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

Phase 2TerminatedNCT01601626

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections71 enrolled

Overview

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.

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.

Interventions

Standard-dose Lopinavir/RitonavirDRUG

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

Double-dose Lopinavir/RitonavirDRUG

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

RaltegravirDRUG

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

IsoniazidDRUG

300 mg orally once daily from entry through Week 24.

PyridoxineDRUG

25 mg orally once daily from entry to Week 24.

PyrazinamideDRUG

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).

EthambutolDRUG

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).

RifabutinDRUG

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.

RifampinDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (9)

Hospital Nossa Senhora da Conceicao CRS (12201)

Porto Alegre, Rio Grande do Sul, Brazil

Instituto de Pesquisa Clinica Evandro Chagas (12101)

Rio de Janeiro, Brazil

Les Centres GHESKIO CRS (30022)

Port-au-Prince, Haiti

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

Port-au-Prince, Haiti

Moi University Clinical Research Center CRS (12601)

Eldoret, Kenya

Investigaciones Medicas en Salud (INMENSA) (11302)

San Isidro, Lima region, Peru

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

Lima, Peru

Wits HIV CRS (11101)

Johannesburg, Gauteng, South Africa

Durban Adult HIV CRS (11201)

Durban, South Africa

Outcomes

Primary Outcomes

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.

Time frame: 48 weeks

Secondary Outcomes

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.

Time frame: 8 weeks

Percent of Participants Who Experienced TB Treatment Failure

TB treatment failure was defined as having a MTB-positive culture after 16 weeks of TB treatment for a participant who was documented to be taking TB medications. The percent of participants who experienced TB treatment failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After 16 weeks and through week 72

Percent of Participants Who Experienced TB Relapse/Recurrence

TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The percent of participants who experienced TB relapse/recurrence was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: At or after 24 weeks and through week 72

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

TB relapse/recurrence was defined as having had 2 consecutive MTB-negative cultures and subsequently had clinical or radiographic deterioration consistent with active TB at or after week 24 and before week 72. The drug resistance was determined based on phenotypic methods. The percent of participants who experienced TB relapse/recurrence and who had TB drug resistance was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: At or after 24 weeks and through week 72

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

The percent of participants whose HIV viral load was less than 50 copies/mL at week 48 was calculated with an associated standard error. Participants who were lost-to-follow-up or dead by week 48 or had missing RNA at week 48 were coded as having HIV viral load greater than 50 copies/mL. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: 48 weeks

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

The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) sign or symptom were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality

The number of participants reporting a grade 3 (severe) or grade 4 (life-threatening) laboratory abnormality were summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

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

The percent of participants who interrupted or discontinued at least one HIV drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

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

The percent of participants who interrupted or discontinued at least one TB drug due to toxicity was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through to the discontinuation of the last TB drug

Percent of Participants Who Experienced HIV Virologic Failure

Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. Participants who were missing data due to being lost-to-follow-up or dead were coded as virologic failures. The percent of participants who experienced HIV virologic failure was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: At weeks 16, 24, 48, and 72

Cumulative Probability of HIV Virologic Failure at Week 72

Virologic failure was defined as the occurrence of two consecutive plasma HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and within 24 weeks of treatment initiation or ≥400 copies/mL at or after 24 weeks of treatment, regardless of whether randomized ART was being taken at the time of virologic failure. The percent of participants with HIV virologic failure at week 72 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: At weeks 16, 24, 48, and 72

Number of Participants Who Experienced MTB IRIS

The number of participants who experienced MTB immune reconstitution inflammatory syndrome (IRIS) was summarized. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

CD4 Count Change From Baseline to Week 8

The difference in CD4 count from baseline to week 8 was calculated as the CD4 count at week 8 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: Baseline and 8 weeks

CD4 Count Change From Baseline to Week 24

The difference in CD4 count from baseline to week 24 was calculated as the CD4 count at week 24 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: Baseline and 24 weeks

CD4 Count Change From Baseline to Week 48

The difference in CD4 count from baseline to week 48 was calculated as the CD4 count at week 48 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: Baseline and 48 weeks

CD4 Count Change From Baseline to Week 72

The difference in CD4 count from baseline to week 72 was calculated as the CD4 count at week 72 minus the CD4 count at baseline. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: Baseline and 72 weeks

Percent of Participants Who Experienced a New AIDS-defining Illness

New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness was calculated with an associated standard error. The confidence interval was calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

Percent of Participants Who Died

The percent of participants who died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

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

New post-randomization diagnoses were considered AIDS-defining based on the CDC classification system. The percent of participants who experienced a new AIDS-defining illness or died was calculated with an associated standard error. Confidence intervals were calculated using Wilson's score method. As stated in the Detailed Study Description of the Protocol Section, formal statistical comparisons were not undertaken because of limited sample size.

Time frame: After randomization and through week 72

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

Overview

Conditions

Interventions

Eligibility

Locations (9)

Outcomes

Primary Outcomes

Secondary Outcomes