HIV Infection, Tuberculosis
Conditions
Brief summary
There is a rapidly-growing need to identify evidence-based, safe, and effective co-treatment regimens for HIV-related tuberculosis (TB) among patients who require protease inhibitor (PI)-based antiretroviral therapy (ART). This study compared three alternative co-treatment options among participants in high TB endemic resource-constrained settings, in which one co-treatment option explores if an additional anti-HIV drug needs to be used when patients are being treated with a PI together with rifabutin-based anti-TB treatment.
Detailed description
Rifampin (RIF), the cornerstone of TB treatment, has very problematic drug-drug interactions with PIs. The use of relatively high doses of ritonavir appear necessary to overcome this interaction, but it is unclear whether the co-treatment regimen of RIF-based TB treatment and double-dose PI-based ART will be safe and tolerable for patients with HIV-related TB and effective in treating both HIV and TB. The study proposed to determine if, for HIV-1-infected participants with active TB who require PI-based ART, a standard-dose lopinavir/ritonavir (LPV/r) regimen, with or without raltegravir (RAL), coupled with rifabutin (RBT)-based TB treatment is superior to a double-dose LPV/r regimen coupled with RIF-based TB treatment. At study entry, participants were randomized (1:1:1) to receive standard-dose LPV/r-based HIV treatment plus RBT-based TB treatment (Arm A), double-dose LPV/r-based HIV treatment plus RIF-based TB treatment (Arm B), or standard-dose LPV/r-based HIV treatment plus RAL plus RBT-based TB treatment (Arm C). Accrual was planned to take place in two accrual periods. Accrual period 1 would enroll 60 participants who would undergo an initial dose-finding period before continuing regular study follow-up. Once the review of the dose-finding pharmacokinetic (PK) and safety data from accrual period 1 participants was completed, accrual period 2 was planned to open to accrual. Study duration was 72 weeks. Visits occurred at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 72. The key evaluations included physical examination, clinical assessments, TB evaluations including chest x-ray, acid-fast bacilli (AFB) smear, mycobacterial culture, and drug susceptibility testing, CD4 cell count, HIV viral load, hematology, chemistry, and pregnancy testing in women of reproductive potential. Sputum, serum, and urine were stored for use in future analyses. An intensive PK visit occurred at day 12. PK blood draws in participants in Arms A and C were at RBT pre-dose and at 2, 4, 5, 6, and 24 hours RBT post-dose. PK blood draws in participants in Arm B were at LPV/r pre-dose and at 2, 4, 5, and 6 hours LPV/r post-dose. The target sample size was 471 participants, but the study was terminated after 71 participants due to feasibility concerns. The 71 participants were followed for the planned 72 weeks. Because of the limited sample size, formal statistical comparisons were not undertaken as originally planned.
Interventions
DRUGStandard-dose Lopinavir/Ritonavir
Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72.
DRUGDouble-dose Lopinavir/Ritonavir
Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72.
DRUGRaltegravir
One 400 mg tablet orally twice daily from entry to Week 72.
DRUGIsoniazid
300 mg orally once daily from entry through Week 24.
DRUGPyridoxine
25 mg orally once daily from entry to Week 24.
DRUGPyrazinamide
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).
DRUGEthambutol
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).
DRUGRifabutin
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.
DRUGRifampin
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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Brazil, Haiti, Kenya, Peru, South Africa
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.
Participants by arm
| Arm | Count |
|---|---|
| A: Standard-dose LPV/r w/RBT 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. | 24 |
| B: Double-dose LPV/r w/RIF 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. | 24 |
| C: Standard-Dose LPV/r + RAL w/RBT 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. | 23 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 | 0 |
| Overall Study | Not Willing to Adhere to Requirements | 1 | 0 | 0 |
| Overall Study | Unable to Get to Clinic | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | C: Standard-Dose LPV/r + RAL w/RBT | B: Double-dose LPV/r w/RIF | A: Standard-dose LPV/r w/RBT |
|---|---|---|---|---|
| Acid Fast Bacilli (AFB) Smear Negative | 40 Participants | 16 Participants | 14 Participants | 10 Participants |
| Acid Fast Bacilli (AFB) Smear No Results Available | 6 Participants | 1 Participants | 2 Participants | 3 Participants |
| Acid Fast Bacilli (AFB) Smear Positive | 25 Participants | 6 Participants | 8 Participants | 11 Participants |
| Age, Continuous | 37 years | 38 years | 35 years | 42 years |
| Body Mass Index (BMI) | 19.6 kg/m^2 | 18.9 kg/m^2 | 20.4 kg/m^2 | 19.9 kg/m^2 |
| CD4 Cell Count | 130 cells/mm^3 | 158 cells/mm^3 | 117 cells/mm^3 | 128 cells/mm^3 |
| Mycobacteria Tuberculosis (MTB) Culture MTB-Negative | 32 Participants | 13 Participants | 13 Participants | 6 Participants |
| Mycobacteria Tuberculosis (MTB) Culture MTB-Positive | 30 Participants | 9 Participants | 8 Participants | 13 Participants |
| Mycobacteria Tuberculosis (MTB) Culture No Results Available | 9 Participants | 1 Participants | 3 Participants | 5 Participants |
| Qualitative HIV RNA Greater than or equal to 40 copies/mL | 62 Participants | 20 Participants | 22 Participants | 20 Participants |
| Qualitative HIV RNA Less than 40 copies/mL | 9 Participants | 3 Participants | 2 Participants | 4 Participants |
| Quantitative HIV RNA | 4.6 log10 copies/mL | 4.2 log10 copies/mL | 4.8 log10 copies/mL | 4.7 log10 copies/mL |
| Race/Ethnicity, Customized Black African | 18 Participants | 4 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Black of African Origin | 21 Participants | 6 Participants | 8 Participants | 7 Participants |
| Race/Ethnicity, Customized Mestizo | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Mixed Black | 11 Participants | 3 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Mixed, of Predominantly African Ancestry | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 6 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Brazil | 28 participants | 10 participants | 10 participants | 8 participants |
| Region of Enrollment Haiti | 18 participants | 6 participants | 6 participants | 6 participants |
| Region of Enrollment Kenya | 9 participants | 2 participants | 3 participants | 4 participants |
| Region of Enrollment Peru | 6 participants | 2 participants | 2 participants | 2 participants |
| Region of Enrollment South Africa | 10 participants | 3 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 37 Participants | 15 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 34 Participants | 8 Participants | 15 Participants | 11 Participants |
| Tuberculosis (TB) Diagnosis Certainty Confirmed Extrapulmonary TB | 5 Participants | 3 Participants | 1 Participants | 1 Participants |
| Tuberculosis (TB) Diagnosis Certainty Confirmed Pulmonary and Extrapulmonary TB | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Tuberculosis (TB) Diagnosis Certainty Confirmed Pulmonary TB | 27 Participants | 6 Participants | 8 Participants | 13 Participants |
| Tuberculosis (TB) Diagnosis Certainty Probable Extrapulmonary TB | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Tuberculosis (TB) Diagnosis Certainty Probable Pulmonary TB | 37 Participants | 13 Participants | 15 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 24 | 1 / 24 | 1 / 23 |
| other Total, other adverse events | 24 / 24 | 23 / 24 | 23 / 23 |
| serious Total, serious adverse events | 4 / 24 | 5 / 24 | 5 / 23 |
Outcome results
Primary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. | 58.3 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. | 66.7 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Whose HIV Viral Load Was Less Than 400 Copies/mL at Week 48. | 60.9 percentage of participants |
Secondary
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
Population: Participants who had CD4 cell count data available at baseline and week 24 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | CD4 Count Change From Baseline to Week 24 | 20 cells/mm^3 |
| B: Double-dose LPV/r w/RIF | CD4 Count Change From Baseline to Week 24 | 56 cells/mm^3 |
| C: Standard-Dose LPV/r + RAL w/RBT | CD4 Count Change From Baseline to Week 24 | 13 cells/mm^3 |
Secondary
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
Population: Participants who had CD4 cell count data available at baseline and week 48 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | CD4 Count Change From Baseline to Week 48 | 99 cells/mm^3 |
| B: Double-dose LPV/r w/RIF | CD4 Count Change From Baseline to Week 48 | 119 cells/mm^3 |
| C: Standard-Dose LPV/r + RAL w/RBT | CD4 Count Change From Baseline to Week 48 | 74 cells/mm^3 |
Secondary
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
Population: Participants who had CD4 cell count data available at baseline and week 72 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | CD4 Count Change From Baseline to Week 72 | 126 cells/mm^3 |
| B: Double-dose LPV/r w/RIF | CD4 Count Change From Baseline to Week 72 | 212 cells/mm^3 |
| C: Standard-Dose LPV/r + RAL w/RBT | CD4 Count Change From Baseline to Week 72 | 54 cells/mm^3 |
Secondary
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
Population: Participants who had CD4 cell count data available at baseline and week 8 were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | CD4 Count Change From Baseline to Week 8 | 7 cells/mm^3 |
| B: Double-dose LPV/r w/RIF | CD4 Count Change From Baseline to Week 8 | 26 cells/mm^3 |
| C: Standard-Dose LPV/r + RAL w/RBT | CD4 Count Change From Baseline to Week 8 | 37 cells/mm^3 |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Cumulative Probability of HIV Virologic Failure at Week 72 | 29.2 cumulative events per 100 participants |
| B: Double-dose LPV/r w/RIF | Cumulative Probability of HIV Virologic Failure at Week 72 | 50.0 cumulative events per 100 participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Cumulative Probability of HIV Virologic Failure at Week 72 | 30.4 cumulative events per 100 participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality | 6 Participants |
| B: Double-dose LPV/r w/RIF | Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality | 3 Participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Number of Participants Reporting a Grade 3 or 4 Laboratory Abnormality | 5 Participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Number of Participants Reporting a Grade 3 or 4 Sign or Symptom | 7 Participants |
| B: Double-dose LPV/r w/RIF | Number of Participants Reporting a Grade 3 or 4 Sign or Symptom | 5 Participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Number of Participants Reporting a Grade 3 or 4 Sign or Symptom | 5 Participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Number of Participants Who Experienced MTB IRIS | 1 Participants |
| B: Double-dose LPV/r w/RIF | Number of Participants Who Experienced MTB IRIS | 2 Participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Number of Participants Who Experienced MTB IRIS | 3 Participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Died | 4.2 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Died | 4.7 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Died | 4.3 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced a New AIDS-defining Illness | 0.0 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced a New AIDS-defining Illness | 4.2 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced a New AIDS-defining Illness | 0.0 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced a New AIDS-defining Illness or Died | 4.2 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced a New AIDS-defining Illness or Died | 8.3 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced a New AIDS-defining Illness or Died | 4.3 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced HIV Virologic Failure | 29.2 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced HIV Virologic Failure | 50.0 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced HIV Virologic Failure | 30.4 percentage of participants |
Secondary
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced Sputum Conversion at Week 8. | 87.5 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced Sputum Conversion at Week 8. | 81.8 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced Sputum Conversion at Week 8. | 70.0 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced TB Relapse/Recurrence | 0.0 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced TB Relapse/Recurrence | 4.2 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced TB Relapse/Recurrence | 4.3 percentage of participants |
Secondary
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
Population: All participants who experienced TB relapse/recurrence were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance | 0 participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced TB Relapse/Recurrence and Who Had TB Drug Resistance | 0 participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Experienced TB Treatment Failure | 0.0 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Experienced TB Treatment Failure | 0.0 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Experienced TB Treatment Failure | 0.0 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity | 20.8 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity | 16.7 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Interrupted or Discontinued at Least One HIV Drug Due to Toxicity | 21.7 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity | 20.8 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity | 8.3 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Who Interrupted or Discontinued at Least One TB Drug Due to Toxicity | 13.0 percentage of participants |
Secondary
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
Population: All randomized participants were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48 | 45.8 percentage of participants |
| B: Double-dose LPV/r w/RIF | Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48 | 54.2 percentage of participants |
| C: Standard-Dose LPV/r + RAL w/RBT | Percent of Participants Whose HIV Viral Load Was Less Than 50 Copies/mL at Week 48 | 56.5 percentage of participants |
Other Pre-specified
LPV AUC in Participants Enrolled in Arms A, B, and C
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | LPV AUC in Participants Enrolled in Arms A, B, and C | 159796 hours*ng/mL |
| B: Double-dose LPV/r w/RIF | LPV AUC in Participants Enrolled in Arms A, B, and C | 161772 hours*ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | LPV AUC in Participants Enrolled in Arms A, B, and C | 149247 hours*ng/mL |
Other Pre-specified
LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| A: Standard-dose LPV/r w/RBT | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Minimum Concentration (Cmin) | 9920 ng/mL |
| A: Standard-dose LPV/r w/RBT | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Maximum Concentration (Cmax) | 18531 ng/mL |
| B: Double-dose LPV/r w/RIF | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Maximum Concentration (Cmax) | 18138 ng/mL |
| B: Double-dose LPV/r w/RIF | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Minimum Concentration (Cmin) | 8033 ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Maximum Concentration (Cmax) | 16802 ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | LPV Cmax and Cmin in Participants Enrolled in Arms A, B, and C | Minimum Concentration (Cmin) | 8548 ng/mL |
Other Pre-specified
RAL AUC in Participants Enrolled in Arm C
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| C: Standard-Dose LPV/r + RAL w/RBT | RAL AUC in Participants Enrolled in Arm C | 11338 hours*ng/mL |
Other Pre-specified
RAL Cmax and Cmin in Participants Enrolled in Arm C
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| C: Standard-Dose LPV/r + RAL w/RBT | RAL Cmax and Cmin in Participants Enrolled in Arm C | Maximum Concentration (Cmax) | 2830 ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | RAL Cmax and Cmin in Participants Enrolled in Arm C | Minimum Concentration (Cmin) | 166 ng/mL |
Other Pre-specified
RBT AUC in Participants Enrolled in Arms A and C
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| A: Standard-dose LPV/r w/RBT | RBT AUC in Participants Enrolled in Arms A and C | 7374 hours*ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | RBT AUC in Participants Enrolled in Arms A and C | 5516 hours*ng/mL |
Other Pre-specified
RBT Cmax and Cmin in Participants Enrolled in Arms A and C
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
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| A: Standard-dose LPV/r w/RBT | RBT Cmax and Cmin in Participants Enrolled in Arms A and C | Maximum Concentration (Cmax) | 461 ng/mL |
| A: Standard-dose LPV/r w/RBT | RBT Cmax and Cmin in Participants Enrolled in Arms A and C | Minimum Concentration (Cmin) | 161 ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | RBT Cmax and Cmin in Participants Enrolled in Arms A and C | Maximum Concentration (Cmax) | 349 ng/mL |
| C: Standard-Dose LPV/r + RAL w/RBT | RBT Cmax and Cmin in Participants Enrolled in Arms A and C | Minimum Concentration (Cmin) | 115 ng/mL |