		2/24 (8.3%)		1/23 (4.3%)
Obesity	0/24 (0%)		0/24 (0%)		2/23 (8.7%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/24 (8.3%)		1/24 (4.2%)		0/23 (0%)
Nervous system disorders
Altered state of consciousness	2/24 (8.3%)		0/24 (0%)		0/23 (0%)
Dizziness	2/24 (8.3%)		2/24 (8.3%)		1/23 (4.3%)
Headache	2/24 (8.3%)		3/24 (12.5%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	2/24 (8.3%)		3/24 (12.5%)		1/23 (4.3%)
Dyspnoea	1/24 (4.2%)		1/24 (4.2%)		3/23 (13%)
Oropharyngeal plaque	1/24 (4.2%)		3/24 (12.5%)		0/23 (0%)
Rales	0/24 (0%)		1/24 (4.2%)		3/23 (13%)
Rhinorrhoea	0/24 (0%)		2/24 (8.3%)		0/23 (0%)
Tachypnoea	0/24 (0%)		0/24 (0%)		2/23 (8.7%)
Skin and subcutaneous tissue disorders
Blister	1/24 (4.2%)		2/24 (8.3%)		1/23 (4.3%)

Limitations/Caveats

The study was terminated after 71 of 471 participants enrolled. Therefore, the study was under-powered and formal statistical comparisons between study arms were not undertaken as originally planned. Instead, summaries within study arm were provided.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.