Clinical trial NCT01601626
Conditions: HIV Infection Tuberculosis
Sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Start date: 2013-07-13; Completion date: 2017-06-28
Enrollment: 71 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: 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). arm 2: 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). arm 3: 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).
Interventions: intervention 1: Standard-dose Lopinavir/Ritonavir intervention 2: Double-dose Lopinavir/Ritonavir intervention 3: Raltegravir intervention 4: Isoniazid intervention 5: Pyridoxine intervention 6: Pyrazinamide intervention 7: Ethambutol intervention 8: Rifabutin intervention 9: Rifampin
Intervention descriptions: intervention 1: Two LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry to Week 72. intervention 2: Four LPV 200 mg/RTV 50 mg fixed-dose combination tablets orally twice daily from entry through Week 72. intervention 3: One 400 mg tablet orally twice daily from entry to Week 72. intervention 4: 300 mg orally once daily from entry through Week 24. intervention 5: 25 mg orally once daily from entry to Week 24. intervention 6: 20 to 30 mg/kg orally once daily (not to exceed 2 g per day) from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants). intervention 7: 15 to 20 mg/kg orally once daily from entry through Week 8 study visit (or until completion of intensive TB treatment as determined after dose adjustment in accrual period 1 participants). intervention 8: 300 mg of rifabutin orally once until LPV/RTV is started; then the dose will be reduced to 150 mg daily from the start of LPV/RTV through Week 24. intervention 9: 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.

Protocol documents:
SAP_002.pdf: 
Filename: U:\CTgov\documentation\A5290AnalysisPlanV2_final.docx 
Directory mapping: \home\kendall\ 
Printed on: January 3, 2018 
A5290 Statistical Analysis Plan 
Version 2.0 (PK and Safety Interim Analysis) 
 
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 
 
ClinicalTrials.gov Identifier: NCT01601626 
 
7 October 2016 
 


A5290 Statistical Analysis Plan V2.0 
 
 
 
 
 
 
 
7 October 2016 
 
 
Page 2 of 10 
Table of Contents 
TABLE OF CONTENTS ............................................................................................................................... 2 
1 
INTRODUCTION .................................................................................................................................... 3 
1.1 
Purpose ........................................................................................................................................ 3 
1.2 
Closed Team Roster .................................................................................................................... 3 
1.3 
Protocol Overview ....................................................................................................................... 3 
1.4 
Study Monitoring History............................................................................................................ 4 
1.5 
PK and Safety Interim Objectives .............................................................................................. 4 
1.5.1 
PK Criteria.......................................................................................................................... 4 
1.5.2 
Safety Criteria .................................................................................................................... 4 
1.6 
PK Study Objectives ................................................................................................................... 5 
2 
STUDY CONDUCT................................................................................................................................. 5 
3 
BASELINE CHARACTERISTICS .......................................................................................................... 5 
4 
SAFETY .................................................................................................................................................. 5 
4.1 
Grade 3 or Higher Adverse Events ............................................................................................ 5 
4.2 
Study Treatment Tolerability ...................................................................................................... 6 
4.3 
Diagnoses .................................................................................................................................... 6 
4.4 
MTB-IRIS ....................................................................................................................................... 6 
4.5 
Deaths ........................................................................................................................................... 6 
5 
PHARMACOKINETICS (PK) ................................................................................................................. 7 
5.1 
PK Interim Objectives ................................................................................................................. 7 
5.1.1 
Lopinavir (LPV) .................................................................................................................. 7 
5.1.2 
Rifabutin (RBT) .................................................................................................................. 8 
5.2 
PK Study Objectives ................................................................................................................... 8 
5.2.1 
Lopinavir (LPV) .................................................................................................................. 8 
5.2.2 
Rifabutin (RBT) .................................................................................................................. 9 
5.2.3 
Raltegravir (RAL) ............................................................................................................... 9 
5.2.4 
Ritonavir (RTV) ................................................................................................................ 10 
5.3 
Adherence for PK Evaluable Participants............................................................................... 10 
6 
SUMMARY ........................................................................................................................................... 10 
 
 
 


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1 
Introduction 
1.1 
Purpose  
This statistical analysis plan has been developed to (1) facilitate discussion of the key statistical 
analysis components amongst the study team; and (2) provide agreement between the study team 
and statisticians regarding the statistical analyses to be performed. 
The plan contains details of all statistical analyses that will be completed prior to the preparation of 
the PK and Safety Interim Analysis report. 
1.2 
Closed Team Roster 
The PK and Safety Interim Analysis report will be distributed to the team members who attend the 
SMC Review.  This may include, but may not be limited to, the following team members:  Protocol 
Co-Chairs, Protocol Vice-Chair, Protocol Pharmacologist, DAIDS Clinical Representative, 
Statisticians, and Clinical Trials Specialist. 
1.3 
Protocol Overview 
A5290 is a prospective, randomized, open-label, phase 2b study comparing three lopinavir/ritonavir 
(LPV/r)-based antiretroviral (ARV) regimens among participants in high tuberculosis (TB) endemic 
resource-constrained settings undergoing treatment for TB and HIV and requiring protease inhibitor 
(PI)-based antiretroviral therapy (ART). A two accrual period design is being used, including a full 
pharmacokinetic (PK) and safety evaluation to be conducted when 54-60 participants enrolled during 
accrual period 1 have completed 28 days of ARV treatment and day 12 ± 2 (after initiation of study-
provided ART and TB medications) drug levels are available. An early assessment by the team will 
also be completed when 10-12 participants per arm have completed 28 days of ARV treatment and 
day 12 ± 2 drug levels are available. 
The study population is HIV-infected persons (male or female) at least 18 years of age with 
documented HIV infection, a clinical diagnosis of probable or confirmed active TB (including 
extrapulmonary TB) with susceptibility to rifampin (RIF), and who require a PI-based ARV regimen. 
471 participants will be randomized in a 1:1:1 ratio to receive either: 
 
Arm A 
ART: LPV 400 mg/RTV 100 mg twice daily (BID) + two NRTIs. 
Anti-TB therapy: Isoniazid (INH), rifabutin (RBT), ethambutol (EMB), pyrazinamide (PZA), and 
pyridoxine.  
After completion of TB treatment through week 72: LPV 400mg/RTV 100mg BID + two NRTIs. 
 
Arm B 
ART: LPV 800 mg/RTV 200 mg BID + two NRTIs. 
Anti-TB therapy: INH, rifampin (RIF), EMB, PZA, and pyridoxine.  
After completion of TB treatment through week 72:  LPV 400mg/RTV 100mg BID + two NRTIs.  


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 
Arm C 
ART: LPV 400 mg/RTV 100 mg BID + two NRTIs + raltegravir (RAL) 400 mg BID. 
Anti-TB therapy: INH, RBT, EMB, PZA, and pyridoxine.  
After completion of TB treatment through week 72: LPV 400mg/RTV 100mg BID + two NRTIs 
+ RAL. 
 
Accrual will place in two accrual periods.  Accrual period 1 will enroll 60 participants (20/arm) who will 
undergo an initial dose-finding period before continuing regular study follow-up.  Accrual will then be 
suspended until the last SMC review of the interim PK and safety evaluation has been completed. 
Accrual period 2 will open and randomize the remaining participants to either three arms (n=411) or to 
the remaining two arms (n=TBD) and will be monitored by the DSMB. 
Each participant will be followed until week 72. 
The primary hypothesis is that, for HIV-1-infected participants with active tuberculosis (TB) who 
require protease inhibitor (PI)-based antiretroviral therapy (ART), a standard dose LPV/r regimen, 
with or without RAL, coupled with RBT-based TB treatment is superior to a double dose LPV/r 
regimen coupled with RIF-based TB treatment. 
1.4 
Study Monitoring History 
Besides summarizing the monitoring history of A5290, a brief summary of the Early Assessment will 
be prepared specifically for this report.  The Early Assessment occurred when 10-12/arm accrual 
period 1 participants completed 28 days of ART and day 12 ± 2 (after initiation of study-provided ART 
and TB medications) PK results were available.  The report was sent to the SMC with the TDM’s 
team decision on 14 January 2016. 
1.5 
PK and Safety Interim Objectives 
1.5.1 
PK Criteria 
1) For LPV in Arm B, the primary PK parameter is the day 12 ± 2 (after initiation of study-provided 
ART and TB medications) Cmin (C12), and the acceptable lower limit value is ≥ 1 mg/L. LPV 
concentrations in Arm B will be judged acceptable if no more than three participants have a Cmin < 
1 mg/L. 
2) For RBT (Arms A and C), equivalence analyses will compare day 12 ± 2 (after initiation of study-
provided ART and TB medications) RBT 24-hour AUC and Cmax with control data derived from 
prior PK studies, as determined by whether the 90% confidence intervals of the ratios of the RBT 
concentrations (when co-administered with LPV/r) relative to daily RBT concentrations in the 
absence of LPV/r are fully contained within the pre-specified NEB of 67%-150%. RBT 
concentrations in Arms A and C will be judged acceptable if equivalence is declared according to 
these PK parameters. 


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1.5.2 
Safety Criteria 
1) No more than three participants in any treatment arm experience a Grade 3 or Grade 4 AE 
“related to study-provided drug(s)” (as deemed by the TDM Team:  DAIDS Clinical 
Representative, Protocol Co-Chairs, Protocol Vice Chair, Protocol Pharmacologist, Statisticians, 
Data Manager, Laboratory Data Manager, and Clinical Trials Specialist) by 28 days after initiation 
of study-provided ART and TB medications. 
2) No more than three participants in any treatment arm discontinue study-provided drug(s) for 
treatment-limiting toxicity or intolerance (such that PK assessments within the day 12 ± 2 [after 
initiation of study-provided ART and TB medications] window cannot be completed). 
1.6 
PK Study Objectives 
Since Accrual Period 2 will not open to enroll participants, the PK objectives outlined in the protocol will 
also be analyzed at this time. 
1) To evaluate LPV characteristics (area under the curve [AUC], maximum concentration [Cmax], 
minimum concentration [Cmin]) in participants enrolled in Arms A, B, and C, accrual periods 1 and 
2.  
2) To evaluate the RBT PK characteristics (AUC, Cmax, Cmin) in participants enrolled in Arms A and 
C, accrual periods 1 and 2. 
3) To evaluate RAL PK characteristics (AUC, Cmax, Cmin) in participants enrolled in Arm C, accrual 
period 2.   
2 
Study Conduct 
 
Table summarizing the number of participants enrolled by month and by site, by treatment arm. 
 
Table of study status categories (i.e., completed, death, etc.) by treatment arm. 
 
Table summarizing weeks from randomization to last clinic visit by treatment arm. 
3 
Baseline Characteristics 
 
Table of age, sex, race, and ethnicity by treatment arm. 
 
Table of Karnofsky performance score and body mass index (BMI) by treatment arm.  
 
Table of CD4 count and HIV RNA (log10 copy number and number below lower limit of 
quantification). 
 
Table of reason PI-based therapy was needed from eligibility checklist [Q0017-Q0018] (category 
and specific reason if category=other) by treatment arm.  
 
Table of AFB smear and mycobacterial culture results by treatment arm. 
 
Table of RIF and INH drug susceptibility testing (DST) results by treatment arm. 
 
Table summarizing days from randomization to TB treatment initiation, days from randomization 
to study-provided ARV treatment initiation, and days from TB treatment initiation to ARV 
treatment initiation by treatment arm. 


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4 
Safety 
4.1 
Grade 3 or Higher Adverse Events  
 
Table summarizing all grade 3 or higher adverse events within 28 days after study-provided ART 
and TB treatment initiation that the TDM Team deemed “related to study-provided drug(s)” or 
“probably related to study-provided drug(s)” or “possibly related to study-provided drug(s)” by 
treatment arm [Safety Criterion #1; see section 1.5.2].  
 
Table summarizing all new, post-baseline grade 2 or higher signs/symptoms and laboratory 
toxicities within 28 days after ART initiation from EVW0206 and EVW0207 forms, by type and by 
treatment arm. 
 
Table summarizing all grade 3 or higher adverse events beyond 28 days after study-provided 
ART and TB treatment initiation that the TDM Team deemed “related to study-provided drug(s)” 
or “probably related to study-provided drug(s)” or “possibly related to study-provided drug(s)” by 
treatment arm  
 
Table summarizing all new, post-baseline grade 2 or higher signs/symptoms and laboratory 
toxicities beyond 28 days after ART initiation from EVW0206 and EVW0207 forms, by type and 
by treatment arm. 
4.2 
Study Treatment Tolerability 
 
Table summarizing discontinuations of study-provided drugs within 28 days after study-provided 
ART and TB treatment initiation by treatment arm [Safety Criterion #2; see section 1.5.2].  
 
Table summarizing discontinuations of study-provided drugs beyond 28 days after study-provided 
ART and TB treatment initiation by treatment arm. 
4.3 
Diagnoses 
 
Table summarizing all new, post-baseline diagnoses by treatment arm. 
 
Table summarizing of all new, post-baseline primary diagnoses of grade 3+ and primary 
diagnoses that had grade 3+ associated signs, symptoms, and laboratory abnormalities from 
EVW0206 and EVW0207 forms, by type, with associated signs/symptoms and laboratory 
abnormalities by treatment arm. 
4.4 
MTB-IRIS 
 
Table summarizing MTB-IRIS diagnoses with time from TB treatment initiation, grade, and time to 
resolution, if available, by treatment arm. 
 
Table summarizing the MTB-IRIS diagnoses, with associated signs/symptoms and laboratory 
abnormalities by treatment arm. 


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4.5 
Deaths 
 
Table summarizing the primary and contributing causes of death with time from study-provided 
ART and TB medications initiation and attribution to study drug, by treatment arm. 
 
 


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5 
Pharmacokinetics (PK) 
 
Notes:   
o 
These analysis programs will require validation (successful execution).  Verification that the 
programs correctly determined the PK evaluable participants will be done by comparing lists 
with the pharmacology lab.  
o 
For analysis, the LDMS analcd for each drug was as follows:  LPV=131, RBT=116, 
desRBT=216, RAL=770, and RTV=114. 
o 
Study participants will be included in the analyses of the PK interim and the PK study 
objectives based on the following criteria: 
 
There were no missed doses of any TB or HIV medication on the day prior to the PK 
study; and 
 
The pharmacology lab did not determine the participant unevaluable based on the 
participant’s PK profile. 
 
For the PK interim objectives, the following additional criteria were required: 
o 
The LPV C12 was not BLQ; and 
o 
The RBT pre-dose concentration was not BLQ. 
o 
From the Protocol Pharmacologist:  In the comparison of the RBT PK parameters with the 
Naiker paper, a comment about Clast vs. Cmin.  These PK parameters are subject to some 
imprecision in use.  Clast is the last measured concentration.  For RBT in A5290, that is at 24 
hours post dose.  Cmin by definition is the minimum concentration observed.  While that 
usually occurs right before the next dose is given, it doesn’t always.  There are drugs, for 
example, where a lag phase is seen after the dose is taken and concentrations can actually 
go down for a short time after dose intake until absorption starts.  So, Cmin is not necessarily 
the same as Clast and we saw this in A5290.  There were some PIDs (e.g., 1211756) where 
the 2 hour post dose concentration was lower than the pre-dose concentration.   Thus, that 
2 hour value would be the Cmin, and the Clast value would be that obtained at 24 hours, 
which for the PID I mentioned, is higher than the 2 hour concentration.  In the RBT PK file 
that I transferred, I included values for both Clast and Cmin.  In the Naiker paper, Table 1, 
they provide Cmin but define it as at 24h or 48 hours, thus, they are really defining their Cmin 
as a Clast.  In my summary table that I sent where I provided historical comparisons, you will 
see then that I showed the Naiker Cmin values as being compared with our Clast, because 
their Cmin is really a Clast.   
 
Table summarizing the reasons why PK samples were not collected strictly within the time frame 
specified in the protocol by treatment arm. 
5.1 
PK Interim Objectives 
5.1.1 
Lopinavir (LPV) 
 
Note:  The LPV PK interim analysis will be analyzed in Arm B only. 


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 
Table summarizing the number of participants excluded from the LPV interim PK analysis with 
reasons. 
 
Table summarizing the number of participants in Arm B whose Cmin is <1 mg/L.  LPV 
concentrations in Arm B will be judged acceptable if no more than three participants have a Cmin 
<1 mg/L. [PK Criterion #1; see section 1.5.1]. 
 
Table summarizing the number of participants in Arm B whose Cmin is <1 mg/L, including those 
participants the pharmacologist deemed PK-evaluable (based on the participants’ plasma LPV 
concentrations).  LPV concentrations in Arm B will be judged acceptable if no more than three 
participants have a Cmin <1 mg/L. [PK Criterion #1; see section 1.5.1]. 
 
Table of Cmin and Cmax values for participants meeting the LPV PK criterion of Cmin <1 mg/mL. 
5.1.2 
Rifabutin (RBT) 
 
Note:  Only Arms A and C will be included. 
 
Table summarizing the number of participants excluded from the RBT PK interim analysis with 
reasons by treatment arm. 
 
Table summarizing the comparison of the RBT AUC and Cmax to historical controls (Sekar) with 
ratios and 90% confidence intervals around the ratios by treatment arm.  RBT concentrations in 
Arms A and C will be judged acceptable if the 90% confidence intervals of the ratios of the RBT 
concentrations (when co-administered with LPV/r) relative to daily RBT concentrations in the 
absence of LPV/r are fully contained within the pre-specified NEB of 67%-150%. [PK Criterion #2; 
see section 1.5.1]. 
 
Table summarizing the comparison of the RBT AUC and Cmax pooled over Arms A and C to 
historical controls (Sekar) with ratios and 90% confidence intervals around the ratios.  RBT 
concentrations in this analysis will be judged acceptable if the 90% confidence interval of the ratio 
of the RBT concentrations (when co-administered with LPV/r) relative to daily RBT concentrations 
in the absence of LPV/r is fully contained within the pre-specified NEB of 67%-150%.  [PK 
Criterion #2; see section 1.5.1].  
 
Table summarizing the comparison of the RBT AUC and Cmax pooled over Arms A and C and 
including those participants the pharmacologist deemed PK-evaluable (based on the participants’ 
plasma RBT concentrations) to historical controls (Sekar) with ratios and 90% confidence 
intervals around the ratios.  RBT concentrations in this analysis will be judged acceptable if the 
90% confidence interval of the ratio of the RBT concentrations (when co-administered with LPV/r) 
relative to daily RBT concentrations in the absence of LPV/r is fully contained within the pre-
specified NEB of 67%-150%.  [PK Criterion #2; see section 1.5.1]. 
5.2 
PK Study Objectives 
5.2.1 
Lopinavir (LPV) 
 
Note:  The historical controls are Umeh, Schöller-Gyüre, Ngoc Lan, Naiker, and Matteelli. 


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 
Table summarizing the number of participants excluded from the LPV PK analysis with reasons by 
treatment arm. 
 
Table summarizing the LPV PK parameters (all available) with sample size, mean, standard 
deviation, coefficient of variation, median, and quartiles by treatment arm, with Wilcoxon p-values. 
 
Table summarizing the LPV PK parameters (AUC, Cmax, Cmin, Clast) with sample size, mean, 
standard deviation, coefficient of variation, median, and quartiles by Arm B versus pooled Arms A 
and C, with Wilcoxon p-values [PK Study Objective #1; see section 1.6]. 
 
Figure of A5290 and historical control LPV PK parameters (AUC, Cmax, Cmin, Clast).  A5290 data 
will be pooled over all arms and each historical control will be plotted separately [PK Study 
Objective #1; see section 1.6].   
 
Table summarizing the comparison of LPV PK parameters (AUC, Cmax, Cmin, Clast) to historical 
controls, with Wilcoxon p-values.  A5290 data will be pooled over all arms and each historical 
control will be tested separately [PK Study Objective #1; see section 1.6]. 
5.2.2 
Rifabutin (RBT) 
 
Note:  The historical controls are Sekar, Ngoc Lan, and Naiker. Only Arms A and C will be 
included. 
 
Table summarizing the number of participants excluded from the RBT PK interim analysis with 
reasons by treatment arm. 
 
Table summarizing the RBT PK parameters (all available) with sample size, mean, standard 
deviation, coefficient of variation, median, and quartiles by treatment arm, with Wilcoxon test p-
values [PK Study Objective #2; see section 1.6]. 
 
Figure of A5290 and historical control RBT PK parameters (AUC, Cmax, Clast). A5290 data will be 
pooled over both arms and each historical control will be plotted separately [PK Study Objective 
#2; see section 1.6].   
 
Table summarizing the comparison of RBT PK parameters (AUC, Cmax, Clast) to historical controls, 
with Wilcoxon p-values.  A5290 data will be pooled over both arms and each historical control will 
be tested separately [PK Study Objective #2; see section 1.6]. 
 
Table summarizing the desacetyl RBT PK parameters (all available) with sample size, mean, 
standard deviation, coefficient of variation, median, and quartiles by treatment arm, with Wilcoxon 
test p-values [PK Study Objective #2; see section 1.6]. 
 
Figure of A5290 and historical control desRBT PK parameters (AUC, Cmax, Clast). A5290 data will 
be pooled over both arms and each historical control will be plotted separately [PK Study 
Objective #2; see section 1.6].   
 
Table summarizing the comparison of desRBT PK parameters (AUC, Cmax, Clast) to historical 
controls, with Wilcoxon p-values.  A5290 data will be pooled over both arms and each historical 
control will be tested separately [PK Study Objective #2; see section 1.6]. 


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5.2.3 
Raltegravir (RAL) 
 
Note:  The historical controls are Rizk and Brainard.  Only Arm C will be included. 
 
Table summarizing the number of participants excluded from the RAL analysis with reasons. 
 
Table summarizing the RAL PK parameters (all available) with sample size, mean, standard 
deviation, coefficient of variation, median, and quartiles. 
 
Figure of A5290 and historical control RAL PK parameters (AUC, Cmax, Clast).  Each historical 
control will be plotted separately [PK Study Objective #3; see section 1.6]. 
 
Table summarizing the comparison of RAL PK parameters (AUC, Cmax, Clast) to historical controls, 
with Wilcoxon p-values.  Each historical control will be tested separately [PK Study Objective #3; 
see section 1.6]. 
5.2.4 
Ritonavir (RTV)  
 
Note:  The historical controls are Umeh, Schöller-Gyüre, and Ngoc Lan. 
 
Table summarizing the number of participants excluded from the RBT analysis with reasons by 
treatment arm. 
 
Table summarizing the RTV PK parameters (all available) with sample size, mean, standard 
deviation, coefficient of variation, median, and quartiles by treatment arm, with Wilcoxon p-values. 
 
Figure of A5290 and historical control RTV PK parameters (AUC, Cmax, Cmin, Clast).  A5290 data 
will be pooled over all arms and each historical control will be plotted separately.   
 
Table summarizing the comparison of RTV PK parameters (AUC, Cmax, Cmin, Clast) to historical 
controls, with Wilcoxon p-values.  A5290 data will be pooled over all arms and each historical 
control will be tested separately. 
5.3 
Adherence for PK Evaluable Participants 
 
Table summarizing adherence by treatment arm. 
6 
Summary  
The summary will include whether the PK and safety interim criteria were judged to be acceptable 
(see section 1.5).  It will also discuss the PK study objectives and other safety analyses/summaries. 
 

Prot_ICF_003.pdf: 
 
 
A5290 
 
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 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
DAIDS ES # 11703 
 
 
This file contains the current ACTG A5290 protocol, which 
includes the following documents, presented in reverse 
chronological order:  
 
 Clarification Memorandum #1, dated 18 April 2013  
 Protocol Version 1.0, dated 31 January 2012  


 
Clarification Memorandum #1 
          Page 1 of 2 
18 April 2013 
ACTG A5290 Protocol Version 1.0 
Clarification Memorandum #1 for: 
 
ACTG A5290 
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 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
DAIDS ES # 11703 
 
Clarification Memo Date: 18 April 2013 
 
 
This clarification memo is being issued primarily to allow the study to open as quickly as 
possible (ie, before requiring that 4-5 sites are ready to implement the study) (see item #4 
below). This change is being made to ensure the feasibility of the current plan for shipment and 
testing of samples and the near real-time reporting of results (see protocol section 6.3.11). 
Implementation of this plan at a slightly slower pace than would be expected if 4-5 sites began 
enrolling at the same time will allow for rapid correction of any issues that arise.  
 
In addition, this memo includes clarifications related to the requirement for rifampin resistance 
testing (item #1) and to the window for reporting use of certain prescription drugs (item #2), and 
to remove mention of the FDA in several instances where it is not required (item #3). 
 
 
The following are the specific clarifications to individual sections of protocol A5290, Version 1.0, 
02/17/12: 
 
 
1. Note A in section 4.2.3 should be understood to read as shown below: 
 
NOTE A:  All specimens available at entry should be tested for RIF resistance. 
Participants Candidates who meet entry criterion 4.1.3 may be enrolled 
even if no specimens are available or pending the results of RIF drug 
susceptibility testing if by a rapid HAIN GenoType MTBDR Plus line probe 
assay, GeneXpert® MTB/RIF assay, or other rapid MTB RIF drug resistance 
assay result is not yet available. However, if RIF drug-susceptibility test results 
are not available within 60 days after study entry or if any drug susceptibility 
testing subsequently demonstrates RIF resistance, participants will be 
discontinued from the study and referred to their primary clinician/clinical 
facility or TB and ART program and treated with the best available TB and 
ART according to local standards of care. 
 


 
Clarification Memorandum #1 
          Page 1 of 2 
18 April 2013 
ACTG A5290 Protocol Version 1.0 
2. In section 6.3.4, the timeframe for reporting ‘Prescription drugs for treatment of 
opportunistic infections’ should be ‘Within 30 days prior to study entry’ in the 
Medication History table (5th row below headers, 2nd column). The current ‘Complete 
history’ should be deleted. 
 
3. In sections 8.3 (final bullet), 11.3.2, 12.2, and 12.3, references to the US Food and Drug 
Administration (or FDA) are no longer applicable because A5290 is a non-IND study. 
Sites may also remove mention of the FDA from the informed consents’ sections on 
confidentiality.  
 
4. In section 9.4.3, Overall accrual, the first paragraph should be understood to read as 
shown below: 
 
Accrual period 1 will open as soon as the first registered site is ready to enroll 
participants. Once at least 4-5 sites have all regulatory approvals completed and are 
ready to enrolling participants, immediately. The team estimates that these 4-5 sites 
should be able to accrue approximately 4-6 3-5 participants should be enrolled per 
month per site, and . As other sites begin accrual period 1, the team anticipates that full 
enrollment for accrual period 1 (n=60) should be completed within approximately 2-4 
months. 
 
 
 
 
 
 
 


 
A5290 
 
 
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 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
Sponsored by: 
 
The National Institute of Allergy 
and Infectious Diseases 
 
 
Pharmaceutical Support Provided by: 
 
Abbott Laboratories 
Merck & Co., Inc. 
Pfizer, Inc.  
 
IND # 
 
 
 
 
 
The ACTG Tuberculosis Transformative  
Science Group: 
 
 
 
 
Richard Chaisson, MD, Chair     
 
 
Protocol Co-Chairs:  
 
 
 
Constance A. Benson, MD 
 
 
 
 
 
 
 
Umesh Gangaram Lalloo, MD, FRCP 
 
 
 
Protocol Vice Chair: 
Prudence Ive, FCP  
 
 
DAIDS Clinical Representative: 
Jing Bao, MD, PhD 
 
 
Clinical Trials Specialist: 
Katharine J. Bergstrom, MS, CCRP 
 
 
 
FINAL Version 1.0 
January 31, 2012 
 


 
 
A5290 
FINAL Version 1.0 
 
 
01/31/12 
 
 
CONTENTS 
 
 
Page 
 
SITES PARTICIPATING IN THE STUDY .................................................................................... 4 
PROTOCOL TEAM ROSTER ..................................................................................................... 5 
STUDY MANAGEMENT ............................................................................................................. 8 
GLOSSARY OF TERMS ........................................................................................................... 10 
SCHEMA .................................................................................................................................. 12 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 15 
1.1 
Hypothesis ......................................................................................................... 15 
1.2 
Primary Objective ............................................................................................... 15 
1.3 
Secondary Objectives ........................................................................................ 15 
1.4 
Tertiary Objective ............................................................................................... 16 
2.0 
INTRODUCTION ........................................................................................................... 16 
2.1 
Background ........................................................................................................ 16 
2.2 
Rationale ........................................................................................................... 23 
3.0 
STUDY DESIGN ........................................................................................................... 23 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 29 
4.1 
Inclusion Criteria ................................................................................................ 29 
4.2 
Exclusion Criteria ............................................................................................... 32 
4.3 
Study Enrollment Procedures............................................................................. 34 
4.4 
Coenrollment Guidelines .................................................................................... 35 
5.0 
STUDY TREATMENT ................................................................................................... 35 
5.1 
Regimens, Administration, and Duration ............................................................ 35 
5.2 
Study Product Formulation and Preparation ....................................................... 41 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 41 
5.4 
Concomitant Medications ................................................................................... 42 
5.5 
Adherence Assessment ..................................................................................... 43 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 44 
6.1 
Schedule of Events ............................................................................................ 44 
6.2 
Timing of Evaluations ......................................................................................... 46 
6.3 
Instructions for Evaluations ................................................................................ 48 
7.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 56 
7.1 
Toxicity Management ......................................................................................... 57 
7.2 
Specific Management of Toxicities Related to Study-Provided Drugs ................ 57 
7.3 
Pregnancy and Breastfeeding ............................................................................ 61 
8.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 62 
8.1 
Permanent ARV Treatment Discontinuation ....................................................... 62 
8.2 
Permanent TB Treatment Discontinuation ......................................................... 62 


 
 
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8.3 
Premature Study Discontinuation ....................................................................... 63 
9.0 
STATISTICAL CONSIDERATIONS ............................................................................... 63 
9.1 
General Design Issues ....................................................................................... 63 
9.2 
Primary Endpoints .............................................................................................. 63 
9.3 
Randomization and Stratification ........................................................................ 65 
9.4 
Sample Size and Accrual ................................................................................... 66 
9.5 
Monitoring .......................................................................................................... 68 
9.6 
Analyses ............................................................................................................ 74 
10.0 
PHARMACOLOGY PLAN .............................................................................................. 76 
10.1 
Pharmacology Objectives .................................................................................. 76 
10.2 
Pharmacology Study Design for the Dose-Finding Study in Accrual Period 1 
Participants ........................................................................................................ 76 
10.3 
Primary and Secondary Data, Modeling, and Data Analysis for the Dose-Finding 
Study in Accrual Period 1 Participants ............................................................... 78 
10.4 
Anticipated Outcomes for the Dose-Finding Study in Accrual Period 1 
Participants ........................................................................................................ 79 
10.5 
Population Pharmacokinetic Study Design in Participants Enrolled During Accrual 
Period 2 ............................................................................................................. 79 
10.6 
Primary and Secondary Data, Modeling, and Data Analysis for the Population PK 
Study in Accrual Period 2 Participants ............................................................... 80 
10.7 
Anticipated Outcomes in the Population PK Study in Accrual Period 2 
Participants ........................................................................................................ 81 
11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING ........ 82 
11.1 
Records to Be Kept ............................................................................................ 82 
11.2 
Role of Data Management ................................................................................. 82 
11.3 
Clinical Site Monitoring and Record Availability .................................................. 82 
11.4 
Expedited Adverse Event Reporting to DAIDS ................................................... 82 
12.0 
HUMAN PARTICIPANTS .............................................................................................. 84 
12.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 84 
12.2 
Participant Confidentiality ................................................................................... 84 
12.3 
Study Discontinuation ........................................................................................ 84 
13.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 84 
14.0 
BIOHAZARD CONTAINMENT ...................................................................................... 85 
15.0 
REFERENCES .............................................................................................................. 86 
 
APPENDIX I: SAMPLE INFORMED CONSENT FOR ACCRUAL PERIOD 1 (1st ENROLLMENT 
PERIOD) 
 
APPENDIX II: SAMPLE INFORMED CONSENT FOR ACCRUAL PERIOD 2 (2nd 
ENROLLMENT PERIOD)


 
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SITES PARTICIPATING IN THE STUDY 
 
A5290 is a multicenter study open to non-US clinical research sites (CRSs). 
 
At least one research nurse responsible for the conduct of the study at each participating site 
must complete the "PK Tutorial: Pharmacology Study Conduct – Its Impact on PK-PD 
Analyses.” The tutorial is accessible from the Frontier Science and Technology Research 
Foundation web site at www.fstrf.org (either via the “ACTG Data Management” portal or the 
“Clinical Pharmacology Quality Assurance Program” portal). 
 
 
 
 
 


 
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PROTOCOL TEAM ROSTER 
 
Co-Chairs 
Constance A. Benson, MD 
Division of Infectious Diseases  
Antiviral Research Center 
UCSD AVRC CRS 
200 W. Arbor Drive 
Mail Code 8208 
San Diego, CA 92103-8208 USA 
Phone: (619) 543-8080 
FAX: (619) 543-5066 
E-Mail: cbenson@ucsd.edu 
 
Umesh Gangaram Lalloo, MD, FRCP 
Nelson R. Mandela School of Medicine 
DDMRI Building - 3rd floor, Room 302 
719 Umbilo Road 
Durban, KwaZulu Natal 4001 
SOUTH AFRICA 
Phone: 002 731 260 4669 
FAX: 011 273 126 4411 
E-Mail: lalloo@ukzn.ac.za 
 
Vice Chair 
Prudence Ive, FCP 
CHRU, Helen Joseph Hospital 
University of Witwatersrand 
Perth Road, Westdene 
Johannesburg, Gauteng 2042 
SOUTH AFRICA 
Phone: (271) 127-68800 
FAX: (271) 148-22130 
E-Mail: pive@witshealth.co.za 
 
DAIDS Clinical Representative 
Jing Bao, MD, PhD 
Tuberculosis Clinical Research Team  
DAIDS, NIAID, NIH 
6700-A Rockledge Drive, Room 42A129 
Bethesda, MD  20892-7605 USA 
Phone: (301) 896-4041 
FAX: (301) 896-0315 
E-Mail: baoj@mail.nih.gov 
 
Clinical Trials Specialist 
Katharine J. Bergstrom, MS, CCRP 
ACTG Operations Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 USA 
Phone: (301) 628-3389 
FAX: (301) 628-3302 
E-Mail: kbergstrom@s-3.com 
 
Senior Statistician 
Michelle A. Kendall, MS 
Harvard School of Public Health 
Statistical & Data Analysis Center 
FXB Building, Room 545A 
651 Huntington Avenue 
Boston, MA 02115 USA 
Phone: (617) 432-3869 
FAX: (617) 432-3163 
E-Mail: kendall@sdac.harvard.edu 
 
Statistician 
Shirley (Xingye) Wu, MS  
Harvard School of Public Health 
Statistical & Data Analysis Center 
FXB Building, Room 601 
651 Huntington Avenue 
Boston, MA 02115 USA 
Phone: (617) 432-1115 
FAX: (617) 432-2843 
E-Mail: xwu@sdac.harvard.edu 
 
Data Manager 
Susan Owens, RN, MS 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226-1056 USA 
Phone: (716) 834-0900 x7267 
FAX: (716) 834-8675 
E-Mail: owens@fstrf.org 
 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
01/31/12 
 
DAIDS Pharmacist 
Ruth Ebiasah, PharmD, MS, RPh 
Pharmaceutical Affairs Branch 
DAIDS, NIAID, NIH 
6700-B Rockledge Drive, Room 4223 
Bethesda, MD 20817 USA 
Phone: (301) 402-0128 
FAX: (301) 402-1506 
E-Mail: ebiasahrp@niaid.nih.gov 
 
Pharmacologist 
Courtney V. Fletcher, PharmD  
College of Pharmacy 
University of Nebraska Medical Center 
986000 Nebraska Medical Center  
Omaha, NE 68198-6000 USA 
Phone: (402) 559-4333  
FAX: (402) 449-5060  
E-Mail: cfletcher@unmc.edu 
 
Virologist 
Carole Wallis, MScMED, PhD 
Lancet/BARC Laboratories 
Molecular Pathology 
Lancet Laboratories 
Lancet Corner 
Corner of Stanley and Menton 
Richmond 
Johannesburg, Gauteng 2193 
SOUTH AFRICA 
Phone: (27)11-358-0816  
FAX: (27)11-242-7261 
E-Mail: carole.wallis@lancet.co.za 
 
Investigator 
William Burman, MD 
University of Colorado Health Sciences 
Center 
Denver Public Health Department 
605 Bannock Street, Room 240 
Denver, CO 80204-7211 USA  
Phone: (303) 436-7200 
FAX: (303) 436-7211 
E-Mail: bburman@dhha.org 
 
Field Representatives 
Suzanne Fiorillo, MSPH  
University of Colorado Hospital CRS 
Academic Office 1, MS 8205 
12631 East 17th Avenue 
Aurora, CO 80045 USA 
Phone: 303-724-5931 
FAX: 303-724-0802  
E-Mail: suzanne.fiorillo@ucdenver.edu 
 
Beverly Putnam, RN, ANP  
University of Colorado Hospital CRS 
Academic Office 1, MS 8205 
12631 East 17th Avenue 
P.O. Box 6511  
Aurora, CO 80045 USA 
Phone: (303) 724-0762  
FAX: (303) 724-0802  
E-Mail: beverly.putnam@ucdenver.edu 
  
Laboratory Technologist 
Joan Dragavon, MLM, M(ASCP) 
Retrovirus Laboratory 
University of Washington 
Research & Training Building 
Room 725, 300 9th Avenue 
Seattle, WA 98104-2499 USA 
Phone: (206) 897-5210 
FAX:  (206) 897-5237 
E-Mail: dragavon@u.washington.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Nickson Chepkwony  
Walter Reed Project - Kenya Medical 
Research Institute Kericho  
P.O. Box 1893-20200  
Kericho 20200 
KENYA 
Phone: 254-722297234 
E-Mail: chepkwonick@yahoo.com 
 


 
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PROTOCOL TEAM ROSTER (Cont'd) 
01/31/12 
 
Industry Representatives 
Ronald D. D'Amico, DO, MSc 
Medical Affairs, Virology 
Global Pharmaceutical R&D 
Abbott Laboratories 
237 West 15th Street, Apartment 2B 
New York, NY 10011 USA 
Phone: (224) 637-0510 
E-Mail : ronald.damico@abbott.com 
 
Randi Leavitt, MD 
Infectious Diseases-Clinical Research 
Merck & Co., Inc. 
Mail stop UG3D-305  
351 N. Sumneytown Pike 
P.O. Box 1000 
North Wales, PA 19454-2505 USA 
Phone: (267) 305-7518  
FAX: (267) 305-6530  
E-mail: randi_leavitt@merck.com 
 
Simon Portsmouth, MD, FRCP 
Pfizer, Inc.  
219-8 # 30 
Mail stop 219-08-02 
235 East 42nd Street 
New York, NY 10017 USA 
Phone: (212) 733-9913 
FAX: (212) 309-4873 
E-mail: Simon.Portsmouth@pfizer.com 
 
Laboratory Data Coordinators 
Jimi Tutko, BS 
Frontier Science & Technology Research 
Foundation, Inc.  
4033 Maple Road 
Amherst, NY 14226 USA 
Phone: (716) 834-0900 x7382 
FAX: (716) 833-0655 
E-Mail: tutko@fstrf.org 
 
Laboratory Data Coordinators (Cont'd) 
Derek A. Weibel 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 USA 
Phone: (716) 834-0900 
FAX: (716) 833-0655 
E-Mail: weibel@fstrf.org 
 
International Program Specialist  
Christina Blanchard-Horan, PhD, MA, 
CCRP 
ACTG Operations Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD 20910-3714 USA 
Phone: (301) 628-3000 
FAX: (301) 628-3302 
E-Mail: cblanchardhoran@s-3.com 
  
 


 
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STUDY MANAGEMENT 
 
All questions concerning this protocol should be sent to actg.teamA5290@fstrf.org via e-mail. 
The appropriate team member will respond with a "cc" to actg.teamA5290@fstrf.org. A 
response should generally be received within 24 hours (Monday-Friday). 
 
Protocol E-mail Group 
Sites registering to this study must contact the Computer Support Group at the Data 
Management Center (DMC) to have the relevant personnel at the site added to the 
actg.protA5290 email group. Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org. 
 
Clinical Management  
For questions concerning entry criteria, toxicity management, concomitant medications, and 
coenrollment, contact the protocol co-chairs. Send an e-mail message to 
actg.coreA5290@fstrf.org (ATTN: Constance Benson and Umesh Lalloo). Include the protocol 
number, patient identification number (PID), and a brief relevant history. 
 
Laboratory 
For questions specifically related to virologic or pharmacologic laboratory tests, contact the 
protocol virologist or pharmacologist. Send an e-mail message to actg.coreA5290@fstrf.org 
(ATTN: Carole Wallis or Courtney Fletcher). 
 
Data Management 
For nonclinical questions about transfers, inclusion/exclusion criteria, case report forms (CRF), 
the CRF schedule of events (SOE), randomization, delinquencies, and other data management 
issues, contact the data manager.  
• 
For transfers, reference the Patient Transfer from Site to Site SOP 119, and contact Susan 
Owens directly.  
• 
For other questions, send an e-mail message to actg.coreA5290@fstrf.org (ATTN: Susan 
Owens).   
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization 
For randomization questions or problems and study identification number SID lists.  
• 
Send an e-mail message to rando.support@fstrf.org. Call the Statistical and Data Analysis 
Center (SDAC)/DMC Randomization Desk at (716) 898-7301.    
 
Computer and Screen Problems  
Contact the SDAC/DMC programmers. 
• 
Send an e-mail message to actg.support@fstrf.org or call (716) 834-0900 x7302. 
 
Protocol Document Questions 
For questions concerning the protocol document, contact the clinical trials specialist. Send an e-
mail message to actg.teamA5290@fstrf.org (ATTN: Katharine Bergstrom). 
 


 
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STUDY MANAGEMENT (Cont'd) 
01/31/12 
 
Copies of the Protocol 
To request hard copies of the protocol, send a message to ACTGOpsCenter@s-3.com (ATTN: 
Diane Delgado) via e-mail. Electronic copies can be downloaded from the ACTG Web site 
(https://www.actgnetwork.org). 
 
Product Package Inserts or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call (301) 897-1708. 
 
Protocol Registration 
For protocol registration questions: 
• 
Send an e-mail message to Protocol@tech-res.com or call (301) 897-1707.  
 
Study Drug 
For questions or problems regarding study drug, dose, supplies, records, and returns, call Ruth 
Ebiasah, protocol pharmacist, at (301) 496-8213. 
 
IND (Investigational New Drug) Number or Questions  
Contact the DAIDS RSC at Regulatory@tech-res.com or call (301) 897-1706. 
 
Study Drug Orders 
Call the Clinical Research Products Management Center at (301) 294-0741. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or (301) 897-1709; or fax 1-800-275-7619 or (301) 897-1710.  
 
Phone Calls 
Sites are responsible for documenting any phone calls made to protocol team members. Send 
an e-mail to actg.teamA5290@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information concerning study management of ACTG studies can be found on the 
ACTG Web page.


 
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GLOSSARY OF TERMS 
 
AFB 
 
acid fast bacilli 
ALT 
 
alanine aminotransferase 
ANC 
 
absolute neutrophil count 
AST 
 
aspartate aminotransferase 
ATV 
 
atazanavir 
AUC 
 
area under the concentration curve 
BID 
 
twice daily 
BLQ 
 
below the limit of quantitation 
BMI 
 
body mass index 
C12h 
 
12-hour post dose plasma concentration  
C24h  
 
24-hour post dose plasma concentration  
CI 
 
confidence interval 
CL/F 
 
apparent oral clearance 
Cmax 
 
maximum plasma concentration 
Cmin 
 
minimum plasma concentration 
CSF   
cerebrospinal fluid 
CT 
 
computed tomography 
DOT   
directly observed therapy 
EFV 
 
efavirenz  
EMB 
 
ethambutol 
GMR   
geometric mean ratio 
t½ 
 
half life 
INH 
 
isoniazid 
IRIS 
 
immune reconstitution inflammatory syndrome 
LPV 
 
lopinavir 
LPV/r  
lopinavir/ritonavir 
MDR TB 
multidrug-resistant tuberculosis (TB), defined as TB with demonstrated  
 
 
 
resistance to rifampin (RIF) and isoniazid (INH) 
MIC 
 
minimum inhibitory concentration 
MTB 
 
Mycobacterium tuberculosis 
NVP 
 
nevirapine 
OI 
 
opportunistic infection 
PBMC  
peripheral blood mononuclear cells 
PZA 
 
pyrazinamide  
q12h  
every 12 hours 
RAL 
 
raltegravir 
RBT 
 
rifabutin 
RIF 
 
rifampin 


 
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GLOSSARY OF TERMS (Cont'd) 
01/31/12 
 
RNA 
 
ribonucleic acid 
RTV 
 
ritonavir 
TB 
 
tuberculosis 
TIW 
 
three times weekly 
Tmax 
 
time to maximum plasma concentration 
UGT1A1  
UDP-glucuronosyltransferase 1A1 
ULN 
 
upper limit of normal 
XDR 
extensively drug resistant TB, defined as TB with demonstrated resistance to 
RIF, INH, plus resistance to fluroroquinolones, and to at least one second-line 
injectable anti-TB drug (e.g., amikacin, kanamysin, or capreomycin) 
 


 
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SCHEMA 
 
 
A5290 
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 
 
DESIGN 
A5290 is a prospective, randomized (1:1:1), open-label, phase 2b study 
comparing three lopinavir/ritonavir (LPV/r)-based antiretroviral (ARV) 
regimens among participants in high tuberculosis (TB) endemic resource-
constrained settings undergoing treatment for confirmed or probable TB 
and requiring protease inhibitor (PI)-based antiretroviral therapy (ART). A 
two accrual period design will be used, including a full pharmacokinetic 
(PK) and safety evaluation to be conducted when 54-60 participants 
enrolled during the accrual period 1 have completed 28 days of ARV 
treatment and day 12 ± 2 (after initiation of ART) drug levels are available 
(an early interim PK and safety evaluation will also be completed when 
10-12 participants per arm have completed 28 days of ARV treatment and 
day 12 ± 2 drug levels are available). 
 
DURATION 
Each participant will be followed until week 72.  
 
SAMPLE SIZE 
471 participants. 
 
POPULATION 
HIV-infected persons (male or female) at least 18 years of age with 
documented HIV infection, a clinical diagnosis of probable or confirmed 
active TB (including extrapulmonary TB) with susceptibility to rifampin 
(RIF), and who require a PI-based ARV regimen.  
 
REGIMENS 
Study-provided drugs include lopinavir/ritonavir (LPV/r), ritonavir (RTV), 
raltegravir (RAL), and rifabutin (RBT). 
 
Arm A 
• 
ART: LPV 400 mg/RTV 100 mg twice daily (BID) + two NRTIs. 
• 
Anti-TB therapy: Isoniazid (INH) 300 mg daily, RBT 300 mg daily, then 
150 mg daily upon initiation of ART, ethambutol (EMB) (weight-based 
dose) daily, pyrazinamide (PZA) (weight-based dose) daily, and 
pyridoxine 25 mg daily. EMB and PZA will be discontinued after 8 
weeks of treatment (after completion of the intensive TB treatment 
phase); INH, RBT 150 mg daily (or the adjusted dose determined by 
PK testing), and pyridoxine will continue through week 24 for a 
minimum total duration of 24 weeks, and may continue beyond 24 
weeks to a maximum of 48 weeks at the discretion of the primary 
clinician; the protocol core team must be notified 
(actg.corea5290@fstrf.org) if TB treatment is continued beyond 24 
weeks. 


 
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SCHEMA (Cont'd) 
01/31/12 
 
• 
After completion of TB treatment, LPV/r + two NRTIs will be continued 
with LPV/r at standard dosing (400mg/100mg BID) through week 72. 
 
Arm B 
• 
ART: LPV 800 mg/RTV 200 mg BID + two NRTIs. 
• 
Anti-TB therapy: INH 300 mg daily, rifampin (RIF) (weight-based 
dose) daily, EMB (weight-based dose) daily, PZA (weight-based dose) 
daily, and pyridoxine 25 mg daily. EMB and PZA will be discontinued 
after 8 weeks of treatment (after completion of the intensive TB 
treatment phase); INH, RIF, and pyridoxine will continue through week 
24 for a minimum total duration of 24 weeks, and may be continued 
beyond 24 weeks to a maximum of 48 weeks at the discretion of the 
primary clinician; the protocol core team must be notified 
(actg.corea5290@fstrf.org) if TB treatment is continued beyond 24 
weeks.   
• 
After completion of TB treatment, LPV/r + two NRTIs will be continued 
with LPV/r at standard dosing (400mg/100mg BID) through week 72. 
 
Arm C 
• 
ART: LPV 400 mg/RTV 100 mg BID + two NRTIs + RAL 400 mg BID. 
• 
Anti-TB therapy: INH 300 mg daily, RBT 300 mg daily, then 150 mg 
daily upon initiation of ART, EMB (weight-based dose) daily, PZA 
(weight-based dose) daily, and pyridoxine 25 mg daily. EMB and PZA 
will be discontinued after 8 weeks of treatment (after completion of the 
intensive TB treatment phase); INH, RBT 150 mg daily (or the 
adjusted dose determined by PK), and pyridoxine will be continued 
through week 24 for a minimum total duration of 24 weeks, and may 
be continued beyond 24 weeks to a maximum of 48 weeks at the 
discretion of the primary clinician; the protocol core team must be 
notified (actg.corea5290@fstrf.org) if TB treatment is continued 
beyond 24 weeks.   
• 
After completion of TB treatment, LPV/r + two NRTIs + RAL will be 
continued with LPV/r at standard dosing (400mg/100mg) through 
week 72. 
 
If LPV/r is prematurely discontinued at any time during TB treatment for 
Arms A and C, the team must be notified, and the RBT dose should be 
increased to 300 mg daily pending further instructions from the team. 
 
 
 
 
 
 


 
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   Figure 1. Study Schema 
 
 
 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
For HIV-1-infected participants with active tuberculosis (TB) who require protease 
inhibitor (PI)-based antiretroviral therapy (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 rifampin (RIF)-based 
TB treatment.  
 
1.2 
Primary Objective 
 
To compare rates of virologic suppression to < 400 copies/mL at 48 weeks for the two 
standard dose LPV/r and RBT arms versus the double-dose LPV/r and RIF arm. 
 
1.3 
Secondary Objectives 
 
1.3.1 To evaluate TB treatment outcomes (as measured by week 8 mycobacterial 
culture conversion, treatment failure at or after week 24, TB relapse/recurrence 
by week 72) between RBT-containing arms and the RIF-containing arm, to 
include the association between RBT or RIF exposure as well as other factors 
potentially associated with outcomes of TB treatment.  
 
NOTE: TB treatment outcome measurements for participants who enroll with 
probable TB for whom week 8 mycobacterial culture conversion rates 
cannot be assessed will include either week 8 AFB smear conversion rate 
coupled with resolution of signs, symptoms, and radiographic 
abnormalities on which the diagnosis of probable TB was based or solely 
resolution of signs, symptoms, and radiographic abnormalities for 
participants with negative AFB smears or AFB smears that are not 
available at baseline; in addition, TB treatment failure at or after week 24, 
and TB relapse/recurrence by week 72 will be captured as TB outcome 
measures.  
 
1.3.2 To compare rates of virologic suppression to < 50 copies/mL at 48 weeks for the 
two standard dose LPV/r and RBT arms versus the double-dose LPV/r and RIF 
arm. 
 
1.3.3 To compare rates of virologic suppression to < 50 copies/mL and < 400 
copies/mL at 48 weeks for standard dose LPV/r and RBT versus standard dose 
LPV/r, RBT, and RAL. 
 
1.3.4 To compare safety and tolerability during TB treatment of double-dose LPV/r and 
RIF between the three treatment arms.  
 
1.3.5 To compare the proportion of participants with virologic failure and time to 
virologic failure between the three treatment arms. 
 


 
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1.3.6 To compare the emergence of HIV-1 drug resistance mutations in gag, protease, 
reverse transcriptase (RT), and integrase in participants with virologic failure 
between the three treatment arms. 
 
1.3.7 To compare the proportion of participants with TB drug-resistance among cases 
of TB treatment failure and relapse/recurrence of TB between the three treatment 
arms. 
 
1.3.8 To characterize TB immune reconstitution inflammatory syndrome (IRIS) events. 
 
1.3.9 To compare changes in CD4+ T-cell count, and proportion of participants who 
experience new AIDS-defining illness, HIV disease progression (defined as new 
AIDS-defining illness or death), or death between the three treatment arms. 
 
1.3.10 To evaluate LPV pharmacokinetic (PK) characteristics (area under the curve 
[AUC], maximum concentration [Cmax], minimum concentration [Cmin]) in 
participants enrolled in Arms A, B, and C, accrual periods 1 and 2.  
 
1.3.11 To evaluate the RBT PK characteristics (AUC, Cmax, Cmin) in participants enrolled 
in Arms A and C, accrual periods 1 and 2. 
 
1.3.12 To evaluate RAL PK characteristics (AUC, Cmax, Cmin) in participants enrolled in 
Arm C, accrual period 2.   
 
1.3.13 To evaluate the cost-benefit analysis of the addition of RAL.  
 
1.4 
Tertiary Objective 
 
1.4.1 To submit sputum, serum, and urine specimens at specified time points to the 
Consortium for TB Biobank for analysis of biomarkers associated with TB 
treatment response. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
TB is the most common opportunistic infection (OI) among patients living with HIV 
disease globally, most importantly in high TB endemic resource-constrained settings. 
There is an increased risk of HIV disease progression (new AIDS-related OIs or death) 
among ART-naïve HIV-1-infected patients presenting with active TB1. The provision of 
cotrimoxazole2,3 and ART during TB treatment markedly decreases the risk of HIV 
disease progression4,5,6,7. For example, in a large cohort of participants with HIV-related 
TB in Thailand, the risk of death was decreased 83% among those who received ART6. 
Three large randomized controlled trials as well as other cohort studies have also 
demonstrated that early initiation of ART during TB treatment is associated with reduced 
mortality in HIV-infected participants, particularly those with advanced 
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Therefore, patients with HIV-related TB should be a high priority group for evaluation 
and initiation of ART. This issue has been recently addressed in revised World Health 
Organization (WHO) treatment guidelines, which recommend initiation of ART as soon 
as is feasible in all HIV-infected persons with active TB regardless of CD4+ T-cell 
count12.  
 
The standard cotreatment regimen for HIV-related TB and the need for alternatives 
The preferred cotreatment regimen for HIV-related TB in resource-constrained settings 
is RIF-based anti-TB therapy with efavirenz (EFV)-based ART (EFV + 2 nucleoside 
analogue reverse transcriptase inhibitors [NRTIs])13. Nevirapine (NVP) is substituted for 
EFV in some settings when patients cannot take or do not have access to EFV, although 
data from clinical trials in the setting of active TB are less robust in terms of virologic and 
TB outcomes, and NVP cannot be safely used for persons with higher CD4+ T-cell 
counts. Outcomes of EFV-based ART are generally comparable among patients with or 
without concomitant active TB14, although viral suppression rates < 400 copies/mL at 48 
weeks of ART may differ according to when ART is initiated during TB treatment8, 9,10. In 
the SAPiT trial, among participants with active TB starting ART within the first 8 weeks of 
TB treatment initiation, overall viral suppression rates were higher than for those for 
whom ART was delayed until after the completion of TB treatment (although by 6 
months after completion of TB treatment, viral suppression rates were similar)8. 
However, in both the CAMELIA trial and the A5221/STRIDE trial of early vs. deferred 
ART in persons initiating TB treatment, viral suppression rates were comparable when 
ART was started within the first 2 versus 8-12 weeks of TB treatment, despite 
differences in mortality and IRIS rates9, 10. In each of these studies, EFV + 2 NRTIs was 
the ART regimen used, and in general, viral suppression rates were similar to those 
reported among HIV-infected persons initiating ART in the setting of advanced 
immunosuppression but without active TB. However, not all patients with HIV-related TB 
can be treated with this preferred cotreatment regimen. Some patients cannot tolerate 
the neuropsychiatric side effects of EFV or develop other significant treatment-limiting 
toxicities due to EFV or NVP, such as hypersensitivity reactions. Moreover, EFV is 
teratogenic, and, therefore, cannot be used early in pregnancy (the safety of EFV in the 
latter part of pregnancy is currently being evaluated). Children generally cannot be 
treated with EFV as there is no approved formulation of EFV for young children, and the 
correct dosing of EFV in older children is uncertain15. 
 
Combination EFV- or NVP-based ART has been very successful as initial treatment in 
high HIV-burden settings16,17. Nevertheless, virologic failure of initial ARV regimens 
occurs, and such patients often have HIV with high-level resistance to non-NRTIs 
(NNRTIs) and NRTIs commonly available in such settings. In several large cohorts in 
Africa, the rate of virologic failure of initial NNRTI-based ART was approximately 2% per 
year16,17. Cohorts in middle-income countries with more mature ART programs report 
rates of approximately 4% per year. In addition, women who have received single dose 
NVP for the prevention of mother to child transmission of HIV have high virologic failure 
rates associated with initial NVP-based ART, and HIV with high level resistance to NVP 
and EFV has been detected either at baseline or at the time of subsequent virologic 
failure in these women18. While the initial virologic failure rates in many of these studies 
were low with careful follow-up and monitoring, these studies may underestimate the 
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who will need second-line ART is large because of the very success of the ARV roll-out 
in high-burden countries. Furthermore, patients who have failed an initial regimen often 
have advanced immunodeficiency, and, therefore, are at higher risk of developing TB. A 
recent estimate is that there will be 392,000 to 902,000 patients with TB while on 
second-line ART over the next 7 years (Stop TB/HIV Working Group, WHO, 2009). 
Therefore, there is a rapidly growing need to identify cotreatment regimens for HIV-
related TB that can be used among patients in resource-constrained settings who have 
resistance to EFV and NRTIs or who require second-line ART with a protease inhibitor 
(PI)-based regimen. 
 
Managing the interaction between rifamycins and PI-based ART regimens 
At present, there is no satisfactory cotreatment regimen for HIV-related TB among 
patients who have failed initial NNRTI-based ART or require the use of a PI-based 
regimen because they are unable to take or tolerate NNRTIs or for other reasons. The 
basis of second-line ART in many high-burden countries is the HIV-1 PI class of 
medications. RIF markedly decreases the plasma concentrations of all of the available 
PIs, particularly atazanavir/ritonavir (ATV/RTV) and LPV/r, the two recommended PI 
agents in high-burden countries. With the addition of relatively high doses of RTV (up to 
200-400 mg twice-daily), the effect of RIF on selected PIs (notably LPV and saquinavir) 
can be largely overcome19,20, and this approach has been termed “super-boosted” PI 
therapy (or double-dose PI therapy when fixed-dose combinations are used). This 
approach has not been tested with other PIs.  
 
While it is pharmacologically possible to overcome the effect of RIF on PIs, the problem 
of the strategy of double-dose or super-boosted PI therapy is tolerability. The 
combination of higher dose RTV, a second PI, and RIF has been poorly tolerated in 
studies of healthy adult volunteers, with high rates of gastrointestinal symptoms (nausea 
and vomiting) and drug-induced liver injury21,22,23. There is limited published experience 
with double-dose or super-boosted PI therapy among patients with HIV-related TB on 
RIF-based treatment19,21,24,25. In healthy volunteer studies, LPV/r 800 mg/200 mg 
administered twice daily (BID) (double-dose) appears to be better tolerated than a 
regimen utilizing a 400 mg LPV and 400 mg RTV BID dose (super-boosted), although 
the PK variability may be greater for the double-dose regimen, perhaps owing to the fact 
that a 400 mg dose of RTV BID is better able to overcome the RIF drug interaction.  
 
There appear to be substantial differences in response to double-dose or super-boosted 
PI regimens in children compared to adults. Among children, the combination of super-
boosted PI and RIF-based TB treatment was relatively well-tolerated and effective in the 
short term. In a cohort study from Soweto, South Africa, young children treated with RIF-
based TB treatment and super-boosted LPV/r-based ART had similar clinical and 
virologic outcomes as children without TB treated with standard-dose LPV/r-based 
therapy23. In a study of adults with HIV-related TB, super-boosted saquinavir-based ART 
with RIF-based TB treatment had good virologic outcomes among those who remained 
on ART, but only 10 of 20 participants tolerated this cotreatment regimen19. Side effects 
resulting in discontinuation of HIV-TB cotreatment were nausea, vomiting, and drug-
induced liver injury. Thus, in adults, double-dose LPV/r may provide reasonable trough 
concentrations, albeit with perhaps greater variability than super-boosted doses, while 
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tolerated and is associated with better trough concentrations and virologic outcomes 
than double-dose LPV/r. Despite the limitations of published data on the efficacy of 
double-dose or super-boosted PI therapy with RIF-based TB treatment, particularly in 
adults, these combinations continue to be used in high-burden resource-constrained 
settings because of the lack of good alternatives. 
 
There are also issues related to the better tolerability and reduced toxicity in healthy 
volunteers associated with dosing the PI first, followed by the addition of RIF, as 
demonstrated in ACTG A5213. This issue will be difficult to overcome, however, in the 
setting of active TB, as there is an imperative to initiate TB treatment as soon as 
possible once TB is diagnosed, and for the most part, patients must be started on anti-
TB treatment before they are started on ART. Those who need to make a switch in ART 
because they require anti-TB treatment will also likely not be able to start PI-based ART 
first. 
 
Use of an 800 mg/200 mg BID dose of LPV/r may also be easier to administer in 
resource-constrained settings because this dose takes advantage of the better tolerated 
and more stably stored Meltrex co-formulated tablets that do not require a separate 
prescription for extra doses of the additional RTV. This trial will evaluate the strategy of 
double-dose LPV/r in combination with RIF-based TB therapy using the now standard 
heat-stable Meltrex formulation of LPV/r. This regimen of double-dose LPV/r (800 
mg/200 mg BID) is currently being used as standard of care in South Africa and other 
resource-constrained settings for patients being treated for active TB with a RIF-based 
regimen and who require ART containing a PI. A recent small PK study among stable 
participants on LPV/r-based ART showed that serum concentrations of LPV/r were 
dramatically decreased after the addition of RIF, but that doubling the dose of LPV/r 
restored trough concentrations of LPV/r26. Two participants in the study had increased 
liver transaminases following the addition of RIF to LPV/r-based ART, but both 
participants did well with discontinuation of RIF. This strategy has not been evaluated in 
controlled clinical trial settings that evaluate both virologic and TB treatment outcomes, 
and there are very limited data about its tolerability and efficacy for patients with HIV-
related TB.  
 
Some of these PK and dosing issues associated with double-dose LPV/r and RIF were 
addressed in a small PK study conducted in South Africa in HIV-infected adults 
virologically suppressed on a LPV/r regimen27. All study participants had CD4+ T-cell 
counts > 400 cells/µL, viral loads < 400 copies/mL, and none had active TB. Steady 
state PK of LPV/r was evaluated at baseline, one week after initiation of RIF, and one 
week after gradual dose escalation of LPV/r to 1.5 and then 2x the standard dose (i.e., 
double-dose). A total of 21 participants were enrolled. Median LPV 12-hour post dose 
concentration was 3.7 mg/L (IQR 1.2-7.7) with double-dose LPV/r, and there were no 
significant differences in LPV AUC0-12, C0, C12, Cmax, or T1/2 for the baseline vs. double-
dose LPV/r time points after steady state RIF was achieved. The doses were generally 
well-tolerated with only two participants developing asymptomatic Grade 3 or 4 
elevations of liver transaminases. All participants achieved therapeutic C0 trough 
concentrations with double-dose LPV/r; 18/20 did so with a dose of 1.5 times standard 
LPV/r, suggesting this may be effective as a step-down dose for those unable to tolerate 
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treatment of persons with active TB, as these were not included in this study, and safety 
data were available for only 22 days. However, these data do provide support for the 
further evaluation of this regimen in HIV-infected adults with active TB.  
  
In summary, RIF, the cornerstone of TB treatment, has very problematic drug-drug 
interactions with PIs. The use of relatively high doses of RTV appear necessary to 
overcome this interaction, but it is unclear whether the cotreatment 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. 
 
Rifabutin and protease-inhibitors 
RBT is a rifamycin antibiotic with potent activity against Mycobacterium tuberculosis 
(MTB), both in vitro and in animal models of TB treatment. In three randomized clinical 
trials, RBT appeared to be as effective as RIF for the treatment of pulmonary TB, but 
overall numbers of participants treated and the design of the trials have led to the 
conclusion that further careful study, particularly in HIV-infected participants receiving 
ART, is needed28,29,30,31. Of note for the treatment of HIV-related TB, RBT has limited 
effect on serum concentrations of HIV-1 PIs than does RIF32. In fact, RBT has very little 
effect on PIs in common use, i.e., LPV/r and ATV34,35. In small clinical studies, the 
cotreatment regimen of RBT-based TB treatment and PI-based ART has been well-
tolerated and effective36, and it is recommended in the United States for patients unable 
to take EFV-based ART, even though RBT is not licensed for this indication. 
 
However, there are limitations to the use of RBT in PI cotreatment regimens. First, 
experience using RBT for TB treatment is limited, and as outlined above, a Cochrane 
Review of the literature recently concluded that there are insufficient data to be assured 
of RBT’s effectiveness in TB treatment29. Second, RBT is generally not available in high-
burden countries for treatment of HIV-related TB, although this is expected to change 
over time with the addition of RBT to the WHO Essential Medicines list and the 
availability of generic formulations of the drug in some countries. Third, although RBT 
has limited effect on serum concentrations of currently-used PIs, the concentrations of 
RBT and its primary metabolite are markedly increased by PIs, particularly RTV. The 
resulting high concentrations of RBT and its metabolite can cause toxicity – uveitis, 
leucopenia/neutropenia, skin discoloration, and nausea. A recent small PK study of 
atazanavir/ritonavir with RBT in healthy volunteers who received a RBT dose of 150 mg 
twice weekly was stopped prematurely due to excess neutropenia. The RBT Cmax was 
increased by 149% and the 25-O-desacetyl active metabolite of RBT was increased by 
5-10 fold, which probably accounted for the excess neutropenia33. Atazanavir Cmax and 
AUC were decreased by 25% when compared with historical controls using the twice 
weekly dosing of RBT. The authors provided modeling simulations based on the drug 
levels they measured and suggested that RBT should be given in a dose of 150 mg 
three times weekly (TIW) in persons with active TB when administered with ATV/r; 
however, they did not actually evaluate this dose regimen in their study, and there was 
no indication from their models whether the further increase in the RBT and 25-O-
desacetyl metabolite that would accompany the increased dosing frequency might 
further reduce atazanavir Cmax or AUC. Based on all of the aforementioned 
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administered with PIs, but data are urgently needed to understand what should be the 
optimal dose to ensure safe and effective treatment of TB in this setting.   
 
Based primarily on results from studies in healthy volunteers, standard dose reductions 
of RBT have been recommended when administered with PIs, but there is a critical need 
to validate those recommendations among participants with HIV-related TB. Notably, the 
reduced dose of RBT would likely be inadequate for TB treatment if the PI therapy was 
discontinued. Therefore, the approach of reduced dose RBT relies on adherence to a PI 
and there may be differences among PIs with regard to the impact on PK/PD. In one 
small study, 10 HIV-infected participants hospitalized in a TB treatment facility were 
started on RBT-based TB treatment at a dose of 300 mg TIW without LPV/r, had week 2 
RBT concentrations obtained, then added a LPV/r-based ART regimen and reduced 
their RBT dose to 150 mg TIW, per current recommendations37. The Cmax obtained at 
week 4 to 5 was  0.30 µg/mL for 9 of 10 participants while the partially active 25-O-
desacetyl metabolite of RBT was increased, as was the AUC0-24 and AUC0-48. Most 
unbound RBT Cmax values were below the minimum inhibitory concentration (MIC) for 
drug-susceptible MTB and values for the plasma concentration-time curve were below 
those that had been associated with TB treatment failure or relapse (i.e., an AUC0-24 < 
4.5 µg*h/mL) in a previously conducted TB Trials Consortium Study23,35,38. Eight of the 
10 participants in the study were men with a median weight of 74 kg and a median body 
mass index (BMI) of 23.1, a heavier population with a different gender proportion than 
participants likely to be enrolled from some resource-constrained settings. In another 
report, three participants experienced a relapse of TB with a RIF-resistant isolate after 
treatment with a RTV-boosted PI-based ART regimen coupled with a RBT-based TB 
regimen using a 150 mg TIW dose schedule39. These studies raise some uncertainty 
about current dosing recommendations for RBT in the setting of PI-based therapy, 
although results from a recent PK study conducted in South Africa shed further light on 
this issue. In this study, the PK of RBT was evaluated in 16 HIV coinfected participants 
with active TB. These participants were initially treated with a RBT-based anti-TB 
regimen (using RBT in a dose of 300 mg daily) before starting ART that included 
standard doses of LPV/r 400/100 mg BID daily40. Participants were established on their 
anti-TB therapy and were then randomized after starting LPV/r to receive RBT 150 mg 
daily x 4 weeks followed by 150 mg TIW or to the converse dosing strategy. Serial RBT 
and 25-O-desacetyl RBT concentrations were measured after each 4 week interval. The 
median AUC0-24, and Cmax on RBT 300 mg daily, 150 mg TIW, and 150 mg daily, 
respectively, were 3026 ng/mL.h and 297 ng/mL, 2307 ng/mL.h and 168 ng/mL, and 
5010 ng/mL.h and 311 ng/mL. All doses were well tolerated with only one case of uveitis 
that occurred prior to starting LPV/r and one episode each of Grade 2 transaminitis and 
neutropenia reported. When coupled with standard doses of LPV/r, the dose of RBT that 
best approximated the 300 mg dose in the absence of LPV/r, and that achieved a Cmax 
concentration of RBT within recommended target ranges for TB treatment of 300-900 
ng/mL, was the RBT 150 mg daily dose. These data in aggregate suggest that in the 
context of PI-based therapy, the current recommended dose of RBT is insufficient.  
Finally, RBT is not available in fixed-dose combination formulations of TB medications 
that are commonly used in high-burden settings. Therefore, the use of RBT, rather than 
RIF, will be associated with higher pill burdens and will be more complex for patients and 
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In summary, the cotreatment regimen of RBT-based TB treatment and PI-based ART is 
promising for patients unable to take EFV. However, much more data are needed to 
evaluate the most appropriate doses, tolerability, anti-TB efficacy, and programmatic 
aspects of substituting RBT for RIF in this setting. 
 
Ensuring sufficient ARV regimen potency in second-line therapy 
In addition to the difficulty of using a PI with RIF, the standard second-line ARV regimen 
may be unsatisfactory for other reasons. Among patients who have failed an initial 
NNRTI-based regimen, there is a high risk of substantial resistance not only to NNRTIs 
but also to the NRTI class. In many resource-constrained settings, viral load monitoring 
is not routinely available, and decisions about switching to second-line regimens are 
based on CD4+ T-cell count decline, “clinical failure” as defined by a new or recurrent 
OI, or a viral load, if available, above a threshold of 5,000 to 10,000 copies/mL in two 
consecutive measurements. Recent studies have documented that this approach may 
be associated with prolonged virologic failure and accumulation of NRTI resistance 
mutations in a substantial proportion of patients. While cross-resistance between NRTIs 
is not as common as it is between the first generation NNRTIs, it is still substantial, 
particularly for thymidine analogues. Therefore, an additional problem with a second-line 
regimen of a PI and two new NRTIs is the risk of virologic failure due to the inadequacy 
of the NRTI components of the regimen. While data from a small number of studies 
suggest that LPV/r or ATV/r monotherapy can be effective in the short term in patients 
who have failed a first-line regimen, no studies of this approach have been done in 
participants with active TB. When coupled with the drug-drug interactions associated 
with RIF or RBT, there is the potential for a LPV/r or ATV/r-based regimen combined 
with a compromised NRTI backbone to be further compromised by the interaction with 
the rifamycins.  
 
The integrase-inhibitor RAL offers a way to increase the potency of second-line therapy 
regimens following virologic failure of NNRTI and NRTI regimens. Based on data from 
clinical trials, the combination of RAL and a PI-boosted with RTV appears to be potent. 
RAL is metabolized by glucuronidation, an enzymatic process that is upregulated by RIF 
via induction of UDP-glucuronosyltransferase 1A1 (UGT1A1). As a result, RAL 
concentrations are decreased by approximately 50% when given with RIF. The US Food 
and Drug Administration (FDA) has now recommended that the RAL dose be doubled to 
800 mg BID if given with RIF because of this interaction, and the package insert has 
been updated to reflect this change. This increased dose has not been evaluated in 
patients, so uncertainty remains about the efficacy and tolerability of this dose and 
schedule.  
 
Data evaluating the interaction between RAL and RBT have recently been reported41. In 
an open-label two-period study in 16 HIV-uninfected healthy adults, the combination of 
RAL 400 mg every 12 hours (q12h) and RBT 300 mg daily demonstrated no serious 
adverse events (SAEs) and no clinically important alteration in RAL PK. Based on this 
lack of effect, the investigators concluded that RBT could be coadministered with RAL 
without dose adjustment of RBT. No RBT concentrations were evaluated in this study. 
A5290 will provide an important opportunity to evaluate the RBT PK in a treatment arm 
in which RAL is combined with LPV/r, and to assess the impact of the PI-adjusted RBT 
dose on TB treatment outcomes in this important patient population. The results will 


 
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have important implications for the use of both RAL and RBT in the treatment of TB in 
HIV-infected individuals. 
 
Need for PK data in the treatment of HIV-related TB  
There has been limited evaluation of the PK of TB drugs among patients with HIV co-
infection. There have long been concerns that patients with HIV coinfection malabsorb 
first-line TB drugs, though the results of previous small studies have been inconclusive 
(with some studies showing lower drug exposure among patients with HIV-related TB 
than among HIV-uninfected TB patients, but other studies showing similar drug 
exposures). 
 
Very few studies have evaluated the pharmacodynamics of TB drugs among participants 
with HIV-related TB. As above, it appears that low RBT exposure has been associated 
with TB treatment failure with acquired rifamycin resistance, but the details of this 
relationship are not clear from the relatively small studies that have been published. This 
trial is a valuable opportunity to collect sparse PK data from a large group of participants 
with HIV-TB who will be followed for both HIV and TB treatment outcomes. 
 
2.2 
Rationale 
 
There is a rapidly-growing need to identify evidence-based, safe and effective 
cotreatment regimens for HIV-related TB among patients who require PI-based ART. 
This trial will compare three alternative co-treatment regimens:  
 
• 
LPV/r + two NRTIs with RBT-based TB therapy 
• 
Double-dose LPV/r + two NRTIs with RIF-based TB therapy 
• 
LPV/r + two NRTIs + RAL with RBT-based TB therapy 
 
This study is designed to address several urgent and practical questions for endemic TB 
countries with large HIV-infected populations: 1) What is the best approach to HIV 
treatment in participants requiring PI-based ART in the setting of TB co-treatment? 2) Is 
the efficacy of RIF and RBT similar in participants treated with dose-adjusted LPV/r 
regimens and, as a corollary, what is the optimal dose of RBT in the setting of PI-based 
ART? 3) Does the addition of an integrase inhibitor improve the virologic outcome of 
anti-HIV treatment in the setting of drug-drug interactions for participants receiving a 
dose-adjusted PI-based regimen with a rifamycin during TB treatment? 4) What is the 
impact of PK dose-adjusted LPV/r coupled with RBT and/or RAL on TB treatment 
outcomes in HIV-infected persons? The outcome of this trial will have major public 
health implications for areas of the world with high burdens of HIV-related TB. 
 
 
3.0 
STUDY DESIGN 
 
A5290 is a prospective, randomized (1:1:1), open-label, phase 2b study comparing three 
LPV/r-based ARV regimens among participants in high TB endemic resource-
constrained settings undergoing treatment for confirmed or probable TB and requiring 
second-line PI-based ART.  
 


 
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Table 3.1. Regimen Rationale 
 
Arm 
ART 
Anti-TB therapy 
After completion 
of TB treatment 
Rationale 
A 
LPV 400 mg/RTV 
100 mg BID + two 
NRTIs 
Isoniazid (INH) 300 mg daily, 
RBT 300 mg daily, then 150 
mg daily upon initiation of 
ART*, EMB (weight-based 
dose) daily, pyrazinamide 
(PZA, weight-based dose) 
daily, and pyridoxine 25 mg 
daily. EMB and PZA will be 
discontinued after 8 weeks of 
treatment; INH, RBT 150 mg 
daily (or the adjusted dose 
determined by PK), and 
pyridoxine will continue 
through week 24 for a 
minimum total duration of 24 
weeks. INH, RBT, and 
pyridoxine may continue 
beyond 24 weeks to a 
maximum of 48 weeks at the 
discretion of the primary 
clinician; the protocol core 
team must be notified. 
LPV/r + two 
NRTIs will 
continue at 
standard dosing 
through week 72.
This regimen substitutes 
dose-adjusted RBT to 
replace RIF in an 
attempt to overcome the 
adverse drug interaction 
of RIF with standard 
dose LPV/r. 
B 
LPV 800 mg/RTV 
200 mg BID  + two 
NRTIs 
INH 300 mg daily, RIF 
(weight-based dose) daily, 
EMB (weight-based dose) 
daily, PZA (weight-based 
dose) daily, and pyridoxine 25 
mg daily. EMB and PZA will 
be discontinued after 8 weeks 
of treatment; INH, RIF, and 
pyridoxine will continue for a 
minimum total duration of 24 
weeks. INH, RIF, and 
pyridoxine may continue 
beyond 24 weeks to a 
maximum of 48 weeks at the 
discretion of the primary 
clinician; the protocol core 
team must be notified. 
LPV/r + two 
NRTIs will 
continue at 
standard dosing 
through week 72.
This arm allows use of 
standard RIF doses but 
with higher doses of 
LPV/r in an attempt to 
overcome the adverse 
drug interaction of RIF 
with standard dose 
LPV/r. 


 
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Arm 
ART 
Anti-TB therapy 
After completion 
of TB treatment 
Rationale 
C 
LPV 400 mg/RTV 
100 mg tabs BID + 
two NRTIs + RAL 
400 mg BID 
INH 300 mg daily, RBT 300 
mg daily, then 150 mg daily 
upon initiation of ART*, EMB 
(weight-based dose) daily, 
PZA (weight-based dose) 
daily, and pyridoxine 25 mg 
daily. EMB and PZA will be 
discontinued after 8 weeks of 
treatment; INH, RBT 150 mg 
daily (or the adjusted dose 
determined by PK), and 
pyridoxine will continue for a 
minimum total duration of 24 
weeks. INH, RBT, and 
pyridoxine may continue 
beyond the 24 weeks to a 
maximum of 48 weeks at the 
discretion of the primary 
clinician; the protocol core 
team must be notified. 
LPV/r +  two 
NRTIs + RAL will 
continue at 
standard dosing 
through week 72 
 
This regimen follows the 
same rationale as for 
Arm A but adds RAL in 
an attempt to enhance 
the antiviral activity of 
LPV/r when combined 
with RBT to evaluate 
whether this approach is 
associated with a better 
virologic response than 
the other two arms. 
 
*NOTE: In Arms A and C, RBT should be administered at a dose of 300 mg daily until the start 
of antiretroviral therapy at which time the dose should be reduced to the 150 mg daily 
dose. If LPV/r is stopped prematurely during TB treatment, the RBT dose should be 
increased to 300 mg daily and the team should be notified. All participants will receive 
TB treatment according to in-country TB guidelines for daily TB treatment and directly 
observed therapy (DOT), except that all study participants will receive daily TB 
treatment 7 days per week, i.e., participants will not use a 5 days per week schedule 
that may be recommended in some in-country TB programs. 
 
Accrual will take place in two accrual periods. Accrual period 1 will enroll participants 
who will undergo an initial dose-finding period before continuing regular study follow-up 
through 72 weeks. Once review of the dose-finding data in accrual period 1 is 
completed, accrual period 2 will begin.  
 
Accrual Period 1 
Sixty participants will be randomized 1:1:1 (20 participants per arm) to one of three 
treatment arms as detailed above. Anti-TB therapy with study-provided RBT or non-
study-provided RIF and non-study-provided INH, EMB, and PZA should be started within 
72 hours of randomization. ART should be started as soon as possible after initiating 
anti-TB therapy, but may be delayed for up to 7-14 days after starting anti-TB therapy to 
allow participants sufficient time to assess tolerability of TB medications. Participants will 
then undergo a formal PK and safety evaluation to include:  
• 
Steady-state (day 12 ± 2 after initiation of ART) RBT PK parameters (Cmin, Cmax, and 
24-hour AUC) for those randomized to Arm A and Arm C. 


 
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• 
Steady-state (day 12 ± 2 after initiation of ART) LPV PK parameters (Cmin, Cmax, and 
12-hour AUC) for those randomized to Arm B.  
• 
Grade 3 AEs attributed to study-provided drug(s) by 28 days after ART initiation. 
• 
Discontinuations of study-provided drug(s) for treatment-limiting toxicity or 
intolerance (such that PK assessments within the day 12 ± 2 window cannot be 
completed).  
 
Interim PK and safety analysis will be conducted when the first 10-12 accrual period 1 
participants per treatment arm have completed 28 days of ART and day 12 ± 2 (after 
initiation of ART) drug concentrations are available and when 54-60 accrual period 1 
participants have completed 28 days of ART and day 12 ± 2 (after initiation of ART) drug 
concentrations are available. Because participants enrolled during accrual period 1 will 
be undergoing treatment for active TB, they will continue on their randomized therapy 
pending the results of these interim PK and safety analysis. Sites will be encouraged to 
organize recruitment in a manner to ensure rapid accrual to accrual period 1 to the 
extent possible so that participants are not exposed to prolonged treatment in the 
absence of these PK assessments; however, some participants may require dose 
adjustments of RBT and/or LPV/r prior to the completion of the interim analyses, as 
described below. 
 
NOTE: While the intent is to conduct the full accrual period 1 PK and safety interim 
analysis after 54-60 accrual period 1 participants have completed 28 days of 
ART, as previously discussed, available drug concentrations and safety data will 
be assessed weekly by the core team in an unblinded fashion as follows. Sites 
will be asked to batch PK samples and ship them every two weeks to the ACTG 
repository, which will immediately re-ship them to the PK laboratory. The PK 
laboratory will measure drug concentrations as soon as possible after receipt of 
shipments and will report results to the core team within 2 weeks of receiving the 
samples. The core team will monitor all available concentrations weekly for those 
results received to date. An early interim analysis of PK results and safety criteria 
will be conducted after the first 10-12 participants in each arm complete 28 days 
of ART and the day 12 ± 2 PK results are available to assess any early trends 
suggesting lower or higher than expected concentrations of any study drug(s). If 
early assessments indicate concentrations out of acceptable ranges for more 
than three participants in a treatment arm or trends related to safety criteria, an 
early ACTG Study Monitoring Committee (SMC) evaluation will be triggered. Any 
dose adjustments recommended by the SMC in consultation with the core team 
after this interim evaluation will be implemented for any new accrual period 1 
participants enrolled as soon as possible after the review and for any already 
enrolled participants who have drug concentrations clearly out of acceptable 
ranges. However, the decision to revise dose schedules and treatment duration 
of participants with inadequate drug concentrations would be made based not 
just on the drug concentrations, but also on all available clinical data regarding 
TB and HIV endpoints. While true real-time reporting of drug concentrations will 
not be possible, individual participants identified, either during weekly core team 
monitoring or during any early SMC monitoring assessments, who have clearly 
inadequate concentrations of any study-provided drug(s) will be reported to the 
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may be recommended according to the dose adjustment schedule in Table 5.1. 
Accrual period 1 participants for whom early dose adjustments are recommended 
will have drug concentrations repeated 12 ± 2 days after initiating the adjusted 
dose. If no early PK or safety trends are identified during core team or SMC 
monitoring, dosing will continue in participants enrolled during accrual period 1 as 
per assigned treatment arm.  
 
Accrual period 2 will not open until completion of the full accrual period 1 PK and safety 
analysis and determination of subsequent dosing for LPV/r and RBT for participants 
enrolled during accrual period 2 is made. Based on this monitoring, if criteria are 
determined to be unacceptable in any treatment arm before the three cohorts are fully 
enrolled during the accrual period 1, further accrual to the arm in question may be 
stopped. If a dose adjustment of LPV/r or RBT is deemed necessary, as described in the 
note above, accrual period 1 participants identified by the core team with clearly 
inadequate concentrations will be reassigned to the new adjusted dose, the intensive TB 
treatment phase will be extended at the new adjusted dose for participants in the 
relevant treatment arm, and these participants will undergo an additional day 12 ± 2 PK 
assessment. The core team will communicate recommendations to the sites related to 
which participants will require dose adjustments as soon as is feasible. In this 
circumstance, it is possible that a portion of accrual period 1 participants may receive an 
additional 28-42 days (i.e., up to a total of 16 weeks) of intensive phase TB treatment at 
the new adjusted dose before beginning the 16-week continuation phase of TB 
treatment. However, those accrual period 1 participants with drug concentrations 
deemed adequate on their originally-assigned doses of study-provided medications will 
not be required to be reassigned to the new adjusted dose (and additional intensive 
phase TB treatment), but will continue on their originally-assigned dose and proceed to 
their continuation phase of TB treatment and regular study follow-up through week 72. 
 
NOTE: Any participants determined to have clearly inadequate RBT concentrations 
during the accrual period 1 PK evaluation should be monitored closely after dose 
adjustments for TB outcomes throughout the course of their TB treatment. 
 
Refer to Table 5.1 (LPV/r and RBT Dose Adjustment Table) in section 5.1.  
 
 
Monitoring Prior to Opening Accrual Period 2 
The core team, together with the SMC, will review the results of the accrual period 1 
interim PK and safety analysis. If the acceptable PK criteria for RBT and LPV are met, 
and if no more than three participants in each treatment arm report  Grade 3 AEs 
attributed to study-provided drug(s) by 28 days after ART initiation, and if no more than 
three participants in each treatment arm discontinue study-provided drug(s) for 
treatment-limiting toxicity or intolerance (such that PK assessments cannot be 
completed), then accrual period 2 will open at the planned dose schedules of LPV/r and 
RBT.  
 
If acceptable PK criteria are not met, or if more than three participants in one or more 
treatment arms report  Grade 3 AEs attributed to study-provided drug(s) by 28 days 
after initiation of ART, or if more than three participants in one or more treatment arms 
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PK assessments cannot be completed), the SMC, in consultation with the core team, 
may elect to adjust the doses of RBT and/or LPV/r, as described above, for participants 
in the affected arm identified with inadequate drug concentrations, and repeat steady-
state (day 12 ± 2 after dose adjustment) drug concentrations will be obtained for only the 
study arm participants in which a dose was adjusted (see dose adjustment schedule 
above). A second accrual period 1 PK and safety interim analysis will be conducted after 
all accrual period 1 participants undergoing dose adjustment have completed 28 days of 
dose-adjusted treatment and when day 12 ± 2 post-dose adjustment drug concentrations 
are available. This second analysis will include all accrual period 1 participants with 
available data. 
  
The core team and SMC will then review the results of the second accrual period 1 
interim PK and safety analysis. If acceptable PK criteria are not met, or if more than 
three participants in one or more treatment arms report  Grade 3 AEs attributed to 
study-provided drug(s) by 28 days after initiation of ART, or if more than three 
participants in one or more treatment arms discontinue study-provided drug(s) for 
treatment-limiting toxicity or intolerance (such that PK assessments cannot be 
completed, then a decision will be made about whether to continue, modify (e.g., add 
additional participants to the accrual period 1 to assure adequate PK assessment are 
completed), or halt the treatment arm(s) in question, based on analysis of the nature of 
the AEs and reasons for study-provided drug discontinuation, and the degree of PK 
criteria failure. At the second interim review, if three or fewer participants report  Grade 
3 AEs attributed to study-provided drug(s) in all treatment arms, and if three or fewer 
participants in all treatment arms discontinue study-provided drug(s) for treatment-
limiting toxicity or intolerance (such that PK assessments cannot be completed), and 
acceptable PK criteria are met for at least two of the treatment arms, the SMC, in 
consultation with the core team, will determine whether accrual period 2 will open. 
 
If, based on the SMC’s determination, unacceptable PK and/or safety criteria are met 
within two treatment arms, then further enrollment into the study may be stopped, and 
accrual period 1 participants will be managed according to best available local TB and 
ARV treatment. These participants will be followed off study-provided drug (LPV/r, RTV, 
RAL, and/or RBT) for the remainder of study follow-up (up to 72 weeks). 
 
If the SMC determines that accrual period 2 enrollment should proceed, accrual period 2 
participants will be randomized 1:1:1 to Arm A, B, or C (or with equal probability to the 
remaining sample size in the remaining treatment arms) at the doses determined during 
the dose-finding period in accrual period 1 participants. Samples for LPV/r, RBT, and 
RAL steady state plasma concentrations will be obtained as outlined in the Schedule of 
Events. No individual dose adjustments will be made based on drug concentrations for 
accrual period 2 participants. Anti-TB treatment (INH and RIF or RBT) will continue for a 
minimum duration of 24 weeks; EMB and PZA will be discontinued after 8 weeks of TB 
treatment, except as otherwise specified for accrual period 1 participants who had a 
dose adjustment of RBT and/or LPV/r.  
 
NOTE: As participants may enter the study with severe cavitary or extrapulmonary TB, 
or with other manifestations or clinical conditions that meet current 
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(INH and RIF or RBT) beyond 24 weeks up to a maximum of 48 weeks of TB 
treatment will be allowed as determined by the primary clinician and the protocol 
team must be notified. Participants will continue their assigned ARV regimen 
through week 24 or until the completion of anti-TB treatment, and will then 
continue on therapy at the currently recommended standard dose of LPV/r + 2 
NRTIs with or without RAL through week 72. 
 
All participants will receive TB treatment according to in-country TB guidelines for daily 
TB treatment and DOT, except that all study participants will receive daily TB treatment 
7 days per week, i.e., participants will not use a 5 day per week schedule that may be 
recommended in some in-country TB programs.  
 
NOTE: Any participants determined to have clearly inadequate RBT concentrations 
during accrual period 1 evaluation should be monitored closely after dose 
adjustments for TB outcomes throughout the course of their TB treatment. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria  
 
4.1.1 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, plasma 
HIV-1 RNA viral load. 
 
NOTE: The term “licensed” refers to a US FDA-approved kit, which is required for 
all IND studies, or for sites located in countries other than the US, a kit 
that has been certified or licensed by an oversight body within that 
country and validated internally. Non-US sites are encouraged to use US 
FDA-approved methods for IND studies.  
 
WHO and the US Centers for Disease Control and Prevention (CDC) guidelines 
mandate that confirmation of the initial test result must use a test that is different 
from the one used for the initial assessment. A reactive initial rapid test should be 
confirmed by either another type of rapid assay or an E/CIA that is based on a 
different antigen preparation and/or different test principle (e.g., indirect versus 
competitive), or a Western blot, plasma HIV-1 RNA viral load, or an HIV-1 p24 
antigen test. 
 
4.1.2 CD4+/CD8+ T-cell count obtained within 30 days prior to study entry at any 
laboratory that has a CLIA certification or any Division of AIDS (DAIDS) approved 
laboratory. 
 
4.1.3 Confirmed or probable pulmonary or extrapulmonary TB, as defined below. 
 


 
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Confirmed pulmonary TB is defined as the presence of compatible clinical 
symptoms (e.g., cough, hemoptysis, shortness of breath, chest pain, weight loss, 
fever, or night sweats) with or without abnormal chest X-ray, chest computed 
tomography [CT] scan or other chest imaging (e.g., hilar lymphadenopathy, 
paratracheal lymphadenopathy, alveolar consolidation, miliary pattern, lung 
parenchymal breakdown/cavitation, or Ghon focus) and sputum, bronchial 
alveolar lavage fluid, pleural fluid, pleural tissue, lung tissue, or gastric acid 
lavage culture positive for MTB, or a nucleic acid amplification test positive for 
MTB or MTB Complex.  
 
Confirmed extrapulmonary TB is defined as the presence of compatible clinical 
symptoms as previously described plus clinical features of organs involved, such 
as sterile pyuria or other renal involvement, pericarditis, ascites, pleural effusion, 
meningitis, arthritis, orchitis, enteritis, extrathoracic lymphadenitis, or osteitis and 
positive culture for MTB or nucleic acid amplification test positive for MTB or MTB 
Complex from fluid or tissue biopsies from any of these organ or tissue sites, 
including bone marrow, liver, and blood. 
 
Probable Pulmonary TB is based on the clinician’s judgment and includes 
compatible clinical symptoms as previously described, and at least one of the 
following: 1) positive sputum smear for acid fast bacilli (AFB); or  2) abnormal 
CXR, chest CT scan or other chest imaging; or 3) evidence of granulomata with 
organisms positive for AFB or caseating granulomata on lung tissue biopsy; or 4) 
positive tuberculin skin test (TST) (> 5mm) or interferon gamma release assay 
(IGRA); and without concurrent illness that would explain the findings, but MTB 
cultures are negative or not available.  
 
Probable Extrapulmonary TB is based on the clinician’s judgment and includes 
compatible clinical symptoms as previously described plus clinical features of 
organs involved as previously described, or evidence of granulomata with 
organisms positive for AFB or caseating granulomata on tissue biopsy from 
relevant site(s); and specific antituberculous therapy initiated or recommended, 
but MTB cultures are negative or not available.  
 
NOTE: Participants whose qualifying episode of TB was later determined not to 
be TB will continue to be followed on study but off study drugs for safety 
and ART endpoints. 
 
4.1.4 Chest x-ray within 30 days prior to study entry. 
 
4.1.5 A PI-based ART regimen is required, as determined by the participant’s primary 
clinician/clinical facility. 
 
NOTE: Enter the reason, in the eligibility checklist, for the PI-based ART regimen 
from among the following choices: 
 
The PI-based therapy was required: 
 


 
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1)  Because the participant failed an NNRTI regimen or; 
2)  Because the participant had an adverse reaction to an NNRTI regimen or; 
3)  Because the participant received single dose nevirapine during pregnancy 
and could have NNRTI resistance mutations archived at the time the 
participant was starting ART; 
4) Other, specify. 
 
4.1.6 Laboratory values obtained within 14 days prior to study entry: 
 
Accrual period 1 
• 
Absolute neutrophil count (ANC) ≥ 750 cells/mm3 
• 
Hemoglobin ≥ 8.5 g/dL 
• 
Platelet count ≥ 50,000/mm3 
• 
Alanine aminotransferase (ALT) (SGPT)  2 x upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) (SGOT)  5 x ULN 
• 
Total bilirubin  2.5 x ULN 
 
Accrual period 2 
• 
ANC  500 cells/mm3 
• 
Hemoglobin ≥ 7.5 g/dL 
• 
Platelet count ≥ 50,000/mm3 
• 
AST (SGOT) and ALT (SGPT)  5 x ULN 
• 
Total bilirubin  5 x ULN 
 
4.1.7 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.  
 
NOTE: Female participants of reproductive potential are defined as women who 
have reached menarche or who have not been post-menopausal for at 
least 24 consecutive months (i.e., who have had menses within the 
preceding 24 months) or have not undergone surgical sterilization (e.g., 
hysterectomy, or bilateral oophorectomy or salpingectomy). 
 
4.1.8 All participants must agree not to participate in a conception process (e.g., active 
attempt to become pregnant or to impregnate, donate sperm, or in vitro 
fertilization). 
 
4.1.9 Female participants who are participating in sexual activity that could lead to 
pregnancy must agree to use at least two reliable methods of contraception: a 
barrier method of contraception (condoms or cervical cap) together with another 
reliable form of contraception (condoms, with a spermicidal agent; a diaphragm 
or cervical cap with spermicide; an IUD; or hormone-based contraceptive) while 
receiving RIF, or other rifamycin, and for 6 weeks after stopping these drugs.   
 
• 
Female participants who are not of reproductive potential, as defined above, 
or whose male partner(s) have undergone successful vasectomy with 
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reason, are eligible without requiring the use of contraceptives. Participant-
reported history is acceptable documentation of menopause, hysterectomy, 
or bilateral oophorectomy or salpingectomy. 
 
4.1.10 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. 
 
4.1.11 Men and women ≥ 18 years of age, who have attained the minimum age of 
consent, as defined by the local IRB.   
 
4.1.12 Ability to swallow oral medications.  
 
4.1.13 Ability and willingness of participant or legal guardian/representative to provide 
informed consent.   
 
4.2 
Exclusion Criteria 
 
4.2.1 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. 
 
NOTE: Completed TB treatment is defined as completion of an 8-week intensive 
phase of TB treatment with INH and RIF plus at least 2 other anti-TB 
drugs, followed by a 16-week continuation phase of TB treatment with 
INH and RIF for a total duration of at least 24 weeks of TB treatment. 
 
4.2.2 Documented multidrug-resistant tuberculosis (MDR TB) or extensively drug-
resistant (XDR) TB. 
 
NOTE: MDR TB is defined as TB with resistance to RIF and INH. XDR TB is 
defined as MDR TB plus resistance to fluoroquinolones and to at least 
one second-line injectable anti-TB drug. If MDR TB or XDR TB is 
determined based on locally-obtained drug susceptibility testing after 
study entry, the participants will be discontinued from the study and 
referred to their primary clinician/clinical facility or TB and ART program 
and treated with the best available TB and ART according to local 
standards of care. 
 
4.2.3 Participants infected with a rifamycin resistant strain of TB as determined by 
HAIN GenoType MTBDR Plus line probe assay or, GeneXpert® MTB/RIF assay 
(or, following approval of the core team, a result from another locally-obtained 
standardized RIF drug susceptibility test). Participants found to have a rifamycin- 
resistant strain of TB should be referred for management according to the site’s 
standard of care.  
 
NOTE A:  Participants may be enrolled pending the results of RIF drug 
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assay, GeneXpert® MTB/RIF assay, or other rapid MTB RIF drug 
resistance assay result is not yet available. However, if RIF drug-
susceptibility test results are not available within 60 days after study 
entry or if any drug susceptibility testing subsequently demonstrates 
RIF resistance, participants will be discontinued from the study and 
referred to their primary clinician/clinical facility or TB and ART 
program and treated with the best available TB and ART according to 
local standards of care. 
 
NOTE B:  All specimens available from participants at entry should also be tested 
for INH drug susceptibility (as per the SOE and section 6.3.2), 
however, INH monoresistance (i.e., the baseline isolate is resistant 
only to INH) is not an exclusion criterion for enrollment. If the HAIN 
GenoType MTBDR Plus line probe assay is used or if any other rapid 
drug susceptibility test is used that also supplies information on INH 
susceptibility, these results will be recorded. If a GeneXpert MTB/RIF 
assay is used, which only detects RIF resistance, then samples should 
also be tested with another standardized method that also evaluates 
INH susceptibility.  
 
4.2.4 Receipt of more than 28 cumulative days of anti-TB treatment for the current TB 
episode prior to study entry. 
 
NOTE: Receipt of therapy for latent TB is permitted as is receipt of short-term 
augmentin or a fluoroquinolone (for < 14 days) for treatment of bacterial 
infections. 
 
4.2.5 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements. 
 
4.2.6 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.   
 
4.2.7 Pregnant or breastfeeding.  
 
4.2.8 Anticipated receipt of any of the prohibited medications listed in section 5.4.2. 
 
4.2.9 Known intolerance/allergy/sensitivity or any hypersensitivity to components of 
study drugs or their formulations. 
 
4.2.10 History of close contact with known MDR or XDR TB patients at any time prior to 
study entry.  
 
NOTE: Close contact is defined as participant history of prolonged, frequent, or 
intense contact approximating > 8 hours per day with a person known to 
have infectious MDR or XDR TB e.g., household, other congregate living 
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4.3 
Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol consent forms 
approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving 
final approval, sites will submit all required protocol registration documents to the 
Division of AIDS (DAIDS) Protocol Registration Office (PRO) at the Regulatory 
Support Center (RSC). The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been 
received.  
 
For studies at non-US sites, protocol activation is required prior to enrolling 
participants into the study. 
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by 
the DAIDS PRO, and sites will receive an Initial Registration Notification from the 
DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the 
site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an 
amendment, sites should implement the amendment immediately. Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the 
RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICFs 
WILL NOT be reviewed and approved by the DAIDS PRO, and sites will receive 
an Amendment Registration Notification when the DAIDS PRO receives a 
complete registration packet. A copy of the Amendment Registration Notification 
should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific 
documents required for initial and amendment registrations, refer to the current 
version of the DAIDS Protocol Registration Manual. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the participant. The participant will be asked to read and sign the 
approved protocol consent form. For participants from whom a signed informed 
consent has been obtained, an ACTG Screening Checklist must be entered 
through the Data Management Center (DMC) Subject Enrollment System.  
 
4.3.2 Randomization/Subject Registration 
 
For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database.  
 


 
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4.4 
Coenrollment Guidelines 
 
Sites are encouraged to coenroll participants in A5243, “Plan for Obtaining Human 
Biological Samples at Non-US Clinical Research Sites for Currently Unspecified Genetic 
Analyses.” Coenrollment in A5243 does not require permission from the A5290 protocol 
chairs. For specific questions and approval for coenrollment in other studies, sites must 
contact the protocol chairs via e-mail as described in the Study Management section. 
 
 
5.0 
STUDY TREATMENT 
 
5.1 
Regimens, Administration, and Duration 
 
5.1.1 For Participants Enrolled During Accrual Period 1 
 
At entry, participants will be randomized (1:1:1) to one of the following three 
arms: Arm A, Arm B, and Arm C as further defined in this section. Anti-TB 
therapy with study-provided RBT or non-study-provided RIF and non-study- 
provided INH, EMB, and PZA should be started within 72 hours of randomization. 
ART should be started as soon as possible after initiating anti-TB therapy, but 
may be delayed for up to 7-14 days after initiation of anti-TB therapy to allow for 
assessment of initial tolerability of TB medications.    
 
5.1.1.1 Arm A 
 
ART  
Entry through Week 72  
• 
LPV 400 mg/ RTV 100 mg orally twice daily plus 2 NRTIs 
• 
After completion of TB treatment, ART will continue at initial dosing 
through week 72: LPV 400 mg/ RTV 100 mg orally twice daily plus 2 
NRTIs 
 
Anti-TB Therapy 
Participants will receive the following anti-TB medications with 
recommended dosing, unless dose adjustments are required (see Table 
5.1): 
 
Entry through Week 8 study visit (or until completion of intensive TB 
treatment as determined after dose adjustment in accrual period 1 
participants) 
• 
INH 300 mg orally once daily 
• 
RBT 300 mg orally once daily, then 150 mg orally once daily upon 
initiation of ART* 
• 
EMB (15 to 20 mg/kg) orally once daily  
• 
PZA (20 to 30 mg/kg) orally once daily (not to exceed 2 g per day) 
• 
Pyridoxine 25 mg orally once daily 
 


 
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Week 8 study visit through Week 24 (or as determined by primary 
clinician if longer anti-TB treatment required) 
• 
INH 300 mg orally once daily 
• 
RBT 150 mg orally once daily 
• 
Pyridoxine 25 mg orally once daily 
• 
INH, RBT, and pyridoxine will continue through week 24 for a 
minimum total duration of 24 weeks  
 
INH, RBT, and pyridoxine may continue beyond 24 weeks to a maximum 
of 48 weeks at the discretion of the primary clinician, and the protocol 
core team must be notified. 
 
5.1.1.2 Arm B 
 
ART  
Entry through Week 72 
• 
LPV 800 mg/ RTV 200 mg orally twice daily plus 2 NRTIs, unless 
dose adjustments are required (see Table 5.1) 
• 
After completion of TB treatment, ART will change to standard dosing 
(LPV 400 mg/RTV 100 mg orally twice daily plus 2 NRTIs) through 
week 72 
 
Anti-TB Therapy 
Participants will receive the following anti-TB medications with 
recommended dosing: 
 
Entry through Week 8 study visit (or until completion of intensive TB 
treatment as determined after dose adjustment in accrual period 1 
participants) 
• 
INH 300 mg orally once daily 
• 
RIF (weight-based dose; for weight < 45 kg: 450 mg orally once daily; 
for weight > 45 kg: 600 mg orally once daily) orally once daily  
• 
EMB (15 to 20 mg/kg) orally once daily 
• 
PZA (20 to 30 mg/kg) orally once daily (not to exceed 2 g per day) 
• 
Pyridoxine 25 mg orally once daily 
 
Week 8 study visit through Week 24 (or as determined by primary 
clinician if longer anti-TB treatment required) 
• 
INH 300 mg orally once daily 
• 
RIF (weight-based dose; for weight < 45 kg: 450 mg orally once daily; 
for weight > 45 kg: 600 mg orally once daily) orally once daily  
• 
Pyridoxine 25 mg orally once daily 
• 
INH, RIF, and pyridoxine will continue through week 24 for a minimum 
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INH, RIF, and pyridoxine may continue beyond 24 weeks to a maximum 
of 48 weeks at the discretion of the primary clinician and the protocol core 
team must be notified. 
 
5.1.1.3 Arm C 
 
ART  
Entry through Week 72 
• 
LPV 400 mg/ RTV 100 mg orally twice daily plus 2 NRTIs 
• 
RAL 400 mg orally twice daily 
• 
After completion of TB treatment, ART will continue at initial entry 
dosing through week 72: LPV 400 mg/ RTV 100 mg orally twice daily 
plus 2 NRTIs and RAL 400 mg orally twice daily 
 
Anti-TB Therapy 
Participants will receive the following anti-TB medications with 
recommended dosing, unless dose adjustments are required (see Table 
5.1): 
 
Entry through Week 8 study visit (or until completion of intensive TB 
treatment as determined after dose adjustment in accrual period 1 
participants) 
• 
INH 300 mg orally once daily 
• 
RBT 300 mg orally once daily, then 150 mg orally once daily upon 
initiation of ART* 
• 
EMB (15 to 20 mg/kg) orally once daily  
• 
PZA (20 to 30 mg/kg) orally once daily (not to exceed 2 g per day) 
• 
Pyridoxine 25 mg orally once daily 
 
Week 8 study visit through Week 24 (or as determined by primary 
clinician if longer anti-TB treatment required) 
• 
INH 300 mg orally once daily 
• 
RBT 150 mg orally once daily 
• 
Pyridoxine 25 mg orally once daily 
• 
INH, RBT, and pyridoxine will continue through week 24 for a 
minimum total duration of 24 weeks 
 
INH, RBT, and pyridoxine may continue beyond 24 weeks to a maximum 
of 48 weeks at the discretion of the primary clinician, and the protocol 
core team must be notified. 
 
*NOTE: In Arms A and C, RBT should be administered at a dose of 300 
mg daily until the start of antiretroviral therapy at which time the 
dose should be reduced to the 150 mg daily dose. All participants 
will receive TB treatment according to in-country TB guidelines for 
daily TB treatment and Directly Observed Therapy (DOT), except 
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per week, i.e., participants will not use a 5 days per week 
schedule that may be recommended in some in-country TB 
programs. 
 
If dose adjustments of LPV/r or RBT are deemed necessary, the intensive TB 
treatment phase will be extended at the adjusted dose for the relevant 
participants in the affected treatment arm, and participants will undergo additional 
drug level assessment (see detailed description in section 3.0). 
 
Any participants determined to have clearly inadequate RBT concentrations 
during the accrual period 1 PK evaluation should be monitored closely after dose 
adjustments for TB outcomes throughout the course of their TB treatment. 
 
If LPV/r is prematurely discontinued at any time during TB treatment, the team 
should be notified, and the RBT dose should be increased to 300 mg daily 
pending further instructions from the team. 
 
Site pharmacists must receive new prescriptions from an authorized prescriber 
for dosing changes. 
 
NOTE: A two accrual period design will be used as previously described. 
Because participants enrolled in the accrual period 1 will be undergoing 
treatment for active TB, they will continue on their randomized regimen 
pending the outcome of the accrual period 1 interim PK and safety 
evaluations. No participants will be enrolled in the accrual period 2 until 
completion of the accrual period 1 analysis and determination of 
subsequent dosing for LPV/r and RBT is made. 
 
If, based on the SMC’s determination, unacceptable PK or safety criteria are met 
within two treatment arms, then further enrollment into the study may be stopped, 
and the accrual period 1 participants will be managed according to best available 
local TB and antiretroviral treatment. These participants will be followed off study 
medication for the remainder of study follow-up (up to 72 weeks). 
 
Table 5.1. LPV/r and RBT Dose Adjustment Table  
 
 
LPV/r Dose Adjustment 
Rifabutin Dose Adjustment 
Arm A 
No dose adjustment 
RBT PK parameters low: Adjust RBT to RBT 
300 mg orally three times weekly (TIW) or 
300 mg orally once daily (see section 10.4). 
 
RBT PK parameters high: Decrease RBT to 
RBT 150 mg orally TIW 
 
NOTE: The RBT Cmax will be used for the 
purpose of individual dose adjustment for low 
or high RBT concentrations. A low RBT 
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RBT Cmax will be greater than 900 ng/mL. 
Arm B 
• 
LPV Cmin < 1 mg/L and Cmax < 
12 mg/L: add LPV 200 mg/RTV 50 
mg (one additional fixed-dose 
combination tablet) twice daily 
• 
LPV Cmin < 1 mg/L and Cmax > 
12 mg/L: add one additional RTV 
100 mg tab tablet twice daily  
NOTE:  A LPV C12 (or trough) will be used 
to define whether an individual subject’s 
LPV/r dose is too low.   
N/A 
Arm C 
No dose adjustment 
RBT PK parameters low: Adjust RBT to RBT 
300 mg orally TIW or 300 mg orally once 
daily (see section 10.4). 
 
RBT PK parameters high: Decrease RBT to 
RBT 150 mg orally TIW 
 
NOTE: See Arm A for definition of RBT low 
and high concentrations.   
 
Rifabutin Dose Adjustment:  
RBT concentrations clearly associated with therapeutic success or an increased 
incidence of toxicity have not been established, although the range of 300-900 
ng/mL for Cmax has been associated with acceptable TB outcomes in a small 
number of patients. The RBT Cmax will be used for the purpose of individual dose 
adjustment for low or high RBT concentrations. A low RBT Cmax will be defined as 
< 250 ng/mL. This concentration represents the 25th percentile of RBT Cmax 
values in 14 HIV and TB infected persons receiving a RBT dose of 150 mg once 
daily given in conjunction with LPV/RTV40. A high RBT Cmax will be greater than 
900 ng/mL. This concentration is greater than 2 standard deviations in healthy 
volunteers receiving a 300 mg once daily RBT dose43. The 300 mg RBT once 
daily dose is the usual RBT dose prior to an adjustment for the drug-drug 
interaction with LPV/RTV; a Cmax > 900 ng/mL would represent an exposure 
above that usually seen in healthy volunteers or persons with TB.   
 
LPV/r Dose Adjustment: 
A LPV C12 (or trough) less than 1 mg/L will be used to define whether an 
individual participant’s LPV/r dose is too low. A C12 value less than 1 mg/L is less 
than the 25th percentile of C12h concentrations in a small study of HIV and TB 
infected persons receiving double dose LPV/RTV (i.e. 800/200 twice daily) with 
RIF, 600 mg once daily27. A 12-hour post dose plasma concentration (C12h) value 
less than 1 mg/L is also considered the minimum threshold value for LPV by the 
DHHS Guidelines Panel. A Cmax value > 12 mg/L is  the 75th percentile in HIV-
infected persons receiving the usual twice daily 400/100 LPV/RTV dose.   
 


 
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NOTE: No substantive effect of RBT on LPV concentrations is expected based 
on prior PK data with this combination; however, if LPV levels in the 
ranges noted for Arm B are observed in Arm A or Arm C, then dose 
adjustments will be the same as for Arm B. 
 
5.1.2 For Participants Enrolled During Accrual Period 2 
 
Once the accrual period 1 PK and safety analysis is completed and a 
determination is made to begin enrollment to accrual period 2, additional 
participants will be randomized into one of three treatment arms: Arm A, Arm B, 
and Arm C. Dosing for each treatment arm in accrual period 2 will be based on 
final dosing from the corresponding treatment arm during the dose-finding period 
in accrual period 1 participants.   
 
5.1.3 Administration 
 
LPV 400 mg/ RTV 100 mg will be administered as two 200 mg/ 50 mg fixed-dose 
combination tablets orally twice daily. 
 
LPV 800 mg/ RTV 200 mg will be administered as four 200 mg/ 50 mg fixed-dose 
combination tablets orally twice daily. 
 
Additional LPV/r doses, if required as part of dose adjustments, will be 
administered as one 200 mg/ 50 mg fixed-dose combination tablet orally twice 
daily added to the original dose. 
 
Additional RTV doses, if required as part of dose adjustments, will be 
administered as one 100 mg tablet orally twice daily. 
 
RAL will be administered as one 400 mg tablet orally twice daily. 
 
RBT 150 mg will be administered as one 150 mg capsule orally once daily, or if 
dose adjusted, as one 150 mg capsule orally three times weekly. 
 
RBT 300 mg will be administered as two 150 mg capsules orally once daily, or 
when dose adjusted, as 300 mg (two 150 mg capsules) orally three times weekly. 
 
All TB medications and pyridoxine obtained locally by the site will be 
administered as per manufacturer information or package insert. 
 
For accrual period 1 participants in Arms A and C, it is necessary for the once 
daily dose of RBT to be taken with the morning dose of LPV/RTV, and for Arm C 
participants that the morning dose of RAL be taken with the morning dose of 
LPV/RTV and RBT.   
 
In general, RBT, LPV/r, and RTV if used separately, should be taken with food; 
however, high fat meals should be avoided. Other anti-TB medications should be 
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the participant that if he/she does eat prior to coming to the clinic to avoid high fat 
meals. Specific timing of doses for PK assessments may differ from these 
general instructions and are indicated in section 10.0 (also see section 6.3.11). 
 
5.1.4 Duration 
 
ART will continue through week 72 after study entry. Anti-TB treatment will 
continue for a minimum total duration of 24 weeks to a maximum of 48 weeks as 
specified by the participant’s local primary clinician. 
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 Lopinavir/Ritonavir (LPV/RTV, Aluvia, Kaletra): 200 mg LPV and 50 mg RTV in 
each fixed-dose, film-coated tablet. Store at 20°-25°C (68°-77°F); excursions 
permitted to 15°-30°C (59°-86°F). Dispense in original container. Exposure of this 
product to high humidity outside the original container for longer than 2 weeks is 
not recommended.  
 
5.2.2 Raltegravir (RAL, Isentress): 400 mg tablets must be dispensed in the original 
bottle with the desiccant provided. Store at 20°-25°C (68°-77°F); excursions 
permitted to 15°-30°C (59°-86°F).  
 
5.2.3 Ritonavir (RTV, Norvir): 100 mg tablets. Store at 20°-25°C (68°-77°F); excursions 
permitted to 15°-30°C (59°-86°F). Exposure of this product to high humidity 
outside the original or USP equivalent container for longer than 2 weeks is not 
recommended. 
 
5.2.4 Rifabutin (RBT, Mycobutin): 150 mg capsules. Keep tightly closed and dispense 
in a tight container as defined in the USP. Store at 25°C (77°F); excursions 
permitted to 15°-30°C (59°-86°F). 
 
5.2.5 All other TB medications and pyridoxine obtained locally by the site will be stored 
as per manufacturer information or package insert. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Product Supply 
 
Lopinavir/ritonavir and ritonavir will be supplied by Abbott Laboratories. 
 
Raltegravir will be supplied by Merck & Co., Inc. 
 
Rifabutin will be supplied by Pfizer Inc. 
 
Lopinavir/ritonavir, ritonavir, raltegravir, and rifabutin will be made available 
through this study. Isoniazid, rifampin, ethambutol, pyrazinamide, pyridoxine and 
NRTI background will not be provided through the study and must be obtained by 
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Fixed-dose combination TB treatment tablets will be permitted for this study only 
for participants randomized to Arm B. Fixed-dose combination tablets containing 
INH, RIF, EMB, and PZA may be used during the intensive phase of TB 
treatment and fixed-dose combination tablets containing INH and RIF may be 
used for the continuation phase of TB treatment.  
 
Fixed-dose combination TB treatment tablets will not be permitted for participants 
randomized to Arms A or C.  
 
5.3.2 Study Product Acquisition/Distribution 
 
All study-provided ARVs and rifabutin will be available through the NIAID Clinical 
Research Products Management Center (CRPMC). The site pharmacist can 
obtain study product for this protocol by following the instructions in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks in the 
section Study Product Management Responsibilities. 
No other TB treatment agents will be provided through this study.  
 
5.3.3 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. At non-US 
clinical research sites, the site pharmacist must follow the instructions provided in 
the manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks in the section Study Product Management Responsibilities for the 
destruction of unused study products. 
 
5.4 
Concomitant Medications 
 
Below are lists of selected concomitant medications. These lists are only current as of 
the date of this protocol. Therefore, whenever a concomitant medication or study agent 
is initiated or a dose changed, investigators must review the concomitant medications’ 
and study agents' most recent package inserts, Investigator’s Brochures, or updated 
information from DAIDS to obtain the most current information on drug interactions, 
contraindications, and precautions. 
 
Additional drug information may be found in the ACTG Drug Interaction Database on the 
ACTG website at: https://actgnetwork.org/ACTG-Drug-Interactions-Database. 
 
5.4.1 Required Medications 
 
None. 
 
5.4.2 Prohibited Medications 
 
For a list of prohibited medications, refer to the PSWP. 
 


 
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5.4.3 Precautionary Medications 
 
For a list of precautionary medications, refer to the PSWP. 
 
5.5 
Adherence Assessment 
 
Adherence to ARVs and TB treatment will be assessed using study-specific CRFs. Pill 
counts will also be performed. Participants who are receiving TB treatment outside the 
study clinic will be expected to bring their TB treatment records with them to each visit.    
 


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Events  
 
Evaluation 
Screening 
Entry 
PK Visit Day 
12 ± 2 days 
after 
initiation of 
ART*** 
Post-Entry Evaluations 
(Weeks) 
Time 
of 
MTB 
IRIS 
 
Virologic 
Failure 
Time of 
Suspected 
TB 
Treatment 
Failure or 
Recurrence 
Premature 
ARV and/or 
TB Treatment 
and Premature 
Disc. Evals 
Visit Window ± 7 days 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
 
72 
 
Documentation of HIV-1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AFB, TB Culture, and Drug 
Sensitivity* 
 
X 
 
 
X 
X 
If still TB-positive, repeat 
every 4 weeks until 2 
consecutive TB-negative 
cultures 
 
 
 
X 
 
Medical History/Medication 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments, 
Including TB Evaluations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence Assessment - 
Pill Counts 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
TB Treatment Status and 
Outcome Determination 
 
 
 
 
 
 
 
 
 
At 
comple-
tion of 
TB 
treat-
ment 
 
X 
X 
 
 
X 
X 
Chest X-Ray 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
Hematology 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
 
 
X 
Liver Function Tests 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
Blood Chemistries 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
Pregnancy Test** 
X 
X 
 
Repeat as indicated 
 
 
 
 
CD4+/CD8+ 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 


 
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Evaluation 
Screening 
Entry 
PK Visit Day 
12 ± 2 days 
after 
initiation of 
ART*** 
Post-Entry Evaluations 
(Weeks) 
Time 
of 
MTB 
IRIS 
 
Virologic 
Failure 
Time of 
Suspected 
TB 
Treatment 
Failure or 
Recurrence 
Premature 
ARV and/or 
TB Treatment 
and Premature 
Disc. Evals 
Visit Window ± 7 days 
2 
4 
8 
12 
16 
20 
24 
32 
40 
48 
 
72 
 
Plasma HIV-1 RNA 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
HIV Resistance Testing 
(Stored Plasma) 
 
X 
Collect at confirmation of virologic failure 
Stored Plasma and PBMC 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
Population PK for Accrual 
Period 2 (see section 
10.5.2) 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Intensive Pharmacokinetic 
Studies for Accrual Period 
1 (refer to section 10.2.2) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
Stored Urine 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
Sputum Sample Storage 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
* If the participant has exclusively extrapulmonary TB and sputum cannot be induced, a sputum sample is not required, but a specimen from any clinically relevant extrapulmonary 
site, if available (e.g., pleural, pericardial, or peritoneal fluid or tissue biopsy; aspirate of lymph node, cold abscess, bone marrow or joint fluid; cerebrospinal fluid; liver, bone marrow 
or other tissue biopsy or; blood) should be submitted for AFB smear, mycobacterial culture, and TB drug susceptibility testing (see section 6.2.6). Drug susceptibility results for both 
RIF and INH should be recorded when available. 
** The pregnancy test must be negative within 7 days prior to study entry and 72 hours of starting study medications. 
***Unless the week 2 or week 4 visit did not take place, the full Clinical Assessment does not need to be conducted. If the week 2 visit or week 4 visit did take place, only the vital 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to randomization. Screening evaluations 
to determine eligibility must be completed within 14 days prior to study entry 
unless otherwise specified. The pregnancy test must be negative within 7 days 
prior to study entry and 72 hours of starting study medications. CD4+/CD8+ T-
cell count, and viral load should be completed up to 30 days prior to study entry. 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database. A 
Screening Failure Results form must be completed for consented individuals who 
do not enter the study.  
 
6.2.2 Randomization and Entry Evaluations 
 
Entry evaluations will occur after randomization. Entry evaluations and initiation 
of anti-TB therapy with study provided RIF or RBT and non-study provided INH, 
EMB and PZA should be started within 72 hours of randomization. ART should 
be started as soon as possible after initiating anti-TB therapy, but may be 
delayed for up to 7-14 days after initiation of anti-TB therapy to allow participants 
sufficient time to assess tolerability of TB medications. Dates of initiation of all 
study provided and non-study provided anti-TB and ART medications will be 
entered into the ACTG database. 
 
6.2.3 Post-Entry Evaluations 
 
Study visits must be scheduled ± 7 days of the weeks indicated in the Schedule 
of Events (SOE). There should be no study visits after the week 72 (final study) 
visit.  
 
NOTE: The PK visit on day 12 (after initiation of ART) has a window of ± 2 days, 
and therefore, could be combined with the week 2 or 4 visit.  
 
6.2.4 Time of MTB IRIS 
 
Participants who develop symptoms consistent with IRIS or MTB IRIS at any time 
through week 72 should have the evaluations listed in the SOE as soon as 
possible after presentation. See the ACTG definition of MTB IRIS in the current 
ACTG diagnosis appendix or on the ACTG website under Protocol Support 
Resources (the definition is identified on the CRF). MTB IRIS will be reported on 
the MTB IRIS CRF. 
 
Sites must remember that reporting of an IRIS or MTB IRIS event includes 
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related to the IRIS episode on the appropriate IRIS Update Form, as well as 
subsequently recording eventual resolution of that event. 
6.2.5 Virologic Failure 
 
The visit evaluations required at the time of confirmation of virologic failure (as 
per the SOE) will be determined after the results of the second consecutive 
(confirmatory) specimen are available; virologic failure is defined as a confirmed 
HIV-1 RNA level  1000 copies/mL at or after 16 weeks and before 24 weeks of 
ART or  400 copies/mL at or after 24 weeks of treatment. 
 
6.2.6 Time of Suspected TB Treatment Failure or Recurrence 
 
A participant must undergo the evaluations indicated in the SOE under TB 
treatment failure or recurrence within 28 days of the site becoming aware of a 
possible TB treatment failure or recurrence of TB disease as indicated below. TB 
treatment failure should be suspected for participants who have not resolved 
their signs and symptoms related to the qualifying episode of TB or have a 
persistently positive AFB smear in sputum or other body fluid or tissue sample 
after completion of the intensive phase of TB treatment. TB treatment failure is 
confirmed if a TB-positive mycobacterial culture is obtained from any site after 
week 16 of TB treatment. 
 
Participants who have resolved their signs and symptoms related to the 
qualifying episode of TB and have negative AFB smears and mycobacterial 
cultures, if available, but have a recurrence of signs or symptoms of TB at any 
time at or after week 24 and before the week 72 endpoint should return for an 
interim visit as soon as possible after presentation. A sputum sample should be 
obtained for AFB smear and culture, and a chest x-ray or other radiographic 
evaluation as indicated should be performed. Any results from repeated sputum 
and chest x-ray evaluations must be documented. If the participant enrolled with 
exclusively extrapulmonary TB and no new pulmonary signs or symptoms are 
present, a sputum sample is not required, but a specimen from any clinically 
relevant extrapulmonary site, if available (e.g., pleural, pericardial, or peritoneal 
fluid or tissue biopsy; aspirate of lymph node, cold abscess, bone marrow or joint 
fluid; cerebrospinal fluid; liver, bone marrow or other tissue biopsy or; blood) 
should be submitted for AFB smear, mycobacterial culture, and TB drug 
susceptibility testing. Any information that is provided by the local TB clinic 
related to TB recurrence must be recorded on the CRFs when received, as noted 
for TB evaluations above. Any positive sputum or other body fluid or tissue 
culture should be stored at the site or in the local TB laboratory as appropriate to 
site procedures. 
 
6.2.7 Discontinuation Evaluations 
 
Evaluations for Randomized Participants Who Do Not Start Study Treatment 
All CRFs must be completed and keyed for the period up to and including week 
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Premature ARV and/or TB Treatment and Premature Discontinuation Evaluations 
Participants who prematurely discontinue from the study, and participants who 
prematurely discontinue ARV and/or TB treatment, will have the discontinuation 
evaluations performed as noted in the SOE within 4 weeks after the 
discontinuation. If the participant discontinues any study-provided ARV, he/she 
will continue on the remaining study-provided ARVs and the date of the 
discontinuation of any study-provided (or study treatment) ARV drug and reason 
for discontinuation will be entered on the Antiretroviral Regimen Record. If the 
participant discontinues any study-provided TB drug, he/she will continue on the 
remaining TB drugs and the date of the discontinuation of the study-provided (or 
study treatment) TB drug and the reason for discontinuation will be entered on 
the TB Treatment Record. 
 
When the participant takes the last dose of the last study-provided (or study 
treatment) drug (ARV and/or TB drugs), the Permanent Discontinuation of Study 
Drugs form will be completed with the date of study drug discontinuation and the 
reason for discontinuation. If the participant discontinues all study-provided (or 
study treatment) ARV or TB drugs prematurely, he/she will be encouraged to 
continue on study, off study treatment, and receive all evaluations as per the 
SOE through week 72.  
 
6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
Web site for information about what must be included in the source document:  
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/sourced
ocappndx.pdf. 
 
All stated evaluations are to be recorded on the CRF and keyed into the database 
unless otherwise specified. This includes events that meet the International Conference 
on Harmonisation (ICH) definitions for a serious adverse event (SAE), regardless of 
relatedness or association to study medications. Refer to section 11.4.2 for the lists of 
SAEs and additional events required to be recorded on the CRF and keyed into the 
database.  
 
To grade diagnoses, signs and symptoms, and laboratory results, sites must refer to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 1.0, December 2004 (Clarification, August 2009), which can be 
found on the DAIDS RSC Web site: http://rsc.tech-
res.com/safetyandpharmacovigilance/. 
 
6.3.1 Documentation of HIV-1 
 
Please refer to section 4.1.1 regarding assay requirements for HIV-1 
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6.3.2 Acid Fast Bacilli (AFB), TB Culture, and Drug Sensitivity 
 
At or within 30 days prior to study entry, all participants should have a sputum 
sample collected for AFB smear, mycobacterial culture, speciation (if culture 
positive), and TB drug susceptibility (if MTB culture positive) testing to be 
performed locally or at a reference laboratory. The ability to produce a sputum 
sample is not a requirement for enrollment into the study; however, once entered, 
site staff must attempt to obtain a sputum sample and can induce a sputum 
sample if the participant is not able to produce one on his/her own.   
 
NOTE: If the participant has exclusively extrapulmonary TB and sputum cannot 
be induced, a sputum sample is not required, but a specimen from any 
clinically relevant extrapulmonary site (e.g., pleural, pericardial, or 
peritoneal fluid or tissue biopsy; aspirate of lymph node, cold abscess, 
bone marrow or joint fluid; cerebrospinal fluid; liver, bone marrow or other 
tissue biopsy or; blood), if available, should be submitted for AFB smear, 
mycobacterial culture, and TB drug susceptibility testing. 
 
Documentation for the current episode of TB should include any TB treatment 
initiated for the qualifying (current) episode prior to randomization, any known TB 
diagnostic test results available (e.g., culture from any samples, including blood, 
or cerebrospinal fluid (CSF), drug susceptibility test results, and histopathology 
results), and any radiologic exams documenting manifestations of TB. Record 
this information on the CRFs.  
 
At week 8 and week 12, a sputum sample will be collected and tested as above. 
See below for additional sputum collection instructions if the culture is positive for 
TB.    
 
Entry and Subsequent Sputum Collections 
At entry (not required if obtained within 3 days prior to entry), week 8, week 12, 
and at the time of suspected TB treatment failure/TB recurrence, participants will 
be given sterile collection containers to collect first morning expectorated sputum 
the day of their clinic visit. These specimens will be collected by induction if they 
cannot be spontaneously produced. 
 
Sputum will be collected as described below:  
 
• 
If the final dose of intensive phase of INH, RIF or RBT, EMB and PZA 
coincides with the week 8 visit, collect sputum samples within 72 hours of 
ingestion of the final dose of intensive phase of TB treatment and prior to the 
ingestion of the second dose of continuation phase TB medications.  
 
• 
If the final dose of intensive phase INH, RIF or RBT, EMB and PZA does 
NOT coincide with the week 8 visit, (a) collect a sputum sample at week 8, 
and (b) schedule a separate visit within 72 hours of ingestion of the final dose 
of intensive phase of TB treatment and prior to the ingestion of the second 
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• 
From week 16 onward, collect single sputum samples every 4 weeks 
(monthly) for smear and cultures if sputum culture results have not 
demonstrated two consecutive TB-negative cultures after week 12, and 
discontinue monthly smear and cultures once there are two consecutive TB-
negative sputum cultures. Drug susceptibility testing on available samples 
should be done if the sputum culture remains MTB positive after the week 8 
timepoint. 
 
If the sputum sample does not become TB-negative by the week 16 time point, 
the participant has failed TB treatment. The participant will be taken off study TB 
medications and will be treated for possible drug-resistant TB at the discretion of 
the primary clinician according to local, national, or international guidelines used 
for treatment of drug-resistant TB. These participants will be followed on study, 
but off study-provided TB drugs until week 72. If the participant must discontinue 
study-provided TB treatment, he/she may still continue to take study-provided 
ARVs.  
 
Collect sputum in a sterile single-use collection container. If possible, the oral 
cavity should be rinsed with clean water that is expectorated prior to giving the 
sample. The specimen should contain 3-5 mL of sputum. 
 
Participants who are unable to expectorate or who submit an inadequate 
specimen may have sputum collected in the clinic by study staff. Induction by 
aerosolized inhalation of sterile nebulized saline will be required for participants 
who cannot expectorate. Participants who cannot produce sputum even with 
induction will have this noted on the CRF. At subsequent visits, these participants 
will not undergo sputum induction if they remain without a cough, with the 
exception of week 8, at which point all participants will attempt to provide sputum, 
via induction, if necessary. Collection method, timing, volume, and appearance of 
sputum must be recorded on the CRF. Specimens should be refrigerated at 4°C 
within 1 hour of collection whenever possible and should be transported on ice or 
cold pack, if available, to the lab as soon as possible. 
 
NOTE: If the participant entered the study with exclusively extrapulmonary TB 
and does not develop pulmonary signs, symptoms, or cough at any time 
during follow-up, he/she will not have sputa submitted. 
 
6.3.3 Medical History 
 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses. For current criteria, refer to the appendix 
identified in the study CRF. Any allergies to any medications and their 
formulations must be documented.  
 
Documentation of historical information for all prior TB episodes will include any 
available information about diagnosis dates, and any available results of TB 
cultures, AFB smear results, TB drug susceptibility testing, and TB treatment 
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and stop dates if known or estimated duration of prior TB treatment if start and 
stop dates are unavailable), and all other information for prior TB episodes 
should be documented in the source document only. 
 
All other diagnoses identified by the ACTG criteria for clinical events and other 
diseases must be recorded on the CRF and in the source document.  
6.3.4 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history.  
 
Medication Category 
Complete History or Timeframe 
CRF / Source Document 
TB therapy for the 
current episode 
Complete history 
CRF and source document 
Immune-based therapy 
Complete history 
CRF and source document 
Blinded study treatment 
Complete history 
CRF and source document 
HIV-1-related vaccines 
Complete history 
CRF and source document 
Prescription drugs for 
treatment of opportunistic 
infections 
Complete history 
CRF and source document 
Prescription drugs for 
prophylaxis of 
opportunistic infections 
Within 30 days prior to study entry 
CRF and source document  
ART  
Complete history 
CRF 
Prescription drugs (other)
Within 30 days prior to study entry 
CRF and source document 
Non-prescription drugs 
Within 30 days prior to study entry 
Source document 
Alternative therapies 
Currently being taken 
Record as yes/no on CRF;  
if yes, record details in source 
document 
Dietary supplements 
Currently being taken 
CRF 
 
6.3.5 Clinical Assessments, Including TB Evaluations 
 
Complete Physical Exam 
A complete physical examination will be performed at screening only and will 
include at a minimum an examination of the skin, head, mouth, and neck; 
auscultation of the chest; cardiac exam; abdominal exam; examination of the 
lower extremities for edema; and Karnofsky performance score. The complete 
physical exam will also include signs and symptoms, diagnoses, vital signs 
(temperature, pulse, respiration rate, and blood pressure), and a measurement of 
height and weight. Standardized blood pressure is not required for A5290. 
 
Targeted Physical Exam 
After screening, a targeted physical examination is to be driven by any previously 
identified or new signs or symptoms including diagnoses that the participant has 
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(temperature, pulse, respiration rate, and blood pressure), examination for the 
presence of thrush, lymphadenopathy, presence of rash, and lung examination.  
 
Signs and Symptoms 
At entry, all grades that occurred within 30 days prior to study entry must be 
recorded; post-entry, all signs and symptoms  Grade 3 must be recorded. 
Record all signs and symptoms that led to a change in treatment, regardless of 
grade.  
 
At entry, all TB-related signs and/or symptoms that occurred within 30 days prior 
to study entry must be recorded. These include, but are not limited to, fever, 
weight loss, lymphadenopathy, pulmonary signs and symptoms, and evidence of 
extrapulmonary disease (e.g., meningitis), presence of wasting, cold abscesses, 
or abdominal disease. 
 
After entry, resolution of TB-related signs and symptoms reported at entry will be 
recorded. Any new or resolved Grade  2 TB signs or symptoms reported after 
entry will be recorded on the CRF. 
 
TB Evaluations 
A review of all reported results from evaluations for the qualifying episode of TB 
performed at the local clinical or TB program site must be completed for all 
participants. At each visit, all diagnostic, laboratory and radiology results, and 
treatment information available regarding the qualifying (current) episode of TB, 
including any that is provided by the local TB clinic, must be recorded on the 
CRFs when received. This will include TB-related radiologic results, including 
most recent chest x-ray, AFB smear and culture results, and other evaluations 
related to TB diagnosis and evaluation of TB status. Any changes in results from 
repeated radiologic evaluations must be documented.  
 
Participants whose qualifying episode of TB is later identified as drug-resistant 
according to the inclusion and exclusion criteria in section 4.0 will be 
discontinued from the study and referred to their primary clinician/clinical facility 
or TB and ART program and treated with the best available TB and ART 
according to local standards of care. Sites must notify the A5290 core team by e-
mail (actg.corea5290@fstrf.org) within 2 weeks after learning that the 
participant’s TB has been identified as drug-resistant. 
 
Participants whose qualifying episode of TB was later deemed to be not TB will 
continue to be followed on study, off study-provided TB treatment, but on study-
provided ART, for safety and ART endpoints. 
 
Cultures from study samples identified as TB-positive, including any sample that 
is positive for drug-resistance, must be stored at the site laboratory or the local 
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Diagnoses 
Diagnoses identified by the ACTG criteria for clinical events and other diseases 
received since the last visit must be recorded. Refer to the study CRF for the 
appropriate appendix used for the current ACTG criteria.  
 
Concomitant Medications 
After entry, all concomitant prescription medications, excluding TB medications, 
started or stopped since the last visit must be recorded on the CRF. 
Nonprescription medications will be recorded in the source documents only. Non-
study provided TB medications will be recorded on the TB Treatment CRF and all 
non-study provided ART will be recorded on the ARV Treatment CRF.  
 
HIV and TB Study Treatment Modifications 
Record all ARV and anti-TB study drug modifications, including initial doses, 
modifications that were participant-initiated and/or protocol-mandated and/or 
according to local/national/international guidelines, and inadvertent and 
deliberate interruptions of ARVs for > 3 days and anti-TB medications for > 7 
days at each visit. Record any permanent discontinuation of any ARV or anti-TB 
drug. 
 
6.3.6 Adherence Assessment - Pill Counts 
 
Pill counts for all prescribed ARVs and TB medications will be conducted 
according to the SOE.  
 
6.3.7 TB Treatment Status and Outcome Determination 
 
At completion of the entire course of TB treatment, TB treatment status/outcome 
must be recorded on the CRF, and should also be documented again at weeks 
48 and 72, at the time of detection/diagnosis of TB treatment failure or TB 
relapse/recurrence or at the time of premature discontinuation or death. 
 
TB treatment status/outcome will be classified according to the following, 
adapted from ATS guidelines42. 
 
Cure: Completion of all recommended doses of medication and 2 consecutive 
TB-negative mycobacterial cultures. 
 
Treatment failure: TB-positive mycobacterial culture after 16 weeks of TB 
treatment for a participant who was documented to be taking TB medications. 
 
Died: Participant who died for any reason before the completion of TB-treatment. 
 
Default: Participant whose TB-treatment was interrupted for 2 or more 
consecutive months and did not reinitiate TB therapy. 
 
Transfer out/lost to follow-up (LTFU): Participant who was transferred to another 
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Treatment ongoing: At time of evaluation, participant is still undergoing treatment 
for TB. Documentation should be made of why prolonged TB treatment is 
occurring, including: default with reinitiation of TB treatment, initial TB treatment 
failure, and persistent TB-positive mycobacterial cultures.  
 
Relapse/recurrence: Participant who has 2 consecutive TB-negative 
mycobacterial cultures and who subsequently has clinical or radiographic 
deterioration consistent with active TB at or after week 24 and before the week 
72 endpoint.  
 
Treatment completed: Participant who has completed TB treatment but who does 
not meet the criteria to be classified as a cure or a failure. 
 
NOTE: For participants who are enrolled with probable TB and do not have a 
positive mycobacterial culture from any site available to meet these 
outcome definitions, but who have specimens with a positive AFB smear, 
the AFB smear result will be substituted for the mycobacterial culture 
result in assessing TB outcomes. If there are no positive AFB smear 
results, then the assessment of TB outcomes will be based on best 
clinical judgment and further reviewed by the team and an independent 
endpoint reviewer. 
 
6.3.8 Chest X-Ray 
 
A chest X-ray must be performed within 30 days prior to study entry, at weeks 8, 
48, and 72, at the time of suspected TB treatment failure or relapse/recurrence, 
and at premature study discontinuation. Interpretation of the x-ray is to be 
performed by a clinician.  
 
6.3.9 Laboratory Evaluations 
 
At screening and entry all protocol required laboratory values must be recorded 
on the CRFs. For post-entry assessments, record all Grade ≥ 3 laboratory 
values. All laboratory toxicities that led to a change in treatment, regardless of 
grade, must be recorded. 
 
Hematology 
Hemoglobin, hematocrit, red blood cells, mean corpuscular volume, white blood 
cell count (WBC), differential WBC, ANC, and platelets.  
 
Liver Function Tests 
Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase. 
 
Blood Chemistries 
Sodium, potassium, chloride, bicarbonate, creatinine, and albumin.  
 
 
 


 
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Pregnancy Test 
For women with reproductive potential: Serum or urine β-HCG (urine test must 
have a sensitivity of 15-25 mIU/mL). 
 
CD4+/CD8+ 
Obtain absolute CD4+/CD8+ count and percentages within 30 days prior to study 
entry from a laboratory that is certified for protocol testing by the DAIDS 
Immunology Quality Assurance (IQA) Program. For entry and post-entry 
evaluations, the laboratory must be certified by the DAIDS Immunology Quality 
Assurance (IQA) Program.  
 
6.3.10 Virologic Studies 
 
Plasma HIV-1 RNA 
Screening HIV-1 RNA must be performed within 30 days prior to study entry by a 
laboratory that possesses a CLIA certification or equivalent.  
For entry and post-entry evaluations, the laboratory must be certified by the 
DAIDS Virology Quality Assurance (VQA) Program.  
 
HIV Resistance Testing (Stored Plasma) 
HIV resistance testing will be performed retrospectively (not in real time), using a 
VQA certified method. Refer to the A5290 Laboratory Processing Chart (LPC) for 
additional details.  
 
Stored Plasma and PBMC  
Plasma will be stored for future virology testing as indicated in the SOE. Refer to 
the A5290 LPC for details of collection, processing, shipping, and designated 
laboratory. At sites that are able to, PBMCs (viable, whenever possible) will be 
cryopreserved for future virology and immunology testing.  
 
6.3.11 Pharmacokinetic Studies 
 
See section 10.0, Pharmacology Plan. 
 
Participants do not have to be fasting when they come to the clinic for their PK 
study. Site staff should advise the participant that if he/she does eat prior to 
coming to the clinic to avoid high fat meals. If the sites provide a meal on the PK 
day, it should not be a high fat meal and it should be provided 3 hours after the 
dose of LPV/RTV and either RBT or RIF has been given. Any kind of a snack or 
meal can be provided after that 3 hour post dose meal. (See section 5.1.3.) 
 
Participants’ PK samples collected during the dose-finding period in accrual 
period 1 will be batched and shipped to the ACTG repository every 2 weeks with 
immediate re-shipping to the PK laboratory. Otherwise, PK samples will be 
batched and shipped to the ACTG repository periodically. Refer to the A5290 
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6.3.12 Stored Serum  
 
Serum samples will be collected as per the SOE and stored for future 
immunology testing. Refer to the A5290 LPC. 
 
6.3.13 Stored Urine 
 
Urine will be stored for future TB biomarker testing as per the SOE. Refer to the 
A5290 LPC.  
 
6.3.14 Sputum Sample Storage 
 
Samples will be collected as per the SOE and stored as per the A5290 LPC.  
 
 
7.0 
CLINICAL MANAGEMENT ISSUES 
 
A5290 will use the Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 1.0, December 2004, Clarification August 2009, as a guideline 
for grading toxicities.  
 
Toxicity management at non-US sites may require reliance on clinical symptoms, 
clinician judgment, and available laboratory markers, since alternatives to study-provided 
ARV drugs may be very limited and baseline levels of certain laboratory parameters 
(e.g., hemoglobin) may be different than in other settings. 
 
This section provides guidelines for management of pregnancy and breastfeeding and of 
toxicities related to study-provided drugs LPV/r, RBT, and RAL only. When one of the 
ARV drugs is held for resolution of toxicity, all drugs in the ARV regimen should be held 
concurrently. With the exception of RBT, toxicity management of the TB medications will 
be performed by local TB control programs or the site investigator according to local 
standards in close communication with the A5290 protocol team.  
 
Every attempt should be made to continue to follow participants who discontinue ARVs 
and/or TB drugs because of a Grade 3 or 4 AE until resolution of the adverse event can 
be documented.   
 
The A5290 Clinical Management Committee (A5290 CMC) is available to discuss 
toxicity management of study-provided and other ARVs and TB drugs with investigators. 
The A5290 CMC consists of the A5290 protocol chairs, statisticians, DAIDS medical 
officer, DAIDS pharmacist, data managers, clinical trials specialist, and other protocol 
team members selected by the A5290 protocol chairs. 
 


 
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7.1 
Toxicity Management 
 
Grade 1 or 2  
Participants who develop a Grade 1 or 2 AE or toxicity may continue ARVs and TB 
drugs without alteration of the dosage. Participants experiencing Grade 1 or 2 toxicities 
will be managed at the discretion of the site investigator. 
 
Grade 3 
If there is compelling evidence that the AE has NOT been caused by the study-provided 
drugs, dosing may continue at the discretion of the site investigator/clinician. Except as 
stated in the following sections, participants who develop a Grade 3 AE or toxicity 
thought to be secondary to study-provided drugs or of unknown etiology may have all of 
their ARVs and/or TB drugs withheld, at the site investigator’s discretion. Investigators 
are welcome to discuss toxicity management with the A5290 CMC. The participant 
should be reevaluated weekly if at all possible until the AE returns to Grade ≤ 2 or until 
stabilized and no longer in need of such frequent monitoring, as determined by the site 
investigator, at which time ART and/or anti-TB treatment may be reintroduced at the 
discretion of the site investigator or according to standard practice. 
 
Grade 4 
Participants who develop a symptomatic Grade 4 AE or toxicity, not specifically 
addressed below, will have all medications withheld and should be reevaluated weekly if 
at all possible until the AE returns to Grade ≤ 2 or until stabilized and no longer in need 
of such frequent monitoring, as determined by the site investigator. However, under 
certain circumstances the ARV or TB drug thought most likely to be related to the AE 
may be resumed at the discretion of the site investigator. However, if study-provided 
ARV or TB drugs are permanently discontinued due to a toxicity not otherwise specified 
in section 7.2, then the participant should continue to be followed on study, off-study-
provided medications and referred to their primary clinician for best available 
management. 
 
Participants with Grade 4 asymptomatic laboratory abnormalities, not specifically 
addressed below, may continue ART and anti-TB treatment if the site investigator has 
compelling evidence that the toxicity is NOT related to the ART or anti-TB treatment, or if 
benefit of the ART or anti-TB treatment outweighs the potential risk. 
 
7.2 
Specific Management of Toxicities Related to Study-Provided Drugs 
 
7.2.1 AST and ALT Elevation 
 
ARVs, INH, RIF, RBT, and PZA can all cause alterations in liver function tests. 
Concomitant illnesses, including TB, may also alter these laboratory parameters. 
Therefore, changes in AST or ALT should be evaluated within the clinical context 
of the abnormalities.   
 
Participants entering this trial will potentially have advanced HIV disease and 
active TB. Elevation in ALT and AST is expected. Because this study is designed 
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and RBT as an alternative for RIF in this population, participants with  2 x ULN 
for ALT will be allowed to enroll in accrual period 1 and participants with  5 x 
ULN for both parameters will be allowed to enroll in accrual period 2 of the study. 
If the AST or ALT elevation is considered most likely to be due to concomitant 
illness or medication, standard management, including discontinuation of the 
likely causative agent, should be undertaken. 
 
For asymptomatic or symptomatic elevation of AST or ALT > 7.5 × ULN (Grade 
3), all medications should be discontinued and held until levels and symptoms 
are Grade ≤ 2, at which time therapy may be reintroduced. All medications may 
be restarted if the laboratory abnormalities were thought secondary to a 
concomitant illness. 
 
If the elevation of AST or ALT is thought to be due to RBT, anti-TB medications 
should be reintroduced one at a time in 3-7 day increments, and if all other anti-
TB medications are tolerated, RBT should be added last, initially at a reduced 
dose according to Table 5.1. If the participant was already receiving RBT at a 
reduced-dose then the re-challenge dose should be the dose the participant was 
previously receiving. If the RBT dose is tolerated upon re-challenge for 7 days, 
then the ARVs should be restarted. If Grade 3 or higher elevation of AST or ALT 
recurs with the reintroduction of RBT then RBT should be permanently 
discontinued and the participant should be referred to his/her primary clinician or 
local TB program, provided the best available anti-TB therapy according to local 
standards, and the participant should continue to be followed on study but off 
study-provided anti-TB medications. 
 
If the elevation of AST or ALT is thought to be due to LPV/r, anti-TB medications 
should be reintroduced one at a time in 3-7 day increments as described above, 
and if all anti-TB medications are tolerated upon re-challenge, then LPV/r should 
be re-introduced at the reduced dose according to Table 5.1 together with the 
NRTIs. If the participant was already receiving a reduced dose of LPV/r, then the 
re-challenge dose of LPV/r should be the dose the participant was previously 
receiving. If the LPV/r dose is tolerated upon re-challenge for 7 days, then the 
previous dose the participant was receiving, if applicable, may be restarted after 
discussion with the A5290 CMC. If Grade 3 or higher elevation of AST or ALT 
recurs with the reintroduction of LPV/r then LPV/r should be permanently 
discontinued, the participant should be referred to his/her primary clinician or 
local TB program and provided the best available ART according to local 
standards, and the participant should continue to be followed on study but off 
study-provided anti-HIV medications.  
 
7.2.2 Bilirubin 
 
Participants entering this trial will potentially have advanced HIV disease and 
active TB. Elevation in bilirubin is common in this situation; however, 
asymptomatic or symptomatic elevation of bilirubin may also occur with RBT, 
RIF, or LPV/r. Because this study is designed to assess the risk/benefit ratio of 
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in this population, participants with  2.5 X ULN of bilirubin will be allowed to 
enroll in accrual period 1 and participants with  5 X ULN of bilirubin will be 
allowed to enroll in accrual period 2 of the study. If the bilirubin elevation is 
considered most likely to be due to concomitant illness or medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken. 
 
For new Grade 3 bilirubin, study medications can be continued if, in the opinion 
of the site investigator, the possible benefits of therapy outweigh the risks. 
 
For asymptomatic or symptomatic new elevation of bilirubin > 5 x ULN (Grade 4), 
all medications must be discontinued and held until levels are Grade  2, at 
which time therapy may be reintroduced. All medications may be restarted if the 
laboratory abnormalities are thought to be secondary to a concomitant illness.   
If the elevation of bilirubin is thought to be due to RBT, anti-TB medications 
should be reintroduced one at a time in 3-7 day increments, and if all other anti-
TB meds are tolerated, RBT should be added last, initially at a reduced dose 
according to Table 5.1. If the participant was already receiving RBT at a reduced 
dose then the re-challenge dose should be the dose the participant was 
previously receiving. If the RBT dose is tolerated upon re-challenge for 7 days, 
then the ARVs should be restarted. If Grade 4 elevation of bilirubin recurs with 
the reintroduction of RBT, then RBT should be permanently discontinued and the 
participant should be referred to his/her primary clinician or local TB program, 
provided the best available anti-TB therapy according to local standards, and the 
participant should continue to be followed on study but off study-provided anti-TB 
medications. 
 
If the elevation of bilirubin is thought to be due to LPV/r, anti-TB medications 
should be reintroduced one at a time in 3-7 day increments as described above, 
and if all anti-TB medications are tolerated upon re-challenge, then LPV/r should 
be re-introduced at the reduced dose according to Table 5.1 together with the 
NRTIs. If the participant was already receiving a reduced dose of LPV/r, then the 
re-challenge dose of LPV/r should be the dose the participant was previously 
receiving. If the LPV/r dose is tolerated upon re-challenge for 7 days, then the 
previous dose the participant was receiving, if applicable, may be restarted after 
discussion with the A5290 CMC. If Grade 4 elevation of bilirubin recurs with the 
reintroduction of LPV/r, then LPV/r should be discontinued, the participant should 
be referred to his/her primary clinician or local TB program and provided the best 
available ART according to local standards, and the participant should continue 
to be followed on study but off study-provided anti-HIV medications. 
 
7.2.3 Uveitis  
    
Uveitis presents with eye pain, redness, photophobia, blurred vision and/or 
decreased visual acuity. The most likely study drug to be associated with uveitis 
is RBT. Uveitis is reported to occur at a rate of ~3% in persons receiving RBT in 
doses of 450-600 mg/d. If signs or symptoms of uveitis occur in a participant 
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should be referred to a local ophthalmologist or primary clinician for evaluation 
and symptomatic treatment, which may include topical (eye drops) mydriatics 
and/or corticosteroids. Once symptoms resolve, RBT may be restarted at a 
reduced dose according to Table 5.1. If the participant was already receiving a 
reduced dose of RBT, re-challenge with RBT at the previous reduced dose may 
be considered after discussion with the A5290 CMC. If uveitis recurs after re-
challenge with the reduced dose, RBT should be permanently discontinued, the 
participant should be referred to his/her primary clinician or local TB program, 
and provided the best available anti-TB therapy according to local standards, and 
the participant should continue to be followed on study but off study-provided 
anti-TB medications. 
 
7.2.4 Neutropenia 
 
Participants entering this trial will potentially have advanced HIV disease and 
active TB. Neutropenia is expected. Because this study is designed to assess the 
risk/benefit ratio of second-line ART with varying doses of LPV/r and RBT as an 
alternative for RIF in this population, participants with  Grade 2 neutropenia will 
be allowed to enroll in accrual period 1 and participants with  Grade 3 
neutropenia will be allowed to enroll in accrual period 2 of the study. RBT may be 
associated with neutropenia. If Grade 4 neutropenia develops after study entry 
and RBT is considered the likely causative agent, the dose of RBT should be 
reduced according to recommendations in Table 5.1, and the neutrophil count 
should be repeated within 72 hours of the dose reduction. If the participant is 
already receiving a reduced dose of RBT, or if the repeat neutrophil count has 
not improved to Grade 3 or less, then RBT should be held, and the neutrophil 
count should be repeated within 72 hours. If the neutrophil count has improved to 
Grade 3 or less, RBT may be restarted at the reduced dose. If Grade 4 
neutropenia recurs, RBT must be permanently discontinued, the participant 
should be referred to his/her primary clinician or local TB program, and provided 
the best available anti-TB therapy according to local standards, and the 
participant should continue to be followed on study but off study-provided anti-TB 
medications.  
 
7.2.5 Severe Rash/Cutaneous Reaction 
 
Moderate to severe rash potentially related to drug hypersensitivity may occur 
with any of the study provided drugs, although the likeliest agents to cause rash 
in this setting are RIF, RBT, and RAL. It may not be possible to determine which, 
if any of the study drugs is the cause. Participants should be instructed to 
immediately stop taking RIF, RBT, RAL or other suspect drugs, and seek medical 
attention if they develop a rash of Grade 3 or higher, or any rash of Grade 2 or 
higher associated with any of the following symptoms that may be signs of a 
more serious reaction, such as Stevens-Johnson syndrome, toxic epidermal 
necrolysis, or severe hypersensitivity: fever, generalized malaise or fatigue, 
muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, 
swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms 
of liver abnormalities (e.g., jaundice, dark or tea colored urine, pale colored 


 
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stools/bowel movements, nausea, vomiting, loss of appetite, or right upper 
quadrant abdominal pain). If the rash and symptoms are thought to be due to 
RIF, RBT, or RAL, and no other cause can be determined, then RIF, RBT, or 
RAL must be permanently discontinued, the participant should be referred to 
his/her primary clinician or local TB program (if the suspect agent is RIF or RBT), 
and provided the best available anti-HIV and/or anti-TB therapy according to 
local standards. The participant should continue to be followed on study but off-
study-provided RIF, RBT, or RAL.  
 
7.2.6 Nausea and Vomiting 
 
Although common, nausea following initiation of therapy with ARV medications 
and/or TB treatment usually subsides or resolves during the first few weeks of 
treatment. 
 
Steps in the management of nausea include taking the medication with food and 
administration of antiemetics. 
 
7.2.7 Diarrhea 
 
Diarrhea is a common side effect of infection and medication toxicity. If no 
infectious cause of diarrhea is found and onset is temporally related to new 
medication, symptomatic management with antidiarrheal agents is appropriate. 
 
7.2.8 Recommendations for Management of Immune Reconstitution Inflammatory 
Syndromes 
 
Inflammatory syndromes in participants with TB may occur shortly after the 
initiation of either anti-TB treatment or ART. When these syndromes are 
suspected, the management plan presented below should be followed. 
Consultation with the A5290 CMC is recommended. Note that MTB IRIS may be 
observed in participants who have not yet initiated or switched to second-line 
ART. 
 
• 
Continue ART.  
• 
Evaluate for new diagnosis of opportunistic infection or worsening of TB, as 
indicated. 
• 
Continue or initiate specific therapy for the infection, if present. 
• 
Initiate anti-inflammatory agents, initially non-steroidals or, if needed, 
corticosteroids at the discretion of the site investigator. 
 
7.3 
Pregnancy and Breastfeeding 
 
If a participant becomes pregnant during the study, she may choose to continue study-
provided medications during pregnancy and breastfeeding, after discussion with her 
primary clinician and the A5290 CMC, given the lack of optimal alternatives for TB 
treatment in the setting of a PI-based ART regimen. Participants who choose to continue 
all study-provided medications will be followed on study through the completion of the 


 
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pregnancy and the outcome of the pregnancy will be recorded on the CRF. If a 
participant chooses not to continue either study-provided anti-TB or antiretroviral 
medications, she will be referred to local clinics and will receive the best available TB or 
ART as determined by her primary clinician, but will continue to be followed on study but 
off study-provided anti-TB or antiretroviral medications, or both, and the outcome of the 
pregnancy will be recorded on the CRF.  
 
If a woman has completed the study or chooses to discontinue from the study before the 
end of the pregnancy, the site staff should request permission to contact her regarding 
pregnancy outcomes at the end of the pregnancy. If the information is obtained, 
pregnancy outcomes will be submitted on a CRF at the end of the pregnancy.  
A5290 will not provide prenatal or postpartum care to infants born to women on study 
through the protocol; however, women who become pregnant on study will continue to 
be followed as described above but will be referred to local clinics and/or other research 
studies for prenatal and postpartum care.  
 
Pregnancies that occur on study will be reported to The Antiretroviral Pregnancy 
Registry. Intrapartum complications and/or pregnancy outcome will be recorded on the 
CRFs and also reported to The Antiretroviral Pregnancy Registry. More information is 
available at www.apregistry.com. Phone: 800-258-4263; Fax: 800-800-1052.  
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
 
8.1 
Permanent ARV Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 7.1). 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Stopping the last component of study-provided ART.  
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
 
NOTE: Participants must be referred to their primary care clinician/clinical facility or ART 
program and treated with the best available ART if they permanently discontinue 
study-provided ARVs. 
 
8.2 
Permanent TB Treatment Discontinuation 
 
• 
Qualifying episode of suspected TB determined not to be TB. 
• 
Drug-related toxicity (see section 7.1). 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
Stopping the study-provided TB drug.  
• 
Completion of TB treatment as defined in the protocol. 
• 
Request by participant to terminate treatment. 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
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NOTE: Participants must be referred to their primary care clinician/clinical facility or TB 
program and treated with the best available TB treatment if they permanently 
discontinue study-provided anti-TB treatment.  
 
8.3 
Premature Study Discontinuation 
 
• 
Failure by the participant to attend 3 consecutive clinic visits. 
• 
RIF resistance found after study entry. 
• 
Request by the participant to withdraw. 
• 
Request of the primary care provider if he/she thinks the study is no longer in the 
best interest of the participant. 
• 
Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results. 
• 
At the discretion of the ACTG, institutional review board (IRB)/ethics committee (EC), 
US Food and Drug Administration (FDA), Office for Human Research Protections 
(OHRP), NIAID, investigator, pharmaceutical supporter(s), or local governmental 
authorities.  
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
 
This is an open-label, randomized, phase 2b study to evaluate whether 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 rifampin (RIF)-based TB treatment. We intend to recruit 471 HIV-infected 
participants with active TB who require protease inhibitor (PI)-based antiretroviral 
therapy (ART). Each participant will be followed until week 72. We anticipate accrual to 
occur at the rate of approximately 4-5 participants per month per site once all sites are 
registered and enrolling participants. 
 
9.2 
Primary Endpoints 
 
9.2.1 Accrual Period 1 PK Study Endpoints 
 
9.2.1.1 LPV plasma concentrations at day 12 ± 2 (after initiation of ART) in 
Arms A, B, and C.  
 
9.2.1.2 RBT plasma concentrations at day 12 ± 2 (after initiation of ART) in 
Arms A and C.  
 
9.2.1.3 Grade 3 or 4 laboratory value or sign or symptom attributed to study-
provided medication(s) by 28 days of ART. 
 


 
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9.2.1.4 Discontinuation of study-provided drug(s) for treatment-limiting toxicity 
or intolerance (such that PK assessments within the day 12 ± 2 (after 
initiation of ART) window cannot be completed). 
 
9.2.2 Primary endpoint: HIV virologic suppression is defined as plasma HIV-1 RNA 
level < 400 copies/mL at 48 weeks.  
 
9.2.3 Secondary Endpoints  
 
9.2.3.1 TB treatment outcomes: mycobacterial culture conversion at week 8, 
occurrence of TB treatment failure at or after week 24, and occurrence 
of TB relapse/recurrence by week 72. 
 
NOTE A: TB treatment outcomes for participants who enroll with 
probable TB for whom week 8 mycobacterial culture 
conversion cannot be assessed will include week 8 AFB 
smear conversion coupled with resolution of signs, symptoms, 
and radiographic abnormalities on which the diagnosis of 
probable TB was based or solely resolution of signs, 
symptoms, and radiographic abnormalities for participants 
with negative AFB smears or AFB smears that are not 
available at baseline, in addition to TB treatment failure at or 
after week 24, and TB relapse/recurrence by week 72. 
 
NOTE B:  Participants who cannot produce sputum even with induction, 
as noted on the CRF, will be considered MTB culture negative 
and AFB smear negative in analyses. 
 
9.2.3.2 HIV virologic suppression based on two definitions: plasma HIV RNA 
level < 400 copies/mL at 48 weeks and < 50 copies/mL at 48 weeks.  
 
9.2.3.3 Safety and tolerability:  
 
9.2.3.3.1 Highest reported grade of each new Grade 3 or 4 laboratory 
value or sign or symptom that is at least a one grade increase 
from baseline.   
 
9.2.3.3.2 Ordered categorical variable indicating most stringent level of 
ARV drug management due to toxicity that was required over 
the co-treatment period: premature permanent treatment 
discontinuation; treatment hold for more than 3 consecutive 
days; and none of the above. 
 
9.2.3.3.3 Ordered categorical variable indicating most stringent level of 
TB drug management due to toxicity that was required over 
the co-treatment period: premature permanent treatment 
discontinuation; treatment hold for more than 7 consecutive 
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9.2.3.4 HIV virologic failure is defined as two consecutive plasma HIV-1 RNA 
levels  1000 copies/mL at or after 16 weeks and before 24 weeks of 
ART or  400 copies/mL at or after 24 weeks of treatment. 
 
NOTE: This definition of virologic failure will be applied regardless of 
whether or not randomized ART is being taken at the time of 
failure. 
 
9.2.3.4.1 Occurrence of HIV virologic failure.  
 
9.2.3.4.2 Time to HIV virologic failure. 
 
9.2.3.5 TB drug resistance patterns in participants who have TB treatment 
failure or relapse/recurrence of TB. 
 
9.2.3.6  Occurrence of MTB IRIS events. 
 
9.2.3.7 Predictors of disease progression:  
 
9.2.3.7.1 CD4+ T-cell counts at baseline and at weeks 8, 24, 48, and 
72. 
 
9.2.3.7.2  Occurrence of new AIDS-defining illnesses. 
 
9.2.3.7.3 Occurrence of HIV-disease progression (defined as new 
AIDS-defining illness or death). 
 
9.2.3.7.4 Occurrence of death. 
 
9.2.4 Additional endpoints for supportive/exploratory analyses that will be defined in 
more detail in separate analysis plans: 
 
9.2.4.1 HIV-1 drug resistance patterns in participants who have HIV virologic 
failure. 
 
9.2.4.2 LPV plasma concentrations in Arm B, RBT plasma concentrations in 
Arms A and C, and RAL plasma concentration in Arm C at weeks 2 and 
8 in accrual period 2 participants. 
 
9.2.4.3 Cost-benefit measures related to adding RAL. 
 
9.3 
Randomization and Stratification 
 
The participants will be randomized 1:1:1 to three open-label arms using permuted 
blocks. Randomization will not be stratified.  
 
 
 


 
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9.4 
Sample Size and Accrual 
 
Accrual will take place in two periods. Accrual period 1 will enroll participants who will 
undergo an initial dose-finding period before continuing regular study follow-up through 
72 weeks. Once review of the dose-finding period in accrual period 1 participants is 
complete, accrual period 2 will begin. 
 
9.4.1 Sample Size and Accrual for Dose-Finding Study in Accrual Period 1 Participants 
 
For the study design of the dose-finding study in participants enrolled during the 
accrual period 1, the primary driver is equivalence comparing day 12 ± 2 (after 
initiation of ART) RBT 24-hour AUC with control data derived from prior PK 
studies40,43. Subject-level data for 500 studies were simulated with pre-specified 
sample sizes and no-effect boundaries (NEBs). For the simulation study data, 
geometric mean ratios (GMRs), mean GMR, and 90% confidence intervals were 
calculated. Based on this simulation study, eighteen evaluable participants per 
arm are needed for the dose-finding study in accrual period 1 participants to 
adequately evaluate PK parameters and safety. As shown in Table 9.1 below, a 
CV of 32% was assumed with three different NEBs. There is more than 90% 
power to have the 90% CI around the GMR fall entirely within the pre-specified 
NEB of 67%-150%.  
 
Table 9.1. Probability (%) of Declaring Equivalence for the RBT PK Objective 
 
Sample size 
% 
diff 
Prob declare equiv for 
NEB 
Simulated data 
Alone 
Co- 
drug
AUC
50%-
200% 
67%- 
150% 
80%- 
125%
Mean 
GMR 
Typical 90% CI 
14
14
-30
87%
11%
1%
69.7%
(57.1%, 85.2%) 
-20
98%
44%
4%
79.9%
(65.4%, 97.6%) 
-10
100%
76%
12%
89.2%
(73.1%, 108.9%) 
-5
100%
89%
19%
95.4%
(78.2%, 116.3%) 
5
100%
90%
18%
104.2%
(85.4%, 127.1%) 
10
100%
83%
13%
109.2%
(89.4%, 133.4%) 
20
100%
57%
6%
120.4%
(98.7%, 146.8%) 
30
96%
32%
1%
130.1%
(106.5%, 158.9%) 
18
18
-30
93%
9%
0%
69.9%
(58.7%, 83.2%) 
-20
100%
52%
5%
80.1%
(67.3%, 95.4%) 
-10
100%
90%
24%
90.3%
(75.9%, 107.5%) 
-5
100%
93%
30%
94.2%
(79.2%, 112.1%) 
5
100%
94%
30%
105.5%
(88.7%, 125.5%) 
10
100%
90%
26%
110.0%
(92.4%, 131.0%) 
20
100%
70%
9%
119.0%
(99.9%, 141.7%) 
30
99%
36%
2%
130.6%
(109.6%, 155.7%) 
22
22
-30
98%
13%
0%
69.8%
(59.6%, 81.8%) 
-20
100%
55%
4%
79.5%
(68.0%, 93.0%) 
-10
100%
93%
31%
90.3%
(77.0%, 105.9%) 


 
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Sample size 
% 
diff 
Prob declare equiv for 
NEB 
Simulated data 
Alone 
Co- 
drug
AUC
50%-
200% 
67%- 
150% 
80%- 
125%
Mean 
GMR 
Typical 90% CI 
-5
100%
98%
45%
95.0%
(81.3%, 111.1%) 
5
100%
98%
46%
104.8%
(89.5%, 122.8%) 
10
100%
94%
31%
110.5%
(94.5%, 129.3%) 
20
100%
77%
10%
120.0%
(102.6%, 140.2%) 
30
100%
44%
3%
129.5%
(110.6%, 151.7%) 
 
Participants who do not have day 12 ± 2 (after initiation of ART) PK samples will 
not be replaced. Thus, we will enroll 20 participants in each arm, expecting 18 
participants in each arm with evaluable PK data. (However, the accrual period 1 
PK and safety interim analysis may lead to proposing additional accrual period 1 
participants to assure an adequate PK assessment.)   
 
Accrual will be suspended after the last participant is enrolled into the accrual 
period 1.  
 
9.4.2 Overall Sample Size 
 
For the overall study design, we assume that the standard dose LPV/r regimen 
with or without RAL coupled with RBT-based anti-TB therapy will be superior to a 
double-dose LPV/r regimen with RIF-based anti-TB therapy. We estimate the 
virologic suppression rate at 48 weeks for the double-dose LPV/r treatment arm 
will be approximately 50%, for the LPV/r with RBT-based anti-TB therapy to be 
approximately 70%, and for the LPV/r plus RBT plus RAL arm to approach 80-
90%. These numbers are based on the following considerations: 1) the standard 
of care in the US is to switch ART for a failing regimen at earlier time points 
based on viral load monitoring such that background rates of concomitant NRTI 
resistance are relatively low, while this is not the case in resource-constrained 
settings where viral load monitoring is less frequent or not routinely done; 2) 
there are only a limited number of drugs available for use in second-line therapy 
in most resource-constrained settings making it difficult to construct a second-line 
ART regimen with three or more known active drugs; 3) there may be more 
variability in PK with LPV/r coupled with RBT than has been previously 
appreciated, and this might compromise virologic outcomes; 4) there are 
insufficient data available to address this point, which is, in part, why we propose 
to do this study; and 5) we anticipate that there will be an appreciable rate of 
adverse effects of anti-TB treatment as well as of ARTs (especially in the double-
dose LPV/r arm which could lead to poorer adherence and early treatment 
discontinuation, thus, lower efficacy) that might result in repeated episodes of 
short-term treatment interruption for management of side effects, as has been 
observed in A5221 and other TB treatment studies. For these reasons, the 85-
90% virologic suppression rates reported at 48 weeks for studies in resource-rich 
settings may not be achievable in the context of active TB in resource-
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Because the primary objective entails comparing virologic efficacy of Arm A 
versus Arm B and Arm C versus Arm A, we will have two hypothesis tests and 
will use an alpha-level of 0.025 for each test (thus, overall alpha-level = 0.05). If 
we assume the overall virologic efficacy of the double-dose LPV/r arm is 50%, 
and the standard LPV/r dosed arm coupled with RBT is 70% by 48 weeks (and 
80-90% for LPV/r and RAL with RBT-based anti-TB treatment), 147 participants 
per arm will provide 90% power to detect a 20% difference in virologic response 
rates by 48 weeks between the double-dose LPV/r arm and the standard LPV/r 
plus RBT arm and adequate power for the comparison of the standard LPV/r plus 
RBT arm and adequate power for the comparison of the standard LPV/r plus 
RBT plus RAL arm compared to both other treatment arms. This assumes using 
a two-sample, two-sided 0.025-level asymptotically-normal binomial test. 
Participants lost to follow-up will be considered as failures. Participants 
determined to have RIF-resistant TB isolates after enrollment will be taken off 
study, referred to their local clinician or clinical facility to receive best available 
local standard of care, and will not be replaced. Assuming that 3% of participants 
will have RIF resistance at entry and be taken off study, we will need to adjust 
the sample size to require 152 participants per arm. Adjusting the sample size 
again by 3% for interim analyses requires 157 participants per arm. Based on 
these data and assumptions, the estimated overall sample size will be 471 
participants.  
 
9.4.3  Overall accrual 
 
Accrual period 1 will open once at least 4-5 sites have all regulatory approvals 
completed and are ready to enroll participants immediately. The team estimates 
that these 4-5 sites should be able to accrue approximately 4-6 participants per 
month per site. As other sites begin accrual period 1, the team anticipates that 
accrual period 1 (n=60) should be completed within approximately 2-4 months. 
 
Accrual period 2 will open once the accrual period 1 interim PK and safety 
analysis is completed. The team anticipates ultimately 15 sites each enrolling 4-5 
participants per month. Thus, taking into account a slow, early accrual period, 
accrual period 2 (n=411) is anticipated to take approximately nine months. 
 
Not accounting for the time during which accrual is suspended after the accrual 
period 1 closes and until the accrual period 1 interim PK and safety analysis is 
completed, the expected time to reach full accrual (n=471) is approximately 13 
months. 
 
9.5 
Monitoring 
 
9.5.1 Monitoring During the Dose-Finding Period in Accrual Period 1 Participants 
 
Since initiation of ART may be delayed for up to 7-14 days after starting anti-TB 
therapy to allow participants sufficient time to assess tolerability of TB 
medications, PK assessments will be timed based on initiation of ART. Until the 
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the core team will closely monitor adverse events (AEs) and drug concentrations. 
The protocol data manager will provide unblinded detailed AE summary reports 
to the core team on a weekly basis. These reports will be discussed on weekly 
core team calls.  
 
PK and Safety Criteria 
 
• 
For RBT (Arms A and C), equivalence analyses will compare day 12 ± 2 
(after initiation of ART) RBT 24-hour AUC and Cmax with control data derived 
from prior PK studies, as determined by whether the 90% confidence 
intervals of the ratios of the RBT concentrations (when co-administered with 
LPV/r) relative to daily RBT concentrations in the absence of LPV/r are fully 
contained within the pre-specified NEB of 67%-150%. RBT concentrations in 
Arms A and C will be judged acceptable if equivalence is declared according 
to these PK parameters. 
• 
For LPV in Arm B, the primary PK parameter is the day 12 ± 2 (after initiation 
of ART) Cmin (C12), and the acceptable lower limit value is  1 mg/L. LPV 
concentrations in Arm B will be judged acceptable if no more than three 
participants have a Cmin < 1 mg/L. 
• 
No more than three participants in any treatment arm experience a Grade 3 
or Grade 4 AE attributable to study-provided medication by 28 days after ART 
initiation. 
• 
No more than three participants in any treatment arm discontinue study-
provided drug(s) for treatment-limiting toxicity or intolerance (such that PK 
assessments within the day 12 ± 2 (after initiation of ART) window cannot be 
completed). 
 
The justification behind the RBT PK criterion is given in section 9.4.1. The other 
three criteria depend on the number of events (i.e., no more than 3). Based on 
Table 9.2 below, supposing the underlying rate is 10%, with X=3, there is an 87% 
chance of the study regimen in a particular arm going forward to accrual period 2. 
 
Table 9.2. Probability (%) of Deciding the Criterion is Acceptable Based on a 
Range of Underlying Rates 
 
Underlying 
Rate
Probability of X or Fewer Events in 20 Participants  
Given the Underlying Toxicity Rate: 
X=1
X=2
X=3
X=4
X=5
0.05
0.736
0.925
0.984
0.997
0.999
0.10
0.392
0.677
0.867
0.957
0.989
0.15
0.176
0.405
0.648
0.830
0.933
0.20
0.069
0.206
0.411
0.630
0.804
0.25
0.024
0.091
0.225
0.415
0.617
 
The core team will also examine the LPV concentrations in Arms A and C in 
order to determine if RBT affects LPV concentrations. Any dose modifications of 


 
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LPV in Arms A and C will be the guided by the modifications proposed for Arm B 
(see Table 5.1 in section 5.1.1). 
 
While the intent is to conduct the accrual period 1 PK and safety interim analysis 
after 54-60 accrual period 1 participants have completed 28 days of ART, 
available drug concentrations and safety data will be assessed weekly by the 
core team in an unblinded fashion as follows. Sites will be asked to batch PK 
samples and ship them every two weeks to the ACTG repository with immediate 
re-shipping to the PK laboratory. The PK laboratory will measure drug 
concentrations as soon as possible after receipt of shipments and will report 
results within 2 weeks of receiving the samples. The core team will monitor all 
available concentrations weekly for those results received to date. An early 
interim analysis of PK results and safety criteria will be evaluated after the first 
10-12 participants in each treatment arm complete 28 days of ART and the day 
12 ± 2 drug concentrations are available to assess any early trends suggesting 
lower or higher than expected concentrations of any study-provided drug(s). 
(Please see the Study Monitoring Plan for more details on how this early PK 
assessment will be completed.) If the early assessments indicate concentrations 
out of acceptable ranges for more than three participants in a treatment arm or 
trends related to safety concerns, an early ACTG Study Monitoring Committee 
(SMC) evaluation will be triggered. Any dose adjustments recommended by the 
SMC in consultation with the core team after this interim evaluation will be 
implemented for any new accrual period 1 participants enrolled as soon as 
possible after the review and for any already enrolled participants who have drug 
concentrations clearly out of acceptable ranges. However, the decision to revise 
dose schedules and treatment duration of participants with inadequate drug 
concentrations would be made based not just on the drug concentrations, but 
also on all available clinical data regarding TB and HIV endpoints. While true 
real-time reporting of drug concentrations will not be possible, individual 
participants identified, either during weekly core team monitoring or during any 
early SMC monitoring assessments, who have clearly inadequate concentrations 
of any study-provided drug would be reported to the sites as soon as that 
determination is made, and individual dose adjustments may be recommended 
according to the dose adjustment schedule in Table 5.1 in section 5.1.1 Accrual 
period 1 participants for whom early dose adjustments are recommended will 
have drug concentrations repeated 12 ± 2 days after initiating the adjusted dose. 
If no early PK or safety trends are identified during core team or early SMC 
monitoring, dosing will continue in participants enrolled during accrual period 1 as 
per assigned treatment arm.   
 
NOTE: Any participants determined to have clearly inadequate RBT 
concentrations during the accrual period 1 PK evaluation should be 
monitored closely after dose adjustments for TB outcomes throughout the 
course of their TB treatment. 
 
After 54-60 accrual period 1 participants have completed 28 days of ART and 
have drug concentrations available, the core team, together with the SMC, will 
review the results of the full accrual period 1 interim PK and safety analysis.  


 
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If the acceptable PK criteria for RBT and LPV are met, and if three or fewer 
participants in each treatment arm report  Grade 3 AEs attributed to study-
provided drugs(s) by 28 days of ART, and if three or fewer participants in each 
treatment arm discontinue study-provided drug(s) for treatment-limiting toxicity or 
intolerance (such that PK assessments cannot be completed), then accrual 
period 2 will open at the planned dose schedules of LPV/r and RBT.  
 
If acceptable PK criteria are not met, or if more than three participants in one or 
more treatment arms report  Grade 3 AEs attributed to study-provided drug(s) 
by 28 days of ART, or if more than three participants in one or more treatment 
arms discontinue study-provided drug(s) for treatment-limiting toxicity or 
intolerance (such that PK assessments cannot be completed), the SMC, in 
consultation with the core team, may elect to adjust the doses of RBT and/or 
LPV/r, as described above for all participants in the affected arm identified with 
inadequate study-provided drug concentrations. Repeat steady-state (day 12 ± 2 
after dose adjustment) drug concentrations will be obtained for only the study 
arm participants in whom a dose was adjusted. A second accrual period 1 PK 
and safety interim analysis will be conducted after all accrual period 1 
participants undergoing dose adjustment have completed 28 days of dose-
adjusted treatment and when day 12 ± 2 post-dose adjustment levels are. This 
second analysis will include all accrual period 1 participants with available data. 
 
The core team and SMC will then review the results of the second accrual period 
1 interim PK and safety analysis. If acceptable PK criteria are not met, or if more 
than three participants in one or more treatment arms report  Grade 3 AEs 
attributed to study-provided drug(s) by 28 days of ART, or if more than three 
participants in one or more treatment arms discontinue study-provided drug(s) for 
treatment-limiting toxicity or intolerance (such that PK assessments cannot be 
completed), then a decision will be made about whether to continue, modify (e.g., 
add additional participants in the accrual period 1 to assure adequate PK 
assessment are completed), or halt the treatment arm(s) in question, based on 
analysis of the nature of the AEs and reasons for study-provided drug 
discontinuation, and the degree of PK criteria failure. At this second interim 
review, if three or fewer participants report  Grade 3 AEs attributed to study-
provided drug(s), and if three or fewer participants discontinue study-provided 
drug(s) for treatment-limiting toxicity or intolerance (such that PK assessments 
cannot be completed), and if acceptable PK criteria are met for at least two of the 
treatment arms, the SMC, in consultation with the core team, will determine 
whether accrual period 2 will open. 
 
If, based on the SMC’s determination, unacceptable PK and/or safety criteria are 
met within two treatment arms, then further enrollment into the study may be 
stopped, and accrual period 1 participants will be managed according to best 
available local TB and ARV treatment. These participants will be followed off 
study drug for the remainder of study follow-up (up to 72 weeks). 
 
If the SMC determines that accrual period 2 enrollment should proceed, accrual 
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equal probability to the remaining sample size in the remaining treatment arms) 
at the doses determined during the dose-finding period in accrual period 1 
participants. No individual dose adjustments will be made based on drug 
concentrations for participants enrolled during the accrual period 2.   
 
Based on this monitoring, if criteria are determined to be unacceptable in any 
treatment arm before the three accrual period 1 cohorts are fully enrolled, further 
accrual to the arm in question may be stopped.  
 
9.5.2 Overall Study Monitoring 
 
Early deaths, defined as those occurring within the first two months on study, will 
be monitored by the core team. The cumulative number of deaths during the first 
two months on study will be combined across the treatment arms and will be 
calculated on a monthly basis using a Kaplan-Meier estimator and reported to the 
core team. Should more than 15% of the number of participants enrolled die 
during the first two months on study, the team will request that the NIAID DSMB 
review the study for safety. This review will include both safety data and efficacy 
data through week 48, as available. 
 
After the final SMC review of the PK and safety data during the dose-finding 
period in accrual period 1 participants, this study will be reviewed at least 
annually by the NIAID Data Safety and Monitoring Board (DSMB). This DSMB 
will receive a copy of the full accrual period 1 PK and safety interim analysis. For 
all annual reviews, the DSMB will be provided detailed information on safety 
(including mortality and regimen tolerability) and administrative aspects (accrual, 
baseline characteristics of participants, compliance with specimen storage, and 
retention). The first safety review will take place approximately one year after the 
final SMC review. The first efficacy review will be timed to occur while enrollment 
is ongoing so any required changes to the protocol may be made before accrual 
ceases. Thus, the first efficacy review will take place when approximately 25% of 
all participants have completed 48 weeks of follow-up. The timing of the first 
efficacy review will be decided at the first safety review. Efficacy reviews will 
employ group sequential monitoring of survival probabilities with boundaries 
defined by the Haybittle-Peto rule, with repeated 99.995% confidence intervals 
on the difference in proportions with HIV RNA level < 400 copies/mL at 48 weeks 
(Arm B versus Arm A and Arm B versus Arm C). For monitoring efficacy, there 
are three scenarios with respect to the confidence intervals: 
 
1. The lower bound of the CI is >0% 
2. The CI includes 0% 
3. The upper bound of the CI is <0%. 
 
If the lower bound of the 99.995% CI on the difference is greater than 0%, then 
the experimental Arm (A or C) is superior to Arm B as hypothesized and the team 
intends for the study to continue to full accrual and follow-up. If the 99.995% CI 
on the difference includes 0%, then superiority has not been demonstrated (yet) 
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plots39 to evaluate the possibility of demonstrating superiority with trial 
continuation (e.g., evaluate futility) and the team intends for the study to continue 
to full accrual and follow-up since collecting secondary endpoints is desirable in 
this population regardless of possible futility. If the upper bound of the 99.995% 
CI on the difference is less than 0%, meaning Arm (A or C) is inferior, the team 
intends to evaluate this finding in the context of the toxicity and TB endpoints to 
determine whether the study or one of the treatment arms should be stopped 
while using predicted interval plots to evaluate the possibility of demonstrating 
superiority with trial continuation (e.g., evaluate futility). 
 
The efficacy reviews will also include monitoring the TB cure rate. Since the team 
anticipates that Arm A will be non-inferior to Arm B and Arm C will be non-inferior 
to Arm B, there are two contrasts (Arm A vs. Arm B and Arm C vs. Arm B). A 
one-sided 97.5% CI for the difference in cure rates (i.e., A-B and C-B) will be 
calculated for each contrast and the lower bound of the interval will be compared 
to -10% (i.e., 10% is the non-inferiority margin). For interim monitoring of the TB 
cure rate, CIs for the difference in TB cure rates will be constructed as above. 
Again, there are three possible scenarios:   
 
1. The lower bound of the CI is >0% 
2. The lower bound of the CI is >-10% but <0% 
3. The lower bound of the CI is <-10%. 
 
If the lower bound of the CI is >0%, then the experimental arm (A or C) is 
superior to Arm B with respect to the TB cure rate and the team intends to 
evaluate this finding in the context of the HIV RNA and toxicity endpoints to 
determine whether the study should be stopped. If the lower bound of the CI is >-
10% but <0%, then Arm A or C is non-inferior to Arm B and the team intends for 
the study to continue to full accrual and follow-up as designed. If the lower bound 
of the CI is <-10%, then non-inferiority has not been demonstrated (yet) and the 
team intends to evaluate this finding in conjunction with predicted interval plots to 
evaluate the likelihood of demonstrating non-inferiority with trial continuation 
(e.g., evaluate futility). The team discussed the possibility of a futility analysis and 
decided the study should continue to full accrual and follow-up as designed since 
collecting secondary endpoints is desirable in this population. 
 
The number and timing of reviews will depend on the accrual rate and will be 
decided in conjunction with the DSMB.  
 
Reports on adverse events pooled over arms, but summarized by accrual period, 
will be provided to the Division of AIDS Medical Officer every 6 months.  
 
When approximately 25% of participants have completed 48 weeks of follow-up, 
overall sample size will be re-evaluated based on the current study rate of HIV 
virologic suppression in Arm B only. If the suppression rate is much higher than 
the hypothesized 50%, the protocol team will need to consider increasing the 
sample size in order to have sufficient power to detect smaller treatment 
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still hold). If the suppression rate is much lower than the hypothesized 50%, the 
protocol team discussed the possibility of doing a futility analysis but decided that 
collecting secondary endpoints is desirable in this population given that Arm B is 
standard of care in many resource-constrained settings.  As the primary endpoint 
involves comparisons with Arm B, monitoring the Arm B (standard of 
care/control) rate alone will not affect the alpha level for the primary objective.  
 
9.6 
Analyses 
 
9.6.1 Accrual Period 1 PK and Safety Interim Analyses 
 
Interim PK and safety analyses will be conducted when the first 10-12 accrual 
period 1 participants per treatment arm have completed 28 days of ART and day 
12 ± 2 (after initiation of ART) drug concentrations are available.  These early 
assessments will try to identify any early trends suggesting lower or higher than 
expected concentrations of any study-provided drug(s). If early assessments 
indicate concentrations out of acceptable ranges for more than three participants 
in a treatment arm or trends related to safety criteria, an early ACTG Study 
Monitoring Committee (SMC) evaluation will be triggered. 
 
The accrual period 1 PK and safety interim analysis will be conducted when 54-
60 accrual period 1 participants have completed 28 days of ART and day 12 ± 2 
(after initiation of ART) PK results are available. Study participants who 
discontinue study follow-up prior to day 28 will have their safety data included in 
the safety analysis. Furthermore, study participants who are lost-to-follow-up 
prior to day 28 will be considered failures in the safety analysis. Because these 
participants will be undergoing treatment for active TB, they will continue on their 
randomized therapy pending the results of this interim PK and safety analysis, 
but accrual will be suspended until the final accrual period 1 PK and safety 
interim analysis has been reviewed by the SMC.  
 
For RBT (Arms A and C), an equivalence approach will be used to compare day 
12 ± 2 (after initiation of ART) RBT 24-hour AUC and Cmax with control data 
derived from prior PK studies, as determined by whether the 90% CI of the ratios 
of the RBT concentrations (when co-administered with LPV/r) relative to daily 
RBT concentrations in the absence of LPV/r are fully contained within the pre-
specified NEB of 67%-150%. RBT concentrations in Arms A and C will be judged 
acceptable if equivalence is declared according to these PK parameters. (Please 
note:  the control data derived from prior PK studies are described in section 
10.3.) 
 
For LPV (Arm B), the primary PK parameter is the Cmin (trough or 12-hour post 
dose concentration), and the acceptable lower limit value is  1 mg/L. LPV/r 
concentrations in Arm B will be judged acceptable if no more than three 
participants have a Cmin< 1 mg/L. 
 
For all treatment arms, the safety endpoint is all  Grade 3 AEs attributable to 
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study-provided drug(s) for treatment-limiting toxicity or intolerance (such that PK 
assessments within the days 12 ± 2 (after initiation of ART) window cannot be 
completed). The arms will be judged to pass the safety criteria if no more than 
three participants have reported  Grade 3 AEs attributable to study-provided 
drug(s) by 28 days after ART initiation and if no more than 3 participants 
discontinued study-provided drug(s) for treatment-limiting toxicity or intolerance 
(such that PK assessments could not be completed). 
 
9.6.2 Analysis of the Primary Objective 
 
All participants enrolled into A5290 will be included in the analysis of all the 
overall study objectives regardless of any required dose adjustments for accrual 
period 1 participants. The protocol team discussed the effect of including 
participants enrolled during accrual period 1 who underwent dose adjustments in 
the final analysis of the primary endpoint. The protocol team acknowledges that it 
is possible that those enrolled during accrual period 1 who had low LPV 
concentrations and required a dose adjustment might have worse HIV viral load 
responses at week 48, or alternatively, those who underwent a dose adjustment 
of one or more study-provided drugs might have greater toxicity that could 
adversely affect adherence, early treatment discontinuation, and HIV viral load 
responses at week 48. There remains significant uncertainty around what the 
major drivers will be of the week 48 virologic outcomes in this setting, such that 
including all participants in an intent-to-treat analysis accounting for all factors 
that might have contributed to the endpoint, including low levels requiring dose 
adjustment, higher toxicity leading to non-adherence or dose interruptions, 
prolonged intensive TB treatment phase, etc. will be a part of the study analysis 
plan. The protocol team also acknowledges that it is possible that those enrolled 
during the accrual period 1 could be different than those enrolled during the 
accrual period 2. Besides seeking as homogeneous a population as possible, 
baseline tables of factors that could affect drug concentrations (e.g., sex, prior 
ART experience, body weight, etc.) will be summarized by accrual period.  
 
The primary outcome variable will be the rates of virologic suppression at 48 
weeks within each treatment arm. Participants lost-to-follow-up or without 
virologic data will be considered failures (i.e., not suppressed). The rate in the 
double-dose LPV/r arm will be separately compared to the standard dose LPV/r 
arms in two analyses. The rates between the two arms will be compared using 
an asymptotic normal binomial test (Arm A versus Arm B; Arm C versus Arm B). 
 
9.6.3 Analysis of the Secondary Objectives 
 
Secondary objectives and additional analyses will be evaluated with statistical 
techniques appropriate to the data type and specific question, including but not 
limited to Wilcoxon tests and logistic regression for dichotomous endpoints and 
Cox proportional hazards regression for time-to-event endpoints. Some analyses 
will consider change between baseline and target time points, such as weeks 24 
and 48. Continuous variables may be dichotomized based on conventional cut 
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suppression that are reviewed by the DSMB, the alpha-level for these exploratory 
and hypothesis-generating analyses will not be adjusted for multiple testing. 
 
 
10.0 
PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objectives 
 
10.1.1 To evaluate LPV PK characteristics (AUC, Cmax, Cmin) in study participants 
enrolled in Arms A, B, and C, accrual periods 1 and 2.  
 
10.1.2 To evaluate the RBT PK characteristics (AUC, Cmax, Cmin) in study participants 
enrolled in Arms A and C, accrual periods 1 and 2.  
 
10.1.3 To evaluate the RAL PK characteristics (AUC, Cmax, Cmin) in study participants 
enrolled in Arm C, accrual period 2. 
 
10.2 
Pharmacology Study Design for the Dose-Finding Study in Accrual Period 1 Participants 
 
A5290 is a prospective evaluation in participants undergoing treatment for confirmed or 
probable TB and who require PI-based ART. The dose-finding study in accrual period 1 
participants of A5290 is designed to evaluate two primary questions: 1) Is a RBT dose of 
150 mg once daily when given with LPV/r adequate? and 2) Is an LPV/r dose of 800/200 
mg BID when given with RIF adequate? Intensive PK evaluations will be performed on 
day 12 ± 2 (after initiation of ART) of concomitant TB and HIV therapy on all accrual 
period 1 participants.   
 
10.2.1 Sample Size 
 
The sample size for the dose-finding study in accrual period 1 participants will be 
20 participants per treatment arm, randomized 1:1:1 for a total of 60 participants.  
 
10.2.2 Sampling Strategy 
 
Arms A and C, RBT pharmacokinetics. Plasma samples will be obtained just 
prior (pre-dose) and for 24 hours after administration of the morning dose of RBT 
at the following times: 2, 4, 5, 6, and 24 hours (next day) after the dose. Plasma 
will be frozen and batch shipped every 2 weeks to the ACTG repository, which 
will immediately re-ship them to the designated ACTG Pharmacology Support 
Laboratory (PSL). Refer to the A5290 LPC for additional instructions. 
 
Arms A, B, and C LPV pharmacokinetics. Plasma samples will be obtained just 
prior to administration of the morning dose of LPV/r, and at the following times: 2, 
4, 5, and 6 hours after the dose. A pre-dose concentration will be taken to be a 
12-hour post dose concentration. Plasma will be frozen and batch shipped every 
2 weeks to the ACTG repository, which will immediately re-ship them to the 
designated PSL. Refer to the A5290 LPC for additional instructions. 
 


 
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This sampling strategy requires that the once daily dose of RBT be taken with the 
morning dose of LPV/RTV for Arms A and C, and that the morning dose of RAL 
for Arm C be taken with the morning dose of LPV/RTV.   
 
10.2.3 Medication Adherence 
 
All participants should be counseled to ensure strict compliance with their TB and 
HIV medications. Participants should be queried as to the number of doses of TB 
and HIV medications not taken in the previous 3 days, and this number should be 
recorded on the CRF. The time and date of all doses of all TB and HIV 
medications taken the day prior to the PK study day (i.e., day 12 ± 2 of 
concomitant therapy) must be recorded on the CRF. The time of all doses of TB 
and HIV medications given on the day of the PK study should be recorded on the 
CRF. The PK study should not be performed if participants report missing any 
doses of any TB or HIV medication on the day prior to the PK study. If this 
situation occurs, the participant should be counseled about medication 
adherence, and a repeat PK study may be performed  5 days later, and no 
more than 12 days later than the originally scheduled PK study. If on this second 
PK day, the same participant should report missing any doses on the day prior to 
the PK study, the PK study should not be performed and this individual will not be 
considered eligible for the PK study.   
 
A measured LPV pre-dose (or 12-hour post dose concentration) that is below the 
limit of quantitation (BLQ, < 20 ng/mL) will be taken as objective evidence for 
non-adherence. Any participant in Arm B of the accrual period 1 with a LPV C12 
that is BLQ will not be considered for assessment of the accrual period 1 LPV PK 
passing criterion. Similarly, a measured RBT pre-dose concentration that is BLQ 
will be taken as objective evidence of non-adherence for participants in Arms A 
and C of the accrual period 1. Any participant with a RBT pre-dose concentration 
that is BLQ will not be included in evaluation of the accrual period 1 RBT PK 
passing criterion evaluation. Any participants determined to have clearly 
inadequate RBT concentrations during accrual period 1 evaluation should be 
monitored closely for TB outcomes throughout the course of their TB treatment.    
 
10.2.4 RBT and LPV Quantitation 
 
RBT and LPV concentrations will be determined in an ACTG CLIA-certified 
pharmacology laboratory. The goal is for RBT and LPV concentration information 
from the day 12 ± 2 PK study to be available for evaluation by the A5290 core 
team during the dose-finding period in accrual period 1 participants. Accrual 
period 1 participants for whom early dose adjustments are recommended will 
have drug concentrations repeated 12 ± 2 days after initiating the adjusted dose. 
If no early PK or safety trends are identified during core team or SMC monitoring, 
dosing will continue in participants enrolled during accrual period 1 as per 
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10.3 
Primary and Secondary Data, Modeling, and Data Analysis for the Dose-Finding Study 
in Accrual Period 1 Participants 
 
The observed concentrations of RBT and LPV and the times post dose that these 
concentrations were obtained will be summarized.   
The primary PK characteristics for RBT are: Cmax, time to maximum plasma 
concentration (Tmax), 24-hour post dose plasma concentration (C24h), area under the 
concentration-time curve (AUC0-24), and apparent oral clearance (CL/F). Standard 
noncompartmental techniques will be used to assess PK parameters. The AUC will be 
determined using the trapezoidal rule. Cmax will be taken as the maximum observed 
concentration. Tmax is the time at which Cmax occurs. If more than one Cmax and Tmax 
occur in a given profile, the median of these values will be taken. The 24-hour post dose 
concentrations will be the directly measured value. Apparent oral clearance will be 
calculated as CL/F = dose/AUC0-24. The elimination half-life is considered a secondary 
parameter and will be determined using regression analysis when possible.   
 
The primary PK characteristics for LPV are: Cmax, Tmax, C12h, AUC0-12, and CL/F. 
Standard noncompartmental techniques will be used to assess PK parameters. The 
AUC will be determined using the trapezoidal rule. Cmax will be taken as the maximum 
observed concentration. Tmax is the time at which Cmax occurs. If more than one Cmax and 
Tmax occur in a given profile, the median of these values will be taken. The pre-dose 
concentration will be taken as the 12-hour post dose concentration, and will be the 
directly measured value. CL/F will be calculated as CL/F = dose/AUC0-12. The elimination 
half-life is considered a secondary parameter and will be determined using regression 
analysis when possible.  
 
For RBT (Arms A and C), an equivalence approach will be used to compare RBT AUC 
and Cmax with those of two control datasets from previous PK studies, as described 
below. This approach will evaluate whether the 90% CIs of the ratios of the RBT + LPV/r 
relative to daily RBT PK characteristics are fully contained within a specified no effect 
boundary. A no effect range of 0.67 to 1.50 will be used. Arms A and C will be judged to 
pass the RBT PK criterion if equivalence is declared.  
 
For LPV in Arm B, the primary PK parameter is the Cmin (trough or 12-hour post dose 
concentration), and the acceptable lower value is  1 mg/L. Arm B will be judged to pass 
the LPV Cmin criterion if no more than three participants have a Cmin < 1 mg/L. 
 
RBT pharmacokinetics will be evaluated in Arms A and C of A5290 to investigate the 
question of whether a RBT dose of 150 mg once daily is adequate when given with 
LPV/r. An equivalence approach will be used to compare the RBT AUC and Cmax with 
those of two historical controls. For this comparison, we have selected a recent 
publication describing a drug-drug interaction study of darunavir/ritonavir and RBT. In 
this healthy volunteer study, one arm contained RBT only given for 12 days at a dose of 
300 mg once daily. The strength of this control dataset is the 300 mg RBT dose and an 
intensive pharmacokinetic study. The recommended dose reduction strategy for RBT to 
150 mg once daily when given with a ritonavir-boosted PI is intended to approximate the 
exposure of the standard, 300 mg once daily dose. Thus, this selected control dataset 
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and the necessary PK data43. A second control dataset will also be examined. Some 
RBT PK data are now beginning to become available from studies conducted in HIV- 
and TB-infected persons. One study is that of Naiker, et al40. This study is another good 
comparison for A5290 because of similarities in patients, drugs and dosing regimens.  
However, because this study is only available in abstract form, has a limited sample size 
(n=16), and the majority of the available RBT PK data are from studies conducted in 
healthy volunteers, this study will not be used as the sole, control dataset but will be 
used as a supplementary control to the data from the darunavir/ritonavir and RBT PK 
study previously described.   
 
10.4 
Anticipated Outcomes for the Dose-Finding Study in Accrual Period 1 Participants 
 
These data will provide guidance to the A5290 core team and SMC prior to the opening 
of accrual period 2 as to whether the current management approach for the drug-drug 
interaction between RBT and LPV/r (a RBT dose of 150 mg once daily) produces RBT 
plasma concentrations comparable to those of RBT 300 mg once daily without LPV/r 
observed in prior PK studies. Additionally, these accrual period 1 PK evaluations will 
provide guidance as to whether the management strategy for the drug-drug interaction 
between LPV/r and RIF (Arm B) of using double-dose LPV/r (i.e., 800/200 mg BID) 
achieves adequate LPV concentrations.   
 
If the RBT PK data fall outside the effective ranges and the team determines that a dose 
adjustment is warranted, the team will consider two possibilities – an adjustment to 300 
mg TIW as indicated in Table 5.1 or a change to 300 mg daily based on the RBT PK 
from the accrual period 1 dose-finding period and the assessment of which dose 
adjustment would best approximate the reference PK parameters for RBT 300 mg once 
daily given without LPV/r, as described above in section 10.3. If the team determines a 
RBT dose decrease is warranted, the dose will be reduced to the 150 mg TIW dose 
currently recommended. No substantive effect of RBT on LPV/r concentrations is 
expected based on prior PK data with this combination; however, if levels in the ranges 
noted for Arm B are observed in Arm A or Arm C, then dose adjustments will be the 
same as for Arm B. 
 
10.5 
Population Pharmacokinetic Study Design in Participants Enrolled During Accrual Period 
2 
 
10.5.1 Sample Size for Accrual Period 2 
 
411 participants will be randomized 1:1:1 to Arm A, B, or C (or with equal 
probability to the remaining sample size in the remaining treatment arms) at the 
doses determined during the dose-finding period in accrual period 1 participants, 
and with a population PK approach in the accrual period 2.  
 
10.5.2 Sampling Strategy – Specimen Collection 
 
Blood samples for population PK studies will be collected at the week 2 and 
week 8 clinic visits. Two blood samples, if possible, will be collected at each of 
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Plasma will be frozen and periodically batch shipped to the ACTG repository, 
which will re-ship them to designated ACTG PSL.  Refer to the A5290 LPC for 
additional instructions. 
 
At week 2, the priority blood sample should be collected within a window of 6-12 
hours after administration of a dose of LPV/r. This dose of LPV/r may be either 
the evening dose the day before the clinic visit or the morning dose the day of the 
clinic visit. The second blood sample may be collected at any time before or after 
this sample, as long as there is at least a 2-hour interval between sample 
collections.  
 
At week 8, the first and priority blood sample should be collected within a window 
of 2 to 4 hours after administration of RBT. A second blood sample may be 
collected at any time after this blood sample, as long as there is at least a 2-hour 
interval between sample collections. 
 
For participants in Arm C, samples obtained from this sampling schedule at 
weeks 2 and 8 will also be suitable for RAL.   
 
10.5.3 Medication Adherence 
 
All participants should be counseled to ensure strict compliance with their TB and 
HIV medications. Participants should be queried as to the number of doses of TB 
and HIV medications not taken in the previous 3 days, and this number should be 
recorded on the CRF. The time and date of all doses of all TB and HIV 
medications taken the day prior to the PK study day (i.e., weeks 2 and 8) must be 
recorded on the CRF. The time of all doses of TB and HIV medications given on 
the day of the PK study should be recorded on the CRF. The PK study should 
not be performed if participants report missing any doses of any TB or HIV 
medication on the day prior to the PK study. If this situation occurs, the 
participant should be counseled about medication adherence, and a repeat PK 
study may be performed  5 days later, and no more than 12 days later than the 
originally scheduled PK study. If on this second PK day, the same participant 
should report missing any doses on the day prior to the PK study, the PK study 
should not be performed and this individual will not be considered eligible for the 
PK study. 
 
10.5.4 RBT, LPV, and RAL Quantitation 
 
RBT, LPV, and RAL concentrations will be determined in an ACTG CLIA-certified 
pharmacology laboratory. 
 
10.6 
Primary and Secondary Data, Modeling, and Data Analysis for the Population PK Study 
in Accrual Period 2 Participants 
 
For this analysis, the primary interest will be the PK characteristics of RBT and LPV; the 
PK characteristics of RAL are a secondary objective. PK characteristics will be evaluated 
using NONMEM version VI (GloboMax, Hanover, MD). NONMEM uses mixed effects 


 
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(random and fixed) regression to estimate population means and variances of PK 
parameters and identify factors, such as body weight, gender or concomitant drug that 
may influence these parameters. Base models will be developed using first-order 
conditional estimation with interaction. A stepwise procedure will be used to determine 
whether a one- or two-compartment model best fits the plasma data under the principle 
of parsimony. An exponential error distribution will be assumed for the description of 
both interpatient and intrapatient (residual) PK parameter variability. Residual error will 
be modeled as an additive plus proportional error model. If necessary, poorly identified 
structural parameters, such as the absorption rate constant, may be fixed to usual adult 
values. The following covariates will be collected at baseline or during follow-up visits: 
sex, age, weight, race, markers of renal function (estimate creatinine clearance), HIV 
regimen (e.g., Arm A, B, or C) and HIV response markers, and TB regimen and 
response markers. The influence of each covariate on the PK characteristics of RBT and 
LPV will be tested sequentially. At each step, the goodness of fit plots will also be 
evaluated.  
 
At the end of the analysis, all covariates that show an influence on the parameters will 
be evaluated again by comparison of the full model (with all factors included) with a 
model from which each of the factors is deleted sequentially. For forward addition and 
backward elimination a decrease in objective function value by 3.84 (p  0.05) and 6.64 
(p  0.01), respectively, would advocate sufficiently influential covariates. NONMEM 
uses extended least squares to calculate the objective function and the difference in the 
value of the objective function between models is approximately chi-squared distributed. 
A difference in objective function of greater than 6.6 is considered significant (6.6 
corresponds to a chi-square for p=0.01 with 1 degree of freedom) when one parameter 
is added or the covariate (e.g., body weight) is replaced. This is analogous to the 
commonly used F test to select among regression models. The primary outcome of this 
analysis is to identify the model that best describes the plasma PK of RBT, LPV, and 
RAL and to investigate whether any of the covariates influence the PK of these ART and 
TB agents. The final model will include all significant covariates (if any) and the 
parameter estimates for all parameters together with the estimates of residual and 
interpatient variability. The accuracy and robustness of the final population model will be 
assessed using a bootstrap method. A secondary objective of this combined analysis will 
be to develop a linked population PK-PD model in NONMEM to evaluate potential 
relationships between these plasma concentrations/PK characteristics and therapeutic 
outcomes (i.e., response to HIV therapy and to TB treatment, and adverse events). 
 
10.7 
Anticipated Outcomes in the Population PK Study in Accrual Period 2 Participants 
 
These population PK studies will provide data on whether the PK basis for the selection 
of the RBT and LPV dosing strategies during the dose-finding period in accrual period 1 
participants can be confirmed in a much larger population of participants enrolled during 
accrual period 2. Additionally, these population PK data will provide information on the 
concentrations of RAL for participants in Arm C. The PK data for RBT, LPV, and RAL will 
be used to investigate exposure-response relationships among RBT, LPV, and RAL and 
measures of response to HIV therapy and TB therapy, and these data may fill gaps in 
our knowledge, for example, of whether threshold concentrations of RBT are associated 
with positive or negative (e.g., acquired rifamycin resistance) TB treatment outcomes.   


 
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11.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
 
11.1 
Records to Be Kept 
 
Case report forms (CRF) will be provided for each participant. Participants must not be 
identified by name on any CRFs. Participants will be identified by the patient 
identification number (PID) and study identification number (SID) provided by the ACTG 
DMC upon randomization. 
 
11.2 
Role of Data Management 
 
11.2.1 Instructions concerning the recording of study data on CRFs will be provided by 
the ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
11.2.2 It is the responsibility of the ACTG DMC to assure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
11.3 
Clinical Site Monitoring and Record Availability 
 
11.3.1 Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection 
of study participants, compliance with the protocol, and accuracy and 
completeness of records. The monitors also will inspect sites’ regulatory files to 
ensure that regulatory requirements are being followed and sites’ pharmacies to 
review product storage and management. 
 
11.3.2 The site investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily available 
for inspection by the local IRB/EC, the site monitors, the US FDA, the NIAID, the 
OHRP, the local governmental authorities, and the pharmaceutical supporter(s) 
or designee for confirmation of the study data.  
 
11.4 
Expedited Adverse Event Reporting to DAIDS 
 
11.4.1 
Adverse Event Reporting to DAIDS 
 
The Serious Adverse Event (SAE) Reporting Category will be used for this 
study. Requirements, definitions, and methods for SAE and expedited 
reporting of Adverse Events (AEs) are outlined in Version 2.0 of DAIDS EAE 
Manual, which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance/.  
 
The DAIDS Adverse Events Reporting System (DAERS) internet-based 
reporting system must be used for expedited AE reporting to DAIDS. In the 
event of system outages or technical difficulties, expedited AEs may be 
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contact DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also 
be sent from within the DAERS application itself. 
 
Sites where DAERS has not been implemented will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form. This form is 
available on the RSC website: http://rsc.tech-
res.com/safetyandpharmacovigilance/. For questions about EAE reporting, 
please contact the RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
11.4.2 
Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting is required are: LPV/r, 
RTV, RBT, and RAL. 
• 
As per the SAE and EAE Reporting Categories identified above, any of the 
following SAEs require expedited reporting regardless of relatedness or 
association with the study agents listed: 
 
 
Results in death 
 
Life-threatening 
 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Congenital anomaly/birth defects/fetal losses 
 
Other important medical events (may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the 
participant or may require intervention to prevent one of the events 
listed above).  
 
• 
In addition to the SAEs listed above, additional events required to be 
reported in an expedited manner for this protocol include the following:  
 
 
Cancers with no other event, regardless of the association 
 
All overdoses of study medications 
 
IRIS events that are grade 3 or 4 
 
All abnormal outcomes of pregnancies occurring at > 20 weeks 
gestation. 
 
11.4.3 
Grading Severity of Events 
 
The most current Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table) is used and is available 
on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
 
 


 
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11.4.4 
Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is as per the EAE manual.  
• 
After the protocol-defined AE reporting period, unless otherwise noted, 
only suspected, unexpected serious adverse reactions (SUSARs), as 
defined in Version 2.0 of the EAE Manual, will be reported to DAIDS if the 
study staff become aware of the events on a passive basis (from publicly 
available information). 
 
 
12.0 
HUMAN PARTICIPANTS 
 
12.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent documents (Appendix I and Appendix II) and any 
subsequent modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study. A signed consent form will be obtained from the 
participant (or parent, legal guardian, or person with power of attorney for participants 
who cannot consent for themselves, such as those below the legal age of consent). The 
consent form will describe the purpose of the study, the procedures to be followed, and 
the risks and benefits of participation. A copy of the consent form will be given to the 
participant, parent, or legal guardian, and this fact will be documented in the participant’s 
record. 
 
12.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by ACTG, IRB/EC, the US FDA, the 
NIAID, the OHRP, the local governmental authorities, or the pharmaceutical supporter(s) 
or designee.  
 
12.3 
Study Discontinuation 
 
The study may be discontinued at any time by the ACTG, IRB/EC, the NIAID, the 
pharmaceutical supporter(s), the US FDA, the OHRP, or other government agencies as 
part of their duties to ensure that research participants are protected. 
 
 
13.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the 
pharmaceutical supporter(s) prior to submission.  
 
 


 
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14.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control and Prevention and the National Institutes of Health. 
 
All dangerous goods materials, including diagnostic specimens and infectious 
substances, must be transported using packaging mandated by CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations. 


 
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15.0 
REFERENCES 
 
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2. Wiktor SZ, Sassan-Morokro M, Grant AD, et al. Efficacy of trimethoprim- 
sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected 
patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial 
[published erratum appears in Lancet 1999 Jun 12;353(9169):2078] [see comments]. 
Lancet. 1999;353(9163):1469-75. 
3. Nunn AJ, Mwaba P, Chintu C, et al. Role of co-trimoxazole prophylaxis in reducing 
mortality in HIV infected adults being treated for tuberculosis: randomised clinical trial. 
Bmj. 2008;337:a257. 
4. Burman W, Benator D, Vernon A, et al. Acquired rifamycin resistance with twice-weekly 
treatment of HIV-related tuberculosis. Am J Respir Crit C are Med. 2006;173(3):350-6. 
5. Garcia de Olalla P, Martinez-Gonzalez MA, Cayla JA, et al. Influence of highly active 
anti-retroviral therapy (HAART) on the natural history of extra-pulmonary tuberculosis in 
HIV patients. Int J Tuberc Lung Dis. 2002;6(12):1051-7. 
6. Sanguanwongse N, Cain KP, Suriya P, et al. Antiretroviral therapy for HIV-infected 
tuberculosis patients saves lives but needs to be used more frequently in Thailand. J 
Acquir Immune Defic Syndr. 2008;48(2):181-9. 
7. Lawn SD, Badri M, Wood R. Tuberculosis among HIV-infected patients receiving 
HAART: long term incidence and risk factors in a South African cohort. AIDS 2005; 
19:2109-16. 
8. Karim SA, Naidoo K, Grobler A, et al. Timing of initiation of antiretroviral drugs during 
tuberculosis therapy. N Engl J Med 2010; 362:697-706. 
9. Blanc FX, Sok T, Laureillard D, et al. Significant enhancement in survival with early (2 
weeks) vs. late (8 weeks) initiation of highly active antiretroviral treatment (HAART) in 
severely immunosuppressed HIV-infected adults with newly diagnosed tuberculosis. 
AIDS 2010, CAMELIA Study Results; IAS Conference, Vienna, Austria; Abstract No. 
THLBB106. 
10. Havlir D, Ive P, Kendall M, et al. International randomized trial of immediate vs early 
ART in HIV+ patients treated for TB: ACTG 5221 STRIDE Study. 18th Conference on 
Retroviruses and Opportunistic Infections, Boston, MA, 2011; Abstr. 38.  
11. Karim SA, Naidoo K, Padayatchi N, et al. Optimal timing of ART during TB therapy: 
Findings of the SAPiT Trial. 18th Conference on Retroviruses and Opportunistic 
Infections, Bo ston, MA, 2011; Abstr. 39LB 


 
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12. Tuberculosis Control. A short update to the 2009 report. World Health 
Organization,2009; pp. 1-39 ( HYPERLINK "http://www.who. int/tb" www.who.int/tb). 
13. Centers for Disease Control and Prevention. Managing drug interactions in the treatment 
of HIV-related tuberculosis. Vol. 2008; 2007. 
14. Boulle A, Van Cutsem G, Cohen K, et al. Outcomes of nevirapine- and efavirenz-based 
antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. 
Jama. 2008;300(5):530-9. 
15. Ren Y, Nuttall JJ, Egbers C, et al. High prevalence of subtherapeutic plasma 
concentrations of efavirenz in children. J Acquir Immune Defic Syndr. 2007;45(2):133-6. 
16. Badri M, Maartens G, Mandalia S, et al. Cost-effectiveness of highly active antiretroviral 
therapy in South Africa. PLoS Med. 2006;3(1):e4. 
17. Fairall LR, Bachmann MO, Louwagie GM, et al. Effectiveness of antiretroviral treatment 
in a South African program: a cohort study. Arch Intern Med. 2008;168(1):86-93. 
18. A5208/OCTANE Study Team. Lopinavir/ritonavir (LPV/r)-compared to nevirapine (NVP)-
based ART following receipt of single-dose nevirapine for prevention of mother-to-child 
HIV transmission (PTMCT) in South Africa: a cost-effectiveness analysis of the OCTANE 
(ACTG A5208) trial. [Accepted as an oral presentation] 5th IAS Conference on HIV 
Pathogenesis, Treatment & Prevention, July 19-22, 2009, Cape Town, South Africa. 
19. la Porte CJ, Colbers EP, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-
ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Che mother. 
2004;48(5):1553-60. 
20. Rolla VC, da Silva Vieira MA, Pereira Pinto D, et al. Safety, efficacy and 
pharmacokinetics of ritonavir 400mg/saquinavir 400mg twice daily plus rifampicin 
combined therapy in HIV patients with tuberculosis. Clin Drug Investig. 2006;26(8):469-
79. 
21. Burger DM, Agarwala S, Child M, et al. Effect of rifampin on steady-state 
pharmacokinetics of atazanavir with ritonavir in healthy volunteers. Antimicrob Agents 
Chemother. 2006;50:3336-3342. 
22. Haas DW, Koletar SL, Lauhlin L, et al. Hepatotoxicity and gastrointestinal intolerance 
when healthy volunteers taking rifampin add twice-daily atazanavir and ritonavir. J 
Acquir Immune Defic Syndr. 2009;50(3):290-3. 
23. Drug-induced hepatitis with saquinavir/ritonavir + rifampin. AIDS Clin Care. 
2005;17(3):32. 
24. Veldkcamp AI, Hoetelmans RM, Beijnen JH, et al. Ritonavir enables combined therapy 
with rifampin and saquinavir. Clin Infect Dis. 1999;29:1586. 
25. Moultrie H, Meyers T. Antiretroviral and anti-TB co-therapy in children < 3 years in 
Soweto, South Africa: outcomes in the first 6 months. XVI International AIDS 
Conference. Toronto; 2006: 85, Abstract book 1. 
26. Decloedt EH, Maartens G, Smith P, et al.  The pharmacokinetics of lopinavir in South 
African HIV-infected volunteers receiving rifampicin with adjusted doses of 
lopinavir/ritonavir. Abstract HIV-0062. 11th International Workshop on Clinical 
Pharmacology of HIV Therapy. April 7-9, 2010. Sorrento, Italy. 


 
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27. Decloedt EH, McIlleron H, Smith P, et al. The Pharmacokinetics of lopinavir in HIV-
infected adults receiving rifampicin with adjusted doses of lopinavir/ritonavir tablets. 
Antimicrob Agents Chemother 2011; 55(7):3195-2001. 
28. McGregor MM, Olliaro P, Wolmarans L, et al. Efficacy and safety of rifabutin in the 
treatment of patients with newly diagnosed pulmonary tuberculosis. Am J Respir Crit 
Care Med. 1996;154:1462-1467. 
29. Gonzalez-Montaner LJ, Natal S, Yonchaiyud P, et al. Rifabutin for the treatment of 
newly-diagnosed pulmonary tuberculosis: a multinational, randomized, comparative 
study versus rifampicin. Tubercle Lung Dis. 1994;75:341-347. 
30. Schwander S, Rusch-Gerdes S, Mateega A, et al. A pilot study of antituberculosis 
combinations comparing rifabutin with rifampicin in the treatment of HIV-1 associated 
tuberculosis: a single-blind randomized evaluation in Ugandan patients with HIV-1 
infection and pulmonary tuberculosis. Tubercle Lung Dis. 1995;76:210-218. 
31. Davies GR, Cerri S, Richeldi L. Rifabutin for treating pulmonary tuberculosis (Review). 
In: The Cochrane Library, John Wiley & Sons, Ltd.,  2010, Issue 1. 
32. Burman WJ, Gallicano K, Peloquin C. Therapeutic implications of drug interactions in the 
treatment of HIV-related tuberculosis. Clin Infect Dis. 1999;28:419-30. 
33. Zhang J, Zhu L, Stonier M, et al. Determination of rifabutin dosing regimen when 
administered in combination with ritonavir-boosted atazanavir. J Antimicrob Chemother 
2011; 66(9): 2075-82. 
34. Agarwala S, Mummaneni V, Randall D, et al. Pharmacokinetic (PK) effect of rifabutin 
(RIF) on atazanavir (ATV) with and without ritonavir in healthy subjects. 9th Conference 
on Retroviruses and Opportunistic Infections. Seattle, WA; 2002: 221. 
35. Ford SL, Chen YC, Lou Y, et al. Pharmacokinetic interaction between fosamprenavir-
ritonavir and rifabutin in healthy subjects. Antimicrob Agents Chemother. 
2008;52(2):5348. 
36. Narita M, Stambaugh JJ, Hollender ES, et al. Use of rifabutin with protease inhibitors for 
human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis. 
2000;30:779-783. 
37. Boulanger C, Hollender E, Farrell, et al. Pharmacokinetic evaluation of rifabutin in 
combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis. 
Clin Infect Dis. 2009; 49:1305-11. 
38. Weiner M, Benator D, Burman W, et al. Association between acquired rifamycin 
resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV 
and tuberculosis. Tuberculosis Trials Consortium. Clin Infect Dis. 2005; 40:1481-91. 
39. Jenny-Avital E, Joseph K. Rifamycin-resistant Mycobacterium tuberculosis in the highly 
active antiretroviral therapy era: a report of 3 relapses with acquired rifampin resistance 
following alternate day rifabutin and boosted protease inhibitor therapy. Clin Infect Dis. 
2009; 48:1471-4. 
40. Naiker S, Conolly C, Weisner L, et al. Pharmacokinetic evaluation of different rifabutin 
dosing strategies in African TB patients on lopinavir/ritonavir-based ART. 18th 
Conference on Retroviruses and Opportunistic Infections, Boston, MA, 2011; Abstr. 650. 


 
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41. Brainard DM, Petry AS, Fang L, et al. Lack of a clinically important effect of rifabutin 
(RFB) on raltegravir (RAL) pharmacokinetics [Abstr. A1-1296]. In: Abstracts of the 49th 
Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 
CA; American Society for Microbiology, 2009. 
42. American Thoracic Society. American Thoracic Society/Centers for Disease Control and 
Prevention/Infectious Disease Society of America: Treatment of Tuberculosis. Am J 
Respir Crit Care Med 2003; 167:603-662. 
43. Sekar V, Lavreys L, de Casteele TV, et al. Pharmacokinetics of darunavir/ritonavir and 
rifabutin coadministered in HIV-negative healthy volunteers. Antimicrob Agents 
Chemother 2010;54:4440-5. 
 
 
 
 


 
 
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APPENDIX I 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT FOR ACCRUAL PERIOD 1 (1st ENROLLMENT PERIOD) 
 
For protocol: 
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 
A5290, FINAL Version 1.0, Dated 01/31/12 
 
 
SHORT TITLE FOR THE STUDY: Rifampin-Based TB Treatment vs. Rifabutin-Based TB 
Treatment in HIV, A5290, FINAL Version 1.0 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV (the 
virus that causes AIDS), you are taking or planning to take an anti-HIV therapy (ART) regimen 
that contains a protease inhibitor drug (one of several different types of drugs used for treating 
HIV), and your doctor has determined that you may have tuberculosis (TB). This study is 
sponsored by the National Institutes of Health (NIH) in the United States (US). The doctor in 
charge of this study at this site is: (insert name of Principal Investigator). Before you decide if 
you want to be a part of this study, we want you to have information about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
The current preferred treatment for people with TB and HIV starting their first anti-HIV treatment 
regimen contains efavirenz, an anti-HIV drug, called a non-nucleoside reverse transcriptase 
inhibitor (NNRTI). However, not all people with HIV-related TB can be treated with efavirenz, 
Some people cannot tolerate the side effects of efavirenz. Efavirenz also cannot be used in 
women who may be or may become pregnant. Some people may have been previously treated 
with efavirenz or other NNRTI anti-HIV drugs and may have developed resistance to NNRTI 
anti-HIV drugs, meaning the drugs are no longer working. In addition, the current standard 
treatment for TB includes rifampin, an anti-TB drug that can reduce the amount of certain anti-
HIV drugs, particularly protease inhibitor drugs, in the blood to levels that are not able to treat 
HIV. For this reason, when protease inhibitor anti-HIV treatment is needed in people with TB 
and HIV, either a higher dose of the protease inhibitor or a different drug that works similarly to 
rifampin, called rifabutin, is sometimes used instead of rifampin. Even so, the doses of the 


 
 
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protease inhibitor or the rifabutin may need to be adjusted so the amounts in the blood are able 
to treat both HIV and TB. However, the most appropriate doses of protease inhibitors and of 
rifabutin have not been fully studied in people with TB and HIV. Therefore, treatment with 
protease inhibitors or alternative anti-HIV drugs may be necessary for people with HIV and TB. 
The purpose of this study is to find a safe treatment that contains either rifampin or rifabutin that 
works against TB in people who have HIV and are being treated with protease-inhibitor anti-HIV 
drugs. Another purpose of this study is to see how well people are able to take the TB treatment 
that includes a standard amount of rifampin with a double amount of lopinavir/ritonavir instead of 
the regular recommended amounts of lopinavir/ritonavir and rifabutin.  
 
This study will enroll participants in two enrollment periods. The first part of this study 
(participants joining during the 1st enrollment period) will enroll 60 participants and is being 
performed to find out how protease inhibitors act together with certain anti-TB drugs in your 
body. If you join during the 1st enrollment period, you will have the amount of protease inhibitors 
and of certain anti-TB drugs measured in your blood to determine whether these amounts are 
safe enough or whether different doses of these drugs will be needed to continue with the 
second part of the study (participants joining during the 2nd enrollment period). If the amount of 
the protease inhibitor or the anti-TB drug called rifabutin are higher or lower than expected, 
some participants in the 1st enrollment period will have their doses of these drugs changed, and 
they might need to be continued on their assigned TB medications for a longer period of time to 
allow drug levels to be measured again. The results from the 1st enrollment period will be used 
to find a safe amount of study medications to use in the second period of the study (2nd 
enrollment period). The 2nd enrollment period of this study will enroll 411 additional participants 
and is being done to see how well the amount of the protease inhibitor and certain anti-TB drugs 
selected from the 1st enrollment period work to treat HIV and TB. 
 
You are being asked to take part in 1st enrollment (the first part) of this study now and if the 
results show that a safe combination of study medications can be used together in people with 
HIV and TB, you will continue on study for a total of 72 weeks. 
 
This study will compare three different combinations of both anti-HIV drugs and anti-TB drugs, 
as shown in Table 1 below. Each of the three drug combinations includes the protease inhibitor 
drug lopinavir/ritonavir.  
Table 1. Drug Combinations 
Group (Combination of 
Drugs)
HIV Drugs 
TB Drugs 
A
• 
lopinavir/ritonavir  
• 
two nucleoside 
analogue reverse 
transcriptase inhibitors 
(NRTIs) 
• 
isoniazid 
• 
rifabutin  
• 
ethambutol 
• 
pyrazinamide 
•
pyridoxine (vitamin B6)
B
• 
double-dose 
lopinavir/ritonavir  
• 
two NRTIs 
• 
INH  
• 
rifampin 
• 
ethambutol 
• 
pyrazinamide  
•
pyridoxine (vitamin B6)


 
 
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Group (Combination of 
Drugs)
HIV Drugs 
TB Drugs 
C
• 
lopinavir/ritonavir  
• 
two NRTIs 
• 
raltegravir 
• 
isoniazid 
• 
rifabutin 
• 
ethambutol  
• 
pyrazinamide 
•
pyridoxine (vitamin B6)
 
If you decide to join the study, you will receive lopinavir/ritonavir (combined in a fixed dose 
tablet). You might also receive raltegravir, another anti-HIV drug in another class of HIV 
medications called an integrase inhibitor, if you are assigned to Group C. You will also be asked 
to take either rifabutin or rifampin during the study. Rifabutin will be given to you as part of the 
study, but rifampin will not be provided to you through the study. If you are assigned to a Group 
receiving rifampin, this will be provided to you by prescription locally together with your other TB 
medications. 
 
Lopinavir/ritonavir and raltegravir are approved by the US Food and Drug Administration (FDA) 
for treating HIV. Rifampin is approved by the FDA for treating TB. Rifabutin is used as an 
alternative to rifampin in multiple-drug treatments for TB in people infected with HIV who are 
taking certain anti-HIV drugs that when used together with rifampin makes either the anti-HIV 
drug or rifampin not work effectively. Rifabutin is not approved by the FDA for treating TB.  
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study and enroll in the first part of this study (1st enrollment period), you 
will be required to be seen in the clinic about 14 times over 18 months. Most visits will take 
about one hour to complete. Sometimes, a study visit may take longer. The study staff should 
be able to tell you about how long each visit will take. You may need to come to the clinic for 
extra visits if you develop new symptoms of TB, side effects of your medication, or if you switch 
drugs. If the amounts of study medications in your blood measured are higher or lower than 
expected, you might have your dose of one or more study medications changed, and you may 
need to continue your TB medications for a longer duration, up to 8 more weeks, and to come in 
to the clinic for additional visits to measure amounts of study medications in your blood.  
 
Screening Visit 
After you have read and signed this consent form, you will have several tests done to make sure 
that you meet the requirements for joining the study.  
• 
We will check to see if you have HIV. If there is no record, another HIV test will be done. 
You may have to sign a separate consent form before this is done. You will be told the 
results of the HIV test as soon as it is available. If the test results show that you are HIV-
positive, the study staff will give you HIV counseling.  
• 
You will be asked about information related to your TB infection. You may be asked to bring 
your medical records to the clinic at your next visit so the study doctor can review your test 
results and medications prescribed by your doctor from the TB clinic. If you will get TB 
treatment outside of the study clinic, you will be asked to bring your TB treatment records to 
all study visits.  


 
 
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• 
You will have a physical examination and will be asked questions about your health and 
about any medicines you have taken or are taking now. 
• 
You will have a chest x-ray if you have not had one within the past 30 days. 
• 
About 20 mL (about 1 ½ tablespoons) of blood will be drawn for routine lab tests, CD4/CD8 
cell count (a test that shows how many infection-fighting cells you have in your blood), liver 
function tests, and HIV viral load (a test that shows how much HIV is in your blood).  
• 
If you are a woman who is able to become pregnant, you will have a pregnancy test done. 
You will be asked to give a small urine or blood sample for the pregnancy test. You cannot 
enter the study if you are pregnant or breastfeeding. 
• 
You will be asked whether you give permission, and if so, how you can be contacted in case 
you miss a visit or there are problems with your tests.   
 
You will receive the results of the CD4/CD8 count, HIV viral load, and other blood tests as soon 
as they are available. If you have a pregnancy test, you will be told the result as soon as it is 
available. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, 
we will still use some of your information collected during the screening visit.  As part of this 
screening visit, demographic (for example, your age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, routine lab tests, CD4/CD8 cell 
count, HIV viral load, and liver function tests) information is being collected from you. This 
information may be used by ACTG researchers to help determine whether there are patterns or 
common reasons why people do not join a study. The information may also help ACTG 
researchers understand more about HIV and TB treatment. 
 
Entry Visit 
If you are eligible and you agree to join the study, you will be assigned to one of three treatment 
groups that will include both anti-HIV therapy and treatment for TB. Your assignment is random 
(like the flip of a coin), and you will not be able to choose your group. The three groups are 
treatment Groups A, B and C, as listed in the table at the beginning of this form. Both you and 
your doctor will know which of the groups you are in (see Table 1 showing drug combinations A, 
B, and C). No matter which group you are in, you should continue to take your medicines 
according to your doctor’s instructions. You will need to obtain some of your anti-HIV and anti-
TB medicines by prescription from your doctor(s) or through your local TB or HIV clinic. The 
study staff will explain to you how you should obtain any required medicines that are not 
provided by the study.  
 
At this visit, you will also have the following evaluations: 
• 
You may be asked to provide some sputum (phlegm from your lungs) by coughing and then 
spitting into a cup; if you have trouble coughing, you may be asked to breathe a mist of 
saltwater through a tube or mask and then to spit into a cup. Your sputum will be tested to 
detect TB-like organisms. The test will see if TB can be grown in the laboratory from your 
sputum sample. We will also test your sputum to see if regular TB drugs work for you; a 
sample of your sputum will be saved for future testing for biomarkers of anti-TB drug activity.  


 
 
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• 
You will have a physical examination and will be asked questions about your health, about 
symptoms you may have related to TB, and about any changes in the medications you have 
been taking.  
• 
About 20 mL (about 1 ½ tablespoons) of blood will be drawn for routine lab tests, HIV viral 
load, CD4/CD8 count, and liver function tests. The results of these tests will be provided to 
you and your doctor.  
• 
If you are a woman who is able to become pregnant, you will have a pregnancy test done.  
• 
You will be asked questions about how well you are taking your medicines.   
• 
About 30 mL (about 2 tablespoons) of blood will be drawn and about 20 mL of urine will be 
obtained for future HIV tests and TB tests after the study is over.  
 
Scheduled Clinic Visits 
At each of the scheduled visits, you will have the following evaluations: 
• 
You will have a physical examination and will be asked questions about your health and 
about any changes in the medicines you have been taking. 
• 
If you are a woman who is able to become pregnant, you may have a pregnancy test done. 
 
At some study visits you will also have one or more of the following evaluations: 
 
• 
About 10 mL (about 2 teaspoons) of blood will be drawn for routine lab tests and liver 
function tests. The results of these tests will be provided to you and your doctor. 
• 
You will have about 20 mL (about 1 ½ tablespoons) of blood drawn for HIV viral load and 
CD4/CD8 count. The results of these tests will be provided to you and your doctor. 
• 
After about 8 weeks and 24 weeks on study, you will be asked to provide another sputum 
sample for a TB smear, culture and a test to see if regular TB drugs are still working for you. 
A portion of your sputum sample will be saved for future TB testing. 
• 
After about 8 weeks, 48 weeks, and 72 weeks on study, you will have another chest x-ray. 
• 
About 30 mL (about 2 tablespoons) of blood will be drawn and about 20 mL of urine will be 
obtained for future HIV tests and TB tests after the study is over.  
• 
You will be asked how well you have taken the study medications and if you have missed 
any doses.  
• 
If you will get TB treatment outside of the study clinic, you will be asked to bring your TB 
treatment records to all study visits.  
 
For the day 12 visit, you will be asked to remain at the clinic for about 6 hours. You will have 
about an additional 20 mL (about 1 ½ tablespoons) of blood drawn for pharmacokinetic (PK) 
studies that will measure the amounts of lopinavir/ritonavir and rifampin or rifabutin in your 
blood. If you are taking drug combination A or C, you will have blood drawn just before you take 
your medicine, and at 2, 4, 5, and 6, and 24 hours (the next day) after you take your medicine. If 
you are taking drug combination B, you will have blood drawn in the morning, just before you 
take your medicine, and at 2, 4, 5, and 6 hours after you take your medicine. If the amounts of 
lopinavir/ritonavir and/or rifabutin in your blood are higher or lower than expected, your dose of 
lopinavir/ritonavir and/or rifabutin may be changed, and you will continue to be followed after 
you have started the new dose of your study medication(s). If your dose(s) of study 
medication(s) are changed, you may be asked to continue being followed for up to an additional 
8 weeks on your TB medications, and some of the procedures described above will be repeated 
according to the same schedules.  


 
 
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You will be asked to take your drugs for HIV with a low fat meal. You will be asked to take your 
drugs for TB on an empty stomach. 
 
Some of your blood will be stored (with usual protectors of identity) and used for immunologic 
and viral testing that is required for this study. 
 
Other 
Some of your blood that is left over after all required study testing is done may be stored with 
your permission (with usual protectors of identity) and used for ACTG-approved HIV-related or 
TB-related research. 
 
Also, If you agree, about an extra 2 tablespoons of blood will be taken and stored (with usual 
protectors of identity), and may be used for future ACTG-approved HIV-related or TB-related 
research. Please indicate if you agree to this or not by initialing by the yes or no below.  
 
________ YES                     ________ NO 
 
Urine and sputum samples will also be stored for future use and testing as part of the study. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 60 people will take part in the first part (1st enrollment) of the study. An additional 411 
people will take part in the second part (2nd enrollment) of the study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 72 weeks.   
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
the study is cancelled. 
• 
a Data Safety Monitoring Board (DSMB) or Study Monitoring Committee (SMC) 
recommends that the study be stopped early (A DSMB or SMC is an outside group of 
experts who monitor the study.) 
• 
you are not able to attend the study visits as required by the study 
 
The study doctor may also need to take you off the study drug(s) without your permission if: 
 
• 
continuing the study drug(s) may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you are not able to take the study drug(s) as required by the study 
 


 
 
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If you must stop taking the study drug(s) before the study is over, the study doctor may ask you 
to continue to be part of the study and return for some study visits and procedures. 
 
If I have to permanently stop taking study-provided drugs, or once I leave the study, how would 
they be provided? 
 
During the study: 
 
If you must permanently stop taking study-provided drugs before your study participation is 
over, the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
 
After you have finished your study participation, the study will not be able to continue to provide 
you with the drugs you received on the study. If continuing to take these or similar drugs would 
be of benefit to you, the study staff will discuss how you may be able to obtain them. 
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
Risks of 1st Enrollment Period 
It is possible that you may not continue to have high enough levels of drugs in your blood and 
continue to take your assigned treatment regimen over time. If you are not able to maintain 
adequate levels of drugs in your blood, there is a risk that the drugs might not work as well 
against HIV or TB (in other words your symptoms or levels of HIV or TB might worsen) or that 
you might have more side effects of the medications. It is also possible that you may be asked 
to continue taking certain anti-TB drugs for a longer duration than is usually needed. This might 
be required if you need to have doses of your study drugs changed because you are not able to 
maintain adequate levels of certain drugs in your blood with your first assigned treatment 
regimen or because you have more severe TB and your doctor thinks longer anti-TB treatment 
is needed. Other risks include unknown side effects and your ability to take the different doses 
of lopinavir/ritonavir along with the anti-TB drugs. We will monitor your drug levels and any side 
effects, and report to your site any concerns as soon as the information is available. 
 
Risks of CD4 Counts < 50 cells/µL  
It is possible that you may have a CD4 cell (a type of white blood cell that is a measure of how 
well your immune system works when you are infected with HIV) count of less than 50 cells/µL 
in your blood at the time you enroll in this study. People with this CD4 cell count level are at 
increased risk of dying from their HIV or from TB. Research has shown that the risk of death 
might be decreased in some people with TB and HIV who have CD4 cell counts less than 50 
cells/µL if anti-HIV drugs are started earlier after starting anti-TB treatment. Therefore, your 
doctor and the study team will work to get you started on your anti-HIV study medications as 
soon as possible after you have started your anti-TB medications. In addition, some studies 
have shown that some people with HIV and TB who have CD4 cell counts less than 50 cells/µL 
might have lower than expected amounts of anti-TB drugs in their blood during TB treatment. 
We will monitor your drug levels and any side effects and activity of your medications against 
TB and HIV, and report to your site any concerns as soon as the information is available. 


 
 
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Risks of Study Drugs 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, signs and 
symptoms of inflammation from other infections may occur soon after anti-HIV treatment is 
started.    
 
The use of strong anti-HIV drug combinations may be associated with an abnormal placement 
of body fat and wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
Use of Protease Inhibitors 
The use of protease inhibitors may be related to the following: 
  
• 
Increases in the amount of triglycerides and/or cholesterol in the blood  
• 
Development of diabetes or the worsening of high blood sugar 
 
There have been reports of increased bleeding in HIV-infected persons with hemophilia who 
were treated with protease inhibitors. It is not known if protease inhibitors were the cause of 
these bleeding episodes. 
 
Lopinavir/Ritonavir (LPV/r) 
The following serious side effects are associated with the use of LPV/r and some of these could 
occur more often or be more severe if the levels of LPV/r in your blood are higher than expected 
as a result of the doses used in this study: 
 
• 
Abnormal heart rhythm and electrocardiogram (EKG) changes. These changes can lead to 
serious heart problems. Your risk for these problems may be higher if you: 
o Already have a history of abnormal heart rhythm or other types of heart disease 
o Take other medicines that can affect your heart rhythm while you take LPV/r 
 
If you develop abnormal heart rhythm you may experience lightheadedness, fainting spells or an 
abnormal heart beat.  
 


 
 
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• 
Pancreatitis (inflammation of the pancreas), which may cause death. If you develop 
pancreatitis, you may have one or more of the following: 
o Stomach pain, nausea, vomiting or abnormal pancreatic function blood tests  
o Large increases in triglycerides and cholesterol in the blood  
o Liver problems and worsening liver disease, which may result in death. People with 
these conditions may have abnormal liver function blood tests. If you are developing 
liver problems, you may have one or more of the following: yellowing of the skin or 
whites of your eyes, dark urine, pain on the right side of your stomach, loss of 
appetite, upset stomach or vomiting, pale colored stools, itchy skin. 
o Rash, which could blister, and may be severe or life-threatening 
 
Additional side effects may include: 
• 
Abnormal bowel movements (stools), including loose or watery stools, upset stomach and 
stomach pain  
• 
Feeling weak and tired 
• 
Headache 
 
Ritonavir (RTV) 
The following side effects have been associated with the use of RTV and some of these could 
occur more often or be more severe if the levels of RTV in your blood are higher than expected 
as a result of the doses used in this study: 
 
• 
Feeling weak and tired 
• 
Stomach and bowel problems including abdominal pain, upset stomach, vomiting, abnormal 
stools, and loose or watery stools  
• 
Loss of appetite 
• 
Headache 
• 
Dizziness 
• 
Abnormal increases in triglycerides and cholesterol in blood 
• 
Numbness and tingling in the arms, legs and around the mouth  
• 
Rash 
• 
Abnormal liver function blood tests which may be due to possible liver problems. Liver 
problems including cases of death have occurred in people taking RTV. 
• 
A change in the sense of taste  
• 
Pancreatitis, which may cause death. If you develop pancreatitis, you may have one or more 
of the following: stomach pain, nausea, and vomiting. 
• 
Abnormal heart rhythm and EKG changes. If you develop abnormal heart rhythm you may 
experience lightheadedness, fainting spells or an abnormal heart beat.  
• 
Allergic reactions that can be serious that may include symptoms like hives, trouble 
breathing and mild to severe skin rashes or reactions 
 
Raltegravir (RAL) 
The following side effects have been associated with the use of RAL:  
 
• 
Upset  stomach 
• 
Headache 
• 
Tiredness 


 
 
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• 
Weakness 
• 
Trouble sleeping 
• 
Rash, which can be severe  
• 
Feeling anxious 
• 
Depression, suicidal thoughts and actions  
• 
Paranoia (an abnormal sense of fear) 
• 
Low blood platelet count  
• 
Muscle tenderness, weakness or injury which can be serious and lead to kidney damage 
 
Severe and potentially life-threatening rash has been reported with the use of raltegravir. You 
should immediately contact the study staff if you develop rash. The study staff will ask you to 
immediately stop taking raltegravir and possibly other study drugs. If you develop a rash with 
any of the following side effects it may be a sign of a more serious reaction such as Stevens-
Johnson syndrome, toxic epidermal necrolysis, or severe hypersensitivity: fever, generally ill 
feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial 
swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of 
liver problems (yellowing of the skin or whites of the eyes, dark or tea colored urine, pale 
colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or 
sensitivity on the right side below the ribs). If you develop a severe rash, you will be closely 
followed and appropriate therapy will be started.  
 
Rifabutin (RBT) 
The following side effects have been associated with the use of RBT and some of them could 
occur more often or be more severe if the levels of RBT in your blood are higher than expected 
as a result of the doses used in this study: 
 
• 
Abnormal urine discoloration 
• 
Digestive system side effects, including nausea, vomiting, indigestion, belching, and taste 
changes 
• 
Abdominal pain 
• 
Rash 
• 
Fever 
• 
Headache 
• 
Diarrhea, including diarrhea due to Clostridium difficile, a bacteria that interferes with the 
normal function of the bowel 
• 
Loss of appetite 
• 
Jaundice (yellow skin) 
• 
Muscle pain 
• 
Insomnia 
• 
Fatigue 
• 
Decrease in neutrophil count (a type of white blood cell which aids in fighting some types of 
infections, or modest suppression of the total white blood cell counts 
• 
Decrease in platelet counts (a component in blood that helps blood to clot)  
• 
Eye inflammation (uveitis) which can produce eye redness, pain, sensitivity, and decreased 
vision 
• 
Decrease in effectiveness of oral contraceptives (birth control pills) or Norplant 
• 
Decrease in methadone effectiveness 


 
 
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• 
Urine, sweat, sputum, tears, and skin may be colored brown-orange 
 
Rifampin (RIF) 
RIF is commonly prescribed in the United States and worldwide to treat TB, and is generally 
well tolerated. RIF turns urine, sweat, sputum, and tears a red-orange color. The red-orange 
color in urine may stain undergarments. Soft contact lenses may be permanently stained by 
RIF. Less common side effects include: 
 
• 
Hepatitis (inflammation of the liver). This has caused deaths in patients who already had 
liver disease or who were taking other drugs that were toxic to the liver. 
• 
Increases in liver function tests  
• 
Increased bilirubin, which may be associated with yellowing of the eyes 
• 
Upset stomach, vomiting, and diarrhea 
• 
Abdominal pain  
• 
Reduced levels of some of your body's hormones  
• 
Reduced levels of calcium and phosphate in blood 
• 
Decreased effectiveness of hormonal contraceptives and many other medications 
• 
Reduced blood cell counts  
• 
Headache 
• 
Rash and itching 
• 
Fever 
• 
Kidney failure 
 
Risks of Drawing Blood 
Taking blood may cause discomfort, bleeding, and bruising where the blood is drawn. 
Occasionally, there is swelling in the area where the needle enters the body and there is a small 
risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 
Risks of Chest X-rays 
You will be exposed to very small amounts of radiation. The scanning machines will not cause 
any physical discomfort other than from having to be still for the test. 
 
Other Risks 
By taking part in this study, it is possible that it might be difficult for you to keep your HIV status 
secret from people close to you. This may lead to unwelcome discussions about or reactions to 
your HIV status. Please talk with the clinic staff if you have any concerns about this.   
 
You may also have some anxiety or depression regarding the study testing, treatment, and 
results. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if some of the drug combinations in this study would cause harm to unborn 
babies. If you are having sex that could lead to pregnancy, you must agree not to become 
pregnant, or, if you are a man, you must agree not to attempt to make a woman pregnant or 
participate in sperm donation. 


 
 
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Because of the risk involved, you and your partner must use two methods of birth control that 
you discuss with the study staff. You must continue to use both methods until at least 6 weeks 
after you stop the study drug. If you are having sex that could lead to pregnancy, and do not use 
2 types birth control, your study doctor will take you off of the study drugs. You may choose two 
of the birth control methods listed below (one type should be a barrier method): 
 
• 
condoms (barrier method), with or without a spermicidal agent 
• 
a diaphragm or cervical cap (barrier method) with spermicide 
• 
an IUD (intrauterine device) 
• 
hormone-based contraceptive 
 
If you are pregnant, you cannot enter the study. If you think you may be pregnant at any time 
during the study, tell your study staff right away. The study staff will ask you to stay in the study 
so that you can be evaluated. If you become pregnant during the study, after discussion with 
your doctor and the study team, you may choose to continue your study-provided anti-HIV or 
anti-TB medications during your pregnancy and you may choose to breastfeed your baby. If you 
choose to continue your assigned study medications you will be asked to continue on the study 
and information about the outcome of your pregnancy will be recorded in study records. If you 
choose not to continue study-provided anti-HIV or anti-TB medications, you and your doctor will 
decide on the best available HIV and/or TB medications for you to use, but the study staff will 
ask you to stay in the study so that you can continue to be evaluated. If you leave the study 
before the end of your pregnancy, the study staff will request permission for you to be contacted 
at the end of your pregnancy so that you and your baby can be evaluated. 
 
If you become pregnant while you are in the study, your pregnancy will be reported to the 
Antiretroviral Pregnancy Registry.  
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV and TB. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• 
treatment with prescription drugs available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
 


 
 
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WHAT ABOUT CONFIDENTIALITY? 
 
The study team will provide you with an identification number. The identification number (not 
your name or other information that could be used to identify you) will be used for laboratory 
tests or blood work stored for testing in future studies. Your medical records and the list of 
names, addresses, and identification numbers will be kept in a locked room. Only the study staff 
will have the keys. No publication of this study will use your name or identify you personally.  
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law.  
Your records may be reviewed by the ACTG, US Office for Human Resource Protections 
(OHRP), FDA, the drug companies supporting the study, the local institutional review board or 
ethics committee (insert name of site IRB/EC), National Institutes of Health (NIH), your country’s 
national health agency or other regulatory authorities, study staff, and study monitors. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this Web site at any time. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for study-related visits, study-provided drugs, physical 
examinations, laboratory tests, or other procedures. You, your insurance company, or your 
health care system, may need to pay the cost of anti-HIV and anti-TB drugs not provided by the 
study. (Delete references to insurance company or health care system if not applicable at site.)  
In some cases, it is possible that your insurance company will not pay for these costs because 
you are taking part in a research study.   
 
The study will not provide prenatal care, postpartum testing, or care to infants born to women 
who become pregnant while on study.  
 
 
WILL I RECEIVE ANY PAYMENT? 
 
Insert site-specific information on compensation to study participants.  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the US NIH. You will not 
be giving up any of your legal rights by signing this consent form. 
 
 


 
 
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WHAT ARE MY RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research subject, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 
 


 
 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
_________________________________________ 
Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
 
 
____________________________ 
_________________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
____________________________ 
_________________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 


 
 
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APPENDIX II 
 
DIVISION OF AIDS 
AIDS CLINICAL TRIALS GROUP (ACTG) 
SAMPLE INFORMED CONSENT FOR ACCRUAL PERIOD 2 (2nd ENROLLMENT PERIOD) 
 
For protocol: 
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 
A5290, FINAL Version 1.0, Dated 01/31/12 
 
 
SHORT TITLE FOR THE STUDY: Rifampin-Based TB Treatment vs. Rifabutin-Based TB 
Treatment in HIV, A5290, FINAL Version 1.0 
 
 
INTRODUCTION 
 
You are being asked to take part in this research study because you are infected with HIV (the 
virus that causes AIDS), you are taking or planning to take an anti-HIV therapy (ART) regimen 
that contains a protease inhibitor drug (one of several different types of drugs used for treating 
HIV), and your doctor has determined that you may have tuberculosis (TB). This study is 
sponsored by the National Institutes of Health (NIH) in the United States (U.S). The doctor in 
charge of this study at this site is: (insert name of Principal Investigator). Before you decide if 
you want to be a part of this study, we want you to have information about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
The current preferred treatment for people with TB and HIV starting their first anti-HIV treatment 
regimen contains efavirenz, an anti-HIV drug called a non-nucleoside reverse transcriptase 
inhibitor (NNRTI). However, not all people with HIV-related TB can be treated with efavirenz. 
Some people cannot tolerate the side effects of EFV. EFV also cannot be used in women who 
may be or may become pregnant. Some people may have been previously treated with 
efavirenz or other NNRTI anti-HIV drugs and may have developed resistance to NNRTI anti-HIV 
drugs, meaning the drugs are no longer working. Therefore, treatment with protease inhibitors 
or alternative anti-HIV drugs may be necessary for people with HIV and TB. In addition, the 
current standard treatment for TB includes rifampin, an anti-TB drug that can reduce the amount 
of certain anti-HIV drugs, particularly protease inhibitor drugs, in the blood to levels that are not 
able to treat HIV. For this reason, when protease inhibitor anti-HIV treatment is needed in 
people with TB and HIV, either a higher dose of the protease inhibitor or a different drug that 


 
 
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works similarly to rifampin called rifabutin is sometimes used instead of rifampin. Even so, the 
doses of the protease inhibitor or the rifabutin may need to be adjusted so the amounts in the 
blood are able to treat both HIV and TB. However, the most appropriate doses of protease 
inhibitors and of rifampin or rifabutin to use have not been fully studied in people with TB and 
HIV. Therefore, the purpose of this study is to find a safe treatment that contains either rifampin 
or rifabutin that works against TB in people who have HIV and are being treated with protease-
inhibitor anti-HIV drugs.  Another purpose of this study is to see how well people are able to 
take the TB treatment that includes a standard amount of rifampin with a double amount of 
lopinavir/ritonavir instead of the regular recommended amounts of lopinavir/ritonavir and 
rifabutin.  
 
This study will enroll participants in two enrollment periods. The first part of this study 
(participants joining during the 1st enrollment period) will enroll 60 participants and is being 
performed to find out how protease inhibitor anti-HIV drugs act together with certain anti-TB 
drugs in the body. Participants enrolled in the 1st enrollment period will have the amount of 
protease inhibitors and of certain anti-TB drugs measured in the blood to determine whether 
these amounts are safe enough or whether different doses of these drugs will be needed to 
continue with the second part of the study (participants joining during the 2nd enrollment period). 
The results from the 1st enrollment period will be used to find a safe amount of study 
medications to use in the 2nd enrollment period of the study (participants joining during the 2nd 
enrollment period). The 2nd enrollment period of this study will enroll 411 additional participants 
and is being done to see how well the amount of the protease inhibitor and certain anti-TB drugs 
selected from the 1st enrollment period work to treat HIV and TB. 
 
You are being asked to take part in the 2nd enrollment (the second part) of this study now. This 
study will compare three different combinations of both anti-HIV drugs and anti-TB drugs, as 
shown in Table 1 below. Each of the three drug combinations includes the protease inhibitor 
drug lopinavir/ritonavir.  
Table 1. Drug Combinations 
Group (Combination of 
Drugs) 
HIV Drugs 
TB Drugs 
A 
• 
lopinavir/ritonavir  
• 
two nucleoside 
analogue reverse 
transcriptase inhibitors 
(NRTIs) 
• 
isoniazid  
• 
rifabutin 
• 
ethambutol  
• 
pyrazinamide 
• 
pyridoxine (vitamin B6) 
B 
• 
double-dose 
lopinavir/ritonavir 
• 
two NRTIs 
• 
isoniazid  
• 
rifampin 
• 
ethambutol  
• 
pyrazinamide 
• 
pyridoxine (vitamin B6) 
C 
• 
lopinavir/ritonavir  
• 
two NRTIs 
• 
raltegravir 
• 
INH  
• 
RBT  
• 
EMB  
• 
pyrazinamide 
• 
pyridoxine (vitamin B6) 


 
 
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If you decide to join the study, you will receive lopinavir/ritonavir (combined in a fixed dose 
tablet). You might also receive raltegravir, another anti-HIV drug in another class of HIV 
medications called an integrase inhibitor, if you are assigned to Group C. You will also be asked 
to take either rifabutin or rifampin during the study. Rifabutin will be given to you as part of the 
study, but rifampin will not be provided to you through the study. If you are assigned to a Group 
receiving rifampin, this will be provided to you by prescription locally together with your other TB 
medications. 
 
Lopinavir/ritonavir and raltegravir are approved by the US Food and Drug Administration (FDA) 
for treating HIV. Rifampin is approved by the FDA for treating TB. Rifabutin is used as an 
alternative to rifampin in multiple-drug treatments for TB in people infected with HIV who are 
taking certain anti-HIV drugs when used together with rifampin makes either the anti-HIV drug 
or rifampin not work effectively. Rifabutin is not approved by the FDA for treating TB. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
If you decide to join this study and enroll into the second part of this study (2nd enrollment 
period), you will be required to be seen in the clinic about 14 times over 18 months. Most visits 
will take about one hour to complete. Sometimes, a study visit may take longer. The study staff 
should be able to tell you about how long each visit will take. You may need to come to the clinic 
for extra visits if you develop new symptoms of TB, side effects of your medication, or if you 
switch drugs.  
 
Screening Visit 
After you have read and signed this consent form, you will have several tests done to make sure 
that you meet the requirements for joining the study.  
• 
We will check to see if you have HIV. If there is no record, another HIV test will be done. 
You may have to sign a separate consent form before this is done. You will be told the 
results of the HIV test as soon as it is available. If the test results show that you are HIV-
positive, the study staff will give you HIV counseling.  
• 
You will be asked about information related to your TB infection. You may be asked to bring 
your medical records to the clinic at your next visit so the study doctor can review your test 
results and medications prescribed by your doctor from the TB clinic.  If you will get TB 
treatment outside of the study clinic, you will be asked to bring your TB treatment records to 
all study visits.  
• 
You will have a physical examination and will be asked questions about your health and 
about any medicines you have taken or are taking now. 
• 
You will have a chest x-ray if you have not had one within the past 30 days. 
• 
About 20 mL (about 1 ½ tablespoons) of blood will be drawn for routine lab tests, CD4/CD8 
cell count (a test that shows how many infection-fighting cells you have in your blood), liver 
function tests, and HIV viral load (a test that shows how much HIV is in your blood). The 
results of these tests will be provided to you and your doctor.   
• 
If you are a woman who is able to become pregnant, you will have a pregnancy test done. 
You will be asked to give a small urine or blood sample for the pregnancy test. You cannot 
enter the study if you are pregnant or breastfeeding. 
• 
You will be asked whether you give permission, and if so, how you can be contacted in case 
you miss a visit or there are problems with your tests.   


 
 
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You will receive the results of the CD4/CD8 count, HIV viral load, and other blood tests as soon 
as they are available. If you have a pregnancy test, you will be told the result as soon as it is 
available. 
 
If you do not enroll into the study 
If you decide not to take part in this study or if you do not meet the eligibility requirements, 
we will still use some of your information collected during the screening visit.  As part of this 
screening visit, demographic (for example, your age, gender, race), clinical (for example, 
disease condition, diagnosis), and laboratory (for example, routine lab tests, CD4/CD8 cell 
count, HIV viral load, and liver function tests) information is being collected from you. This 
information may be used by ACTG researchers to help determine whether there are patterns or 
common reasons why people do not join a study. The information may also help ACTG 
researchers understand more about HIV and TB treatment. 
 
Entry Visit 
If you are eligible and you agree to join the study, you will be assigned to one of three treatment 
groups that will include both anti-HIV therapy and treatment for TB. Your assignment is random 
(like the flip of a coin), and you will not be able to choose your group. The three groups are 
treatment Groups A, B and C, as listed in the table at the beginning of this form. Both you and 
your doctor will know which of the groups you are in (see Table 1 showing drug combinations A, 
B, and C). No matter which group you are in, you should continue to take your medicines 
according to your doctor’s instructions. You will need to obtain some of your anti-HIV and anti-
TB medicines by prescription from your doctor(s) or through your local TB or HIV clinic. The 
study staff will explain to you how you should obtain any required medicines that are not 
provided by the study.  
 
At this visit, you will also have the following evaluations: 
• 
You may be asked to provide some sputum (phlegm from your lungs) by coughing and then 
spitting into a cup; if you have trouble coughing, you may be asked to breathe a mist of 
saltwater through a tube or mask and then to spit into a cup. Your sputum will be tested to 
detect TB-like organisms. The test will see if TB can be grown in the laboratory from your 
sputum sample. We will also test your sputum to see if regular TB drugs work for you; a 
sample of your sputum will be saved for future testing for biomarkers of anti-TB drug activity.  
• 
You will have a physical examination and will be asked questions about your health, about 
symptoms you may have related to TB, and about any changes in the medications you have 
been taking.  
• 
About 20 mL (about 1 ½ tablespoons) of blood will be drawn for routine lab tests, HIV viral 
load, CD4/CD8 count, and liver function tests. The results of these tests will be provided to 
you and your doctor. 
• 
If you are a woman who is able to become pregnant, you will have a pregnancy test done.  
• 
You will be asked questions about how well you are taking your medicines.   
• 
About 30 mL (about 2 tablespoons) of blood will be drawn and about 20 mL of urine will be 
obtained for future HIV tests and TB tests after the study is over.  
 
Scheduled Clinic Visits 
At each of the scheduled visits, you will have the following evaluations: 
• 
You will have a physical examination and will be asked questions about your health and 
about any changes in the medicines you have been taking. 


 
 
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• 
If you are a woman who is able to become pregnant, you may have a pregnancy test done. 
 
At some study visits you will also have one or more of the following evaluations: 
 
• 
About 10 mL (about 2 teaspoons) of blood will be drawn for routine lab tests and liver 
function tests. The results of these tests will be provided to you and your doctor. 
• 
You will have about 20 mL (about 1 ½ tablespoons) of blood drawn for HIV viral load and 
CD4/CD8 count. The results of these tests will be provided to you and your doctor. 
• 
After about 8 weeks and 24 weeks on study, you will be asked to provide another sputum 
sample for a TB smear, culture and a test to see if regular TB drugs are still working for you. 
A portion of your sputum sample will be saved for future TB testing. 
• 
After about 8 weeks, 48 weeks, and 72 weeks on study, you will have another chest x-ray. 
• 
About 30 mL (about 2 tablespoons) of blood will be drawn and about 20 mL of urine will be 
obtained for future HIV tests and TB tests after the study is over.  
• 
You will be asked how well you have taken the study medications and if you have missed 
any doses.  
• 
If you will get TB treatment outside of the study clinic, you will be asked to bring your TB 
treatment records to all study visits.  
 
For the week 2 and week 8 visits, you will have blood drawn for pharmacokinetic (PK) studies 
that will measure the amounts of lopinavir/ritonavir and rifampin or rifabutin in your blood. At 
week 2, you will have blood collected within 6-12 hours after you receive lopinavir/ritonavir. You 
may receive this dose of lopinavir/ritonavir either the night before your clinic visit or the morning 
of the clinic visit. A second blood sample will be collected at any time before or after this 
sample, as long as there is at least a 2 hour time period between the two blood draws. At week 
8, you will have blood drawn 2 to 4 hours after you take rifabutin. After at least 2 hours have 
passed, you will have a second blood draw. If you are in Group C, you will also have these 
blood draws done.  
 
You will be asked to take your drugs for HIV with a low fat meal. You will be asked to take your 
drugs for TB on an empty stomach. 
 
Some of your blood will be stored (with usual protectors of identity) and used for immunologic 
and viral testing that is required for this study. 
 
Other 
Some of your blood that is left over after all required study testing is done may be stored with 
your permission (with usual protectors of identity) and used for ACTG-approved HIV-related or 
TB-related research. 
 
If you agree, about an extra 2 tablespoons (10 mL) of blood will be taken. This blood will be 
stored (with usual protectors of identity) and may be used for future ACTG-approved HIV-
related or TB-related research. Please indicate if you agree to this or not by initialing by the yes 
or no below.  
 
________ YES                     ________ NO 
 
Urine and sputum samples will also be stored for future use and testing as part of the study. 


 
 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
About 411 people will take part in this part of the study (2nd enrollment period). About 60 people 
will take part in the first part (1st enrollment period) of the study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 72 weeks.   
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
 
• 
the study is cancelled. 
• 
a Data Safety Monitoring Board (DSMB) or Study Monitoring Committee (SMC) 
recommends that the study be stopped early (A DSMB or SMC is an outside group of 
experts who monitor the study.) 
• 
you are not able to attend the study visits as required by the study 
 
The study doctor may also need to take you off the study drug(s) without your permission if: 
 
• 
continuing the study drug(s) may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you are not able to take the study drug(s) as required by the study 
 
If you must stop taking the study drug(s) before the study is over, the study doctor may ask you 
to continue to be part of the study and return for some study visits and procedures. 
 
If I have to permanently stop taking study-provided drugs, or once I leave the study, how would 
they be provided? 
 
During the study: 
 
If you must permanently stop taking study-provided drugs before your study participation is 
over, the study staff will discuss other options that may be of benefit to you. 
 
After the study: 
 
After you have finished your study participation, the study will not be able to continue to provide 
you with the drugs you received on the study. If continuing to take these or similar drugs would 
be of benefit to you, the study staff will discuss how you may be able to obtain them. 
 
 


 
 
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WHAT ARE THE RISKS OF THE STUDY? 
 
The drugs used in this study may have side effects, some of which are listed below. Please note 
that these lists do not include all the side effects seen with these drugs. These lists include the 
more serious or common side effects with a known or possible relationship. If you have 
questions concerning the additional study drug side effects please ask the medical staff at your 
site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study and also before starting any new 
medications while on the study. Also, you must tell the study doctor or nurse before enrolling in 
any other clinical trials while on this study. 
 
Risks of 2nd Enrollment Period 
It is possible that the amounts of anti-HIV and anti-TB drugs that you receive together will result 
in amounts of anti-TB drugs in your blood that may not be able to cure TB. It is also possible 
that the combination will result in amounts of anti-HIV drugs that may not be as able to  treat 
your HIV as what could be prescribed for you outside of the study.  
 
Risks of CD4 Counts < 50 cells/µL  
It is possible that you may have a CD4 cell (a type of white blood cell that is a measure of how 
well your immune system works when you are infected with HIV) count of less than 50 cells/µL 
in your blood at the time you enroll in this study. People with this CD4 cell count level are at 
increased risk of dying from their HIV or from TB. Research has shown that the risk of death 
might be decreased in some people with TB and HIV who have CD4 cell counts less than 50 
cells/µL if anti-HIV drugs are started earlier after starting anti-TB treatment. Therefore, your 
doctor and the study team will work to get you started on your anti-HIV study medications as 
soon as possible after you have started your anti-TB medications. In addition, some studies 
have shown that some people with HIV and TB who have CD4 cell counts less than 50 cells/µL 
might have lower than expected amounts of anti-TB drugs in their blood during TB treatment. 
We will monitor your drug levels and any side effects and activity of your medications against 
TB and HIV, and report to your site any concerns as soon as the information is available. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, signs and 
symptoms of inflammation from other infections may occur soon after anti-HIV treatment is 
started.    
 
The use of strong anti-HIV drug combinations may be associated with an abnormal placement 
of body fat and wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 


 
 
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Use of Protease Inhibitors 
The use of protease inhibitors may be related to the following: 
  
• 
Increases in the amount of triglycerides and/or cholesterol in the blood  
• 
Development of diabetes or the worsening of high blood sugar 
 
There have been reports of increased bleeding in HIV-infected persons with hemophilia who 
were treated with protease inhibitors. It is not known if protease inhibitors were the cause of 
these bleeding episodes. 
 
Lopinavir/Ritonavir 
The following serious side effects are associated with the use of lopinavir/ritonavir: 
 
• 
Abnormal heart rhythm and electrocardiogram (EKG) changes. These changes can lead to 
serious heart problems. Your risk for these problems may be higher if you: 
o Already have a history of abnormal heart rhythm or other types of heart disease 
o Take other medicines that can affect your heart rhythm while you take 
lopinavir/ritonavir 
 
If you develop abnormal heart rhythm you may experience lightheadedness, fainting spells or an 
abnormal heart beat.  
• 
Pancreatitis (inflammation of the pancreas), which may cause death. If you develop 
pancreatitis, you may have one or more of the following: 
o Stomach pain, nausea, vomiting or abnormal pancreatic function blood tests  
o Large increases in triglycerides and cholesterol in the blood  
o Liver problems and worsening liver disease, which may result in death. People with 
these conditions may have abnormal liver function blood tests. If you are developing 
liver problems, you may have one or more of the following: yellowing of the skin or 
whites of your eyes, dark urine, pain on the right side of your stomach, loss of 
appetite, upset stomach or vomiting, pale colored stools, itchy skin. 
o Rash, which could blister, and may be severe or life-threatening 
 
Additional side effects may include: 
• 
Abnormal bowel movements (stools), including loose or watery stools, upset stomach and 
stomach pain  
• 
Feeling weak and tired 
• 
Headache 
 
Ritonavir (RTV) 
The following side effects have been associated with the use of RTV: 
 
• 
Feeling weak and tired 
• 
Stomach and bowel problems including abdominal pain, upset stomach, vomiting, abnormal 
stools, and loose or watery stools  
• 
Loss of appetite 
• 
Headache 
• 
Dizziness 


 
 
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• 
Abnormal increases in triglycerides and cholesterol in blood 
• 
Numbness and tingling in the arms, legs and around the mouth  
• 
Rash 
• 
Abnormal liver function blood tests which may be due to possible liver problems. Liver 
problems including cases of death have occurred in people taking RTV. 
• 
A change in the sense of taste  
• 
Pancreatitis, which may cause death. If you develop pancreatitis, you may have one or more 
of the following: stomach pain, nausea, and vomiting. 
• 
Abnormal heart rhythm and EKG changes. If you develop abnormal heart rhythm you may 
experience lightheadedness, fainting spells or an abnormal heart beat.  
• 
Allergic reactions that can be serious that may include symptoms like hives, trouble 
breathing and mild to severe skin rashes or reactions 
 
Raltegravir 
The following side effects have been associated with the use of raltegravir:  
 
• 
Upset  stomach 
• 
Headache 
• 
Tiredness 
• 
Weakness 
• 
Trouble sleeping 
• 
Rash, which can be severe  
• 
Feeling anxious 
• 
Depression, suicidal thoughts and actions  
• 
Paranoia (an abnormal sense of fear) 
• 
Low blood platelet count  
• 
Muscle tenderness, weakness or injury which can be serious and lead to kidney damage 
 
Severe and potentially life-threatening rash has been reported with the use of raltegravir. You 
should immediately contact the study staff if you develop rash. The study staff will ask you to 
immediately stop taking raltegravir and possibly other study drugs. If you develop a rash with 
any of the following side effects it may be a sign of a more serious reaction such as Stevens-
Johnson syndrome, toxic epidermal necrolysis, or severe hypersensitivity: fever, generally ill 
feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial 
swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of 
liver problems (yellowing of the skin or whites of the eyes, dark or tea colored urine, pale 
colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or 
sensitivity on the right side below the ribs). If you develop a severe rash, you will be closely 
followed and appropriate therapy will be started. 
 
Rifabutin 
The following side effects have been associated with the use of rifabutin: 
 
• 
Abnormal urine discoloration 
• 
Digestive system side effects, including nausea, vomiting, indigestion, belching, and taste 
changes 
• 
Abdominal pain 


 
 
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• 
Rash 
• 
Fever 
• 
Headache 
• 
Diarrhea, including diarrhea due to Clostridium difficile, a bacteria that interferes with the 
normal function of the bowel 
• 
Loss of appetite 
• 
Jaundice (yellow skin) 
• 
Muscle pain 
• 
Insomnia 
• 
Fatigue 
• 
Decrease in neutrophil count (a type of white blood cell which aids in fighting some types of 
infections, or modest suppression of the total white blood cell counts 
• 
Decrease in platelet counts (a component in blood that helps blood to clot)  
• 
Eye inflammation (uveitis) which can produce eye redness, pain, sensitivity, and decreased 
vision 
• 
Decrease in effectiveness of oral contraceptives (birth control pills) or Norplant 
• 
Decrease in methadone effectiveness  
• 
Urine, sweat, sputum, tears, and skin may be colored brown-orange 
 
Rifampin 
Rifampin is commonly prescribed in the United States and worldwide to treat TB, and is 
generally well tolerated. RIF turns urine, sweat, sputum, and tears a red-orange color. The red-
orange color in urine may stain undergarments. Soft contact lenses may be permanently stained 
by rifampin. Less common side effects include: 
 
• 
Hepatitis (inflammation of the liver). This has caused deaths in patients who already had 
liver disease or who were taking other drugs that were toxic to the liver. 
• 
Increases in liver function tests  
• 
Increased bilirubin, which may be associated with yellowing of the eyes 
• 
Upset stomach, vomiting, and diarrhea 
• 
Abdominal pain  
• 
Reduced levels of some of your body's hormones  
• 
Reduced levels of calcium and phosphate in blood 
• 
Decreased effectiveness of hormonal contraceptives and many other medications 
• 
Reduced blood cell counts  
• 
Headache 
• 
Rash and itching 
• 
Fever 
• 
Kidney failure 
 
Risks of Drawing Blood 
Taking blood may cause discomfort, bleeding, and bruising where the blood is drawn. 
Occasionally, there is swelling in the area where the needle enters the body and there is a small 
risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 


 
 
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Risks of Chest X-rays 
You will be exposed to very small amounts of radiation. The scanning machines will not cause 
any physical discomfort other than from having to be still for the test. 
 
Other Risks 
By taking part in this study, it is possible that it might be difficult for you to keep your HIV status 
secret from people close to you. This may lead to unwelcome discussions about or reactions to 
your HIV status. Please talk with the clinic staff if you have any concerns about this.   
 
You may also have some anxiety or depression regarding the study testing, treatment, and 
results. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
 
It is not known if some of the drug combinations in this study would cause harm to unborn 
babies. If you are having sex that could lead to pregnancy, you must agree not to become 
pregnant, or, if you are a man, you must agree not to attempt to make a woman pregnant or 
participate in sperm donation. 
 
Because of the risk involved, you and your partner must use two methods of birth control that 
you discuss with the study staff. You must continue to use both methods until at least 6 weeks 
after you stop the study drug. If you are having sex that could lead to pregnancy, and do not use 
2 types birth control, your study doctor will take you off of the study drugs. You may choose two 
of the birth control methods listed below (one type should be a barrier method): 
 
• 
condoms (barrier method), with or without a spermicidal agent 
• 
a diaphragm or cervical cap (barrier method) with spermicide 
• 
an IUD (intrauterine device). 
• 
hormone-based contraceptive. 
 
If you are pregnant, you cannot enter the study. If you think you may be pregnant at any time 
during the study, tell your study staff right away. The study staff will ask you to stay in the study 
so that you can be evaluated. If you become pregnant during the study, after discussion with 
your doctor and the study team, you may choose to continue your study-provided anti-HIV or 
anti-TB medications during your pregnancy and you may choose to breastfeed your baby. If you 
choose to continue your assigned study medications you will be asked to continue on the study 
and information about the outcome of your pregnancy will be recorded in study records. If you 
choose not to continue study-provided anti-HIV or anti-TB medications, you and your doctor will 
decide on the best available HIV and TB medications for you to use, but the study staff will ask 
you to stay in the study so that you can continue to be evaluated. If you leave the study before 
the end of your pregnancy, the study staff will request permission for you to be contacted at the 
end of your pregnancy so that you and your baby can be evaluated.  
If you become pregnant while you are in the study, your pregnancy will be reported to the 
Antiretroviral Pregnancy Registry.  
 
 


 
 
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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be 
made. It is also possible that you may receive no benefit from being in this study. Information 
learned from this study may help others who have HIV and TB. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• 
treatment with prescription drugs available to you 
• 
treatment with experimental drugs, if you qualify  
• 
no treatment 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices. 
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
The study team will provide you with an identification number. The identification number (not 
your name or other information that could be used to identify you) will be used for laboratory 
tests or blood work stored for testing in future studies. Your medical records and the list of 
names, addresses, and identification numbers will be kept in a locked room. Only the study staff 
will have the keys. No publication of this study will use your name or identify you personally.  
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law.  
Your records may be reviewed by the ACTG, US Office for Human Resource Protections 
(OHRP), FDA, the drug companies supporting the study, the local institutional review board or 
ethics committee (insert name of site IRB/EC), NIH, your country’s national health agency or 
other regulatory authorities, study staff, and study monitors. 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by US law. 
This website will not include information that can identify you. At most, the web site will include a 
summary of the results. You can search this Web site at any time. 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for study-related visits, study-provided drugs, physical 
examinations, laboratory tests, or other procedures. You, your insurance company, or your 
health care system, may need to pay the cost of anti-HIV and anti-TB drugs not provided by the 
study. (Delete references to insurance company or health care system if not applicable at site.)  
In some cases, it is possible that your insurance company will not pay for these costs because 
you are taking part in a research study.   
 


 
 
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The study will not provide prenatal care, postpartum testing, or care to infants born to women 
who become pregnant while on study.  
 
 
WILL I RECEIVE ANY PAYMENT? 
 
Insert site-specific information on compensation to study participants.  
 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the US NIH. You will not 
be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH SUBJECT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies conducted by NIH and will not result in any penalty or loss of benefits to which you 
are otherwise entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your rights as a research subject, contact: 
 
• 
name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
telephone number of above 
 
 


 
 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
_________________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
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Participant’s Legal Guardian (print) 
Legal Guardian’s Signature and Date 
(As appropriate) 
 
 
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Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
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Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 

SAP_001.pdf: 
Filename: U:\CTgov\documentation\A5290AnalysisPlanV3_final.docx 
Directory mapping: \home\kendall\ 
Printed on: December 19, 2017 
 
A5290 Statistical Analysis Plan 
Version 3.0 (Primary Analysis) 
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 
ClinicalTrials.gov Identifier: NCT01601626 
 
14 July 2017 
 


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Page 2 of 11 
Table of Contents 
TABLE OF CONTENTS ............................................................................................................................... 2 
1 
INTRODUCTION .................................................................................................................................... 3 
2 
PROTOCOL OVERVIEW ....................................................................................................................... 3 
2.1 
Protocol Objectives ..................................................................................................................... 4 
2.1.1 
Primary Objective .............................................................................................................. 4 
2.1.2 
Secondary Objectives ........................................................................................................ 4 
2.1.3 
Tertiary Objective ............................................................................................................... 5 
2.2 
Outcome Measures ..................................................................................................................... 5 
2.2.1 
Primary Outcome Measure ................................................................................................ 5 
2.2.2 
Secondary Outcome Measures ......................................................................................... 5 
3 
STATISTICAL METHODS ..................................................................................................................... 6 
4 
REPORT COMPONENTS ...................................................................................................................... 6 
4.1 
Study Accrual .............................................................................................................................. 6 
4.2 
Baseline Characteristics ............................................................................................................. 6 
4.3 
Study Retention ........................................................................................................................... 7 
4.4 
Study Treatment .......................................................................................................................... 7 
4.4.1 
HIV Treatment ................................................................................................................... 7 
4.4.2 
TB Treatment ..................................................................................................................... 7 
4.5 
Adverse Events ............................................................................................................................ 8 
4.6 
Diagnoses .................................................................................................................................... 8 
4.7 
Predictors of HIV Disease Progression ..................................................................................... 8 
4.7.1 
CD4 .................................................................................................................................... 8 
4.7.2 
New AIDS-Defining Illnesses ............................................................................................. 9 
4.8 
Efficacy ......................................................................................................................................... 9 
4.8.1 
HIV Virologic Suppression ................................................................................................. 9 
4.8.2 
HIV Virologic Failure .......................................................................................................... 9 
4.8.3 
TB Treatment Outcomes ................................................................................................. 10 
 
 
 


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1 
Introduction 
This statistical analysis plan has been developed to (1) provide a structured time-frame for database 
completion and preparation of the primary analysis report; (2) facilitate discussion of the key statistical 
analysis components among the study team; (3) provide agreement between the study team and 
statisticians regarding the statistical analyses to be performed; and (4) aid in setting priorities relating 
the data cleaning and development of statistical analysis programs.  
The statistical analysis plan contains details of all statistical analyses that will be completed prior to 
the preparation of the primary analysis report. 
2 
Protocol Overview 
A5290 is a prospective, randomized, open-label, Phase 2b study comparing three lopinavir/ritonavir 
(LPV/r)-based antiretroviral (ARV) regimens among participants in high tuberculosis (TB) endemic 
resource-constrained settings undergoing treatment for TB and HIV and requiring protease inhibitor 
(PI)-based antiretroviral therapy (ART). It was planned to have two accrual periods. Accrual period 1 
aimed to randomize 60 participants in an effort to secure 54-60 evaluable participants for the PK 
interim analysis. It was planned that accrual would be suspended while the interim PK and safety 
evaluation is conducted. However, due to feasibility concerns, accrual period 2 will not open to 
randomize the additional 411 participants. 
The study population is HIV-infected persons (male or female) at least 18 years of age with 
documented HIV infection, a clinical diagnosis of probable or confirmed active TB (including 
extrapulmonary TB) with susceptibility to rifampin (RIF), and who require a PI-based ARV regimen.  
471 participants will be randomized in a 1:1:1 ratio to receive either: 
 
Arm A 
ART: LPV 400 mg/RTV 100 mg twice daily (BID) + two NRTIs. 
Anti-TB therapy: Isoniazid (INH), rifabutin (RBT), ethambutol (EMB), pyrazinamide (PZA), and 
pyridoxine.  
After completion of TB treatment through week 72: LPV 400mg/RTV 100mg BID + two NRTIs. 
 
Arm B 
ART: LPV 800 mg/RTV 200 mg BID + two NRTIs. 
Anti-TB therapy: INH, rifampin (RIF), EMB, PZA, and pyridoxine.  
After completion of TB treatment through week 72:  LPV 400mg/RTV 100mg BID + two NRTIs.  
 
Arm C 
ART: LPV 400 mg/RTV 100 mg BID + two NRTIs + raltegravir (RAL) 400 mg BID. 
Anti-TB therapy: INH, RBT, EMB, PZA, and pyridoxine.  
After completion of TB treatment through week 72: LPV 400mg/RTV 100mg BID + two NRTIs 
+ RAL. 
LPV/r, RTV, RAL, and RBT are available through this study. RIF, INH, EMB, PZA, pyridoxine, and the 
NRTI background are not provided through the study and must be obtained by non-study prescription. 
Each participant will be followed until week 72. 


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The study hypothesis is that, for HIV-1-infected participants with active tuberculosis (TB) who require 
protease inhibitor (PI)-based antiretroviral therapy (ART), a standard dose LPV/r regimen, with or 
without RAL, coupled with RBT-based TB treatment is superior to a double dose LPV/r regimen 
coupled with RIF-based TB treatment. 
2.1 
Protocol Objectives 
2.1.1 
Primary Objective 
To compare rates of virologic suppression to <400 copies/mL at 48 weeks for the two standard dose 
LPV/r and RBT arms versus the double-dose LPV/r and RIF arm [Objective 1.2]. 
2.1.2 
Secondary Objectives 
1. To evaluate TB treatment outcomes (as measured by week 8 mycobacterial culture 
conversion, treatment failure at or after week 24, TB relapse/recurrence by week 72) between 
RBT-containing arms and the RIF-containing arm, to include the association between RBT or 
RIF exposure as well as other factors potentially associated with outcomes of TB treatment 
[Objective 1.3.1]. 
2. To compare rates of virologic suppression to <50 copies/mL at 48 weeks for the two standard 
dose LPV/r and RBT arms versus the double-dose LPV/r and RIF arm [Objective 1.3.2]. 
3. To compare rates of virologic suppression to <50 copies/mL and <400 copies/mL at 48 
weeks for standard dose LPV/r and RBT versus standard dose LPV/r, RBT, and RAL 
[Objective 1.3.3]. 
4. To compare safety and tolerability during TB treatment between the three treatment arms 
[Objective 1.3.4]. 
5. To compare the proportion of participants with virologic failure and time to virologic failure 
between the three treatment arms [Objective 1.3.5]. 
6. To compare the emergence of HIV-1 drug resistance mutations in gag, protease, reverse 
transcriptase (RT), and integrase in participants with virologic failure between the three 
treatment arms [Objective 1.3.6; to be addressed in a subsequent statistical analysis plan].  
7. To compare the proportion of participants with TB drug resistance among cases of TB 
treatment failure and relapse/recurrence of TB between the three treatment arms [Objective 
1.3.7]. 
8. To characterize TB immune reconstitution inflammatory syndrome (IRIS) events [Objective 
1.3.8]. 
9. To compare changes in CD4+ T-cell count, and proportions of participants who experience 
new AIDS-defining illness, HIV disease progression (defined as new AIDS-defining illness or 
death), or death between the three treatment arms [Objective 1.3.9].  
10. To evaluate LPV pharmacokinetic (PK) characteristics (area under the curve [AUC], 
maximum concentration [Cmax], minimum concentration [Cmin]) in participants enrolled in Arms 
A, B, and C, accrual periods 1 and 2 [Objective 1.3.10; addressed in the PK and Safety 
Interim Analysis Report]. 


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11. To evaluate the RBT PK characteristics (AUC, Cmax, Cmin) in participants enrolled in Arms A 
and C, accrual periods 1 and 2 [Objective 1.3.11; addressed in the PK and Safety Interim 
Analysis Report]. 
12. To evaluate RAL PK characteristics (AUC, Cmax, Cmin) in participants enrolled in Arm C, 
accrual period [Objective 1.3.12; addressed in the PK and Safety Interim Analysis Report]. 
13. To evaluate the cost-benefit analysis of the addition of RAL [Objective 1.3.13; to be 
addressed in a subsequent statistical analysis plan]. 
2.1.3 
Tertiary Objective 
To submit sputum, serum, and urine specimens at specified time points for analysis of biomarkers 
associated with TB treatment response [Objective 1.4.1; this objective was not met since A5302 
BioBank for Surrogate Marker Research for TB (B-SMART) did not open during accrual period 1]. 
2.2 
Outcome Measures 
2.2.1 
Primary Outcome Measure 
The primary HIV virologic suppression outcome is the occurrence of plasma HIV-1 RNA level <400 
copies/mL at 48 weeks [Objectives 1.2 and 1.3.3]. 
2.2.2 
Secondary Outcome Measures 
1. The first secondary TB treatment outcome is mycobacterial culture conversion at week 8 
[Objective 1.3.1].  
2. The second secondary TB treatment outcome is occurrence of TB treatment failure at or after 
week 24, where TB treatment failure is defined as an MTB-positive mycobacterial culture after 
16 weeks of TB treatment for a participant who was documented to be taking TB medications 
[Objective 1.3.1].  
3. The third secondary TB treatment outcome is an occurrence of TB relapse/recurrence by week 
72, where relapse/recurrence occurs when a participant has 2 consecutive MTB-negative 
mycobacterial cultures and who subsequently has clinical or radiographic deterioration 
consistent with active TB at or after week 24 and before the week 72 endpoint [Objective 1.3.1].  
4. The secondary HIV virologic suppression outcome is the occurrence of plasma HIV-1 RNA 
level <50 copies/mL at 48 weeks [Objectives 1.3.2 and 1.3.3]. 
5. The secondary safety outcome is occurrence of a grade 3 or grade 4 adverse event or 
laboratory abnormality [Objective 1.3.4]. 
6. The secondary tolerance outcomes are occurrence of an interruption or discontinuation of at 
least one HIV drug due to toxicity and to at least one anti-TB drug due to toxicity [Objective 
1.3.4]. 
7. The secondary HIV virologic failure outcomes are the occurrence of two consecutive plasma 
HIV-1 RNA levels ≥1000 copies/mL at or after 16 weeks and before 24 weeks of ART or ≥400 
copies/mL at or after 24 weeks of treatment, regardless of ART status, and the time from 
randomization to the occurrence of HIV virologic failure [Objective 1.3.5]. 


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8. The secondary TB drug resistance outcome is the occurrence of TB drug resistance among 
cases of TB treatment failure or TB relapse/recurrence [Objective 1.3.7]. 
9. The secondary MTB IRIS outcome is the occurrence of MTB IRIS [Objective 1.3.8]. 
10. The secondary disease progression outcomes are CD4 cell counts, occurrence of new AIDS-
defining illness, and death [Objective 1.3.9]. 
3 
Statistical Methods 
Accrual Period 2 did not open to enroll, leaving a sample size of 71 out of the required 471 
participants. This provides fewer than 25 participants in each arm. Because of the limited sample 
size, formal statistical comparisons will not be made. Instead, the analysis will consist of summarizing 
the proportions and the 95% confidence intervals (CIs) calculated using Wilson’s score method within 
each treatment arm. Time-to-event analyses will consist of Kaplan-Meier plots with 95% pointwise 
CIs. Other outcome measures will be summarized using numbers and proportions. Baseline data will 
be summarized using medians, quartiles, minimum, and maximums if continuous, and percentages if 
categorical.  
All randomized participants will be included in this intent-to-treat analysis. Key study visit weeks were 
baseline (week 0) and weeks 8, 16, 24, 48, and 72. The visit window for baseline was -4.3 weeks to 
0.4 weeks. The post-baseline visit windows were ±1 week. 
4 
Report Components 
4.1 
Study Accrual 
 
Summary of the number of participants enrolled by month and by site by treatment arm. 
4.2 
Baseline Characteristics 
 
Summary of age, sex, race, and ethnicity by treatment arm. 
 
Summary of Karnofsky performance score and body mass index (BMI) by treatment arm.  
 
Summary of CD4 count and HIV RNA (number below lower limit of quantification and log10 copy 
number for those above the lower limit of quantification). 
 
Summary of CD4 count and HIV RNA (number below lower limit of quantification and log10 copy 
number for those above the lower limit of quantification) by treatment arm. 
 
Summary of reason PI-based therapy was needed from eligibility checklist [Q0017-Q0018] 
(category and specific reason if category=other) by treatment arm.  
 
Summary of ANC, hemoglobin, platelet count, AST, ALT, and total bilirubin by treatment arm. 
 
Summary of the number of cumulative days of anti-TB treatment for the current TB episode prior 
to study entry by treatment arm. 
 
Summary of the number of years from completion of TB treatment for the last prior TB episode to 
study entry by treatment arm. 
 
Summary of chest x-ray findings by treatment arm. 


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 
Summary of TST and IGRA results by treatment arm [Note: These data were collected “if 
available;” none are available]. 
 
Summary of AFB smear and mycobacterial culture results by treatment arm (may include non-
study data collected from the local TB program if the specimen was collected within 30 days prior 
to study entry). 
 
Summary of RIF and INH drug susceptibility testing (DST) results by treatment arm (may include 
non-study data collected from the local TB program if the specimen was collected within 30 days 
prior to study entry). 
 
Summary of level of certainty of the current TB episode as defined in Protocol Section 4.1.3 by 
treatment arm. 
4.3 
Study Retention 
 
Summary of weeks from randomization to last clinic visit by treatment arm. 
 
Summary of off-study reasons by treatment arm. 
4.4 
Study Treatment 
 
Summary of days from randomization to TB treatment initiation, days from randomization to 
study-provided ARV treatment initiation, and days from TB treatment initiation to ARV treatment 
initiation by treatment arm. 
4.4.1 
HIV Treatment 
 
Summary of the numbers and proportions of participants who interrupted or permanently 
discontinued at least one HIV drug due to toxicity, with 95% CIs based on Wilson’s score method, 
by treatment arm [Objective 1.3.4]. 
 
Listing of participants who interrupted or permanently discontinued at least one HIV drug due to 
toxicity, with all PK parameters for all drugs and metabolites. 
 
Summary of weeks from study-provided ART initiation to the first interruption, to permanent 
discontinuation, and to the first interruption or permanent discontinuation of an HIV drug due to 
toxicity by treatment arm. 
 
Summary of the reasons for interruptions of HIV drugs due to toxicity by treatment arm. 
 
Summary of the reasons for interruptions of HIV drugs due to other reasons by treatment arm. 
 
Summary of the reasons for permanent discontinuations of HIV drugs due to toxicity by treatment 
arm. 
 
Summary of the reasons for permanent discontinuations of HIV drugs due to other reasons by 
treatment arm. 
4.4.2 
TB Treatment 
 
Summary of the numbers and proportions of participants who interrupted or permanently 
discontinued at least one TB drug due to toxicity, with 95% CIs based on Wilson’s score method, 
by treatment arm [Objective 1.3.4]. 


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 
Listing of participants who interrupted or permanently discontinued at least one TB drug due to 
toxicity, with all PK parameters for all drugs and metabolites. 
 
Summary of weeks from study-provided TB medications initiation to the first interruption, to 
permanent discontinuation, and to the first interruption or permanent discontinuation of a TB drug 
by treatment arm. 
 
Summary of the reasons for interruptions of TB drugs due to toxicity by treatment arm. 
 
Summary of the reasons for interruptions of TB drugs due to other reasons by treatment arm. 
 
Summary of the reasons for permanent discontinuations of TB drugs due to toxicity by treatment 
arm. 
 
Summary of the reasons for permanent discontinuations of TB drugs due to other reasons by 
treatment arm. 
4.5 
Adverse Events  
Note:  TB signs/symptoms grade 2 or higher were reportable; otherwise, grade 3 or higher 
signs/symptoms and laboratory toxicities were reportable. 
 
Summary of all new, post-baseline grade 2 or higher signs/symptoms and laboratory toxicities by 
type and by treatment arm [Objective 1.3.4]. 
 
Listing of participants who developed Grade 3 or 4 AEs, with all PK parameters for all drugs and 
metabolites. 
 
Summary of numbers and proportions of participants who died, with 95% CIs based on Wilson’s 
score method, by treatment arm [Objective 1.3.9]. 
 
Summary of the primary and contributing causes of death with weeks from study-provided ART 
and TB medications initiation and attribution to study drug by treatment arm. 
4.6 
Diagnoses 
 
Summary of all new, post-baseline diagnoses by treatment arm. 
 
Summary of all new, post-baseline primary diagnoses of grade 3 or 4 and primary diagnoses that 
had grade 3 or 4 associated signs, symptoms, and laboratory abnormalities with associated 
signs/symptoms and laboratory abnormalities by treatment arm. 
 
Listing of all uveitis cases with all PK parameters for RBT and des-RBT. 
 
Summary of MTB-IRIS diagnoses with weeks from TB treatment initiation, grade, associated 
signs/symptoms and laboratory abnormalities, and weeks to resolution, if available, by treatment 
arm [Objective 1.3.8]. 
4.7 
Predictors of HIV Disease Progression 
4.7.1 
CD4 
 
Summary of CD4 counts at weeks 8, 24, 48, and 72 by treatment arm. 
 
Summary of change in CD4 count from baseline to week 8, baseline to week 24, baseline to 
week 48, and baseline to week 72 by treatment arm [Objective 1.3.9]. 


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4.7.2 
New AIDS-Defining Illnesses 
 
Summary of numbers and proportions of participants diagnosed with a new AIDS-defining illness, 
with 95% confidence intervals (CIs) based on Wilson’s score method, by treatment arm [Objective 
1.3.9]. 
 
Summary of numbers and proportions of participants diagnosed with a new AIDS-defining illness 
or died, with 95% CIs based on Wilson’s score method, by treatment arm [Objective 1.3.9]. 
4.8 
Efficacy 
4.8.1 
HIV Virologic Suppression 
Note: Participants who were lost-to-follow-up or dead by week 48 will be coded as not suppressed as 
per Protocol Section 9.6.2.  
 
Summary of HIV RNA at weeks 8, 16, 24, 48, and 72 by treatment arm. 
 
Summary of the evaluability of all participants with respect to HIV RNA at week 48 by treatment 
arm. 
 
Summary of numbers and proportions of participants with HIV RNA <400 copies/mL at week 48, 
with 95% CIs based on Wilson’s score method, by treatment arm [Objective 1.2 & Objective 1.3.3]. 
 
Summary of numbers and proportions of participants with HIV RNA <400 copies/mL at week 48, 
with 95% CIs based on Wilson’s score method, by pooled Arms A/C and Arm B [Objective 1.2 & 
Objective 1.3.3]. 
 
Summary of numbers and proportions of participants with HIV RNA <50 copies/mL at week 48, with 
95% CIs based on Wilson’s score method, by treatment arm [Objective 1.3.2 & Objective 1.3.3]. 
 
Summary of numbers and proportions of participants with HIV RNA <50 copies/mL at week 48, with 
95% CIs based on Wilson’s score method, by pooled Arms A/C and Arm B [Objective 1.3.2 & 
Objective 1.3.3]. 
4.8.2 
HIV Virologic Failure 
Note:  HIV virologic failure is defined as two consecutive HIV RNA levels ≥1000 copies/mL at or after 16 
weeks and before 24 weeks of ART or ≥400 copies/mL at or after 24 weeks of treatment (and up to 72 
weeks), regardless of whether or not randomized ART is being taken at the time of failure. 
Note: Participants without the data needed to determine virologic failure will be coded as failures. 
 
Summary of numbers and proportions of participants within each category of virologic failure by 
treatment arm. 
 
Summary of numbers and proportions of participants with virologic failure, with 95% CIs based on 
Wilson’s score method, by treatment arm [Objective 1.3.5]. 
 
Kaplan-Meier plot of time to virologic failure with 95% pointwise CIs, by treatment arm [Objective 
1.3.5]. 


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4.8.3 
TB Treatment Outcomes 
Note:  According to Protocol Section 6.3.7:  “For participants who enroll with probable TB and do not 
have a positive mycobacterial culture from any site available to meet these outcome definitions, but who 
have specimens with a positive AFB smear, the AFB smear result will be submitted for the 
mycobacterial culture result in assessing TB outcomes. If there are no positive AFB smear results, then 
the assessment of TB outcomes will be based on the best clinical judgment and further reviewed by the 
team and an independent endpoint reviewer. 
 
Summary of numbers and proportions of participants for each TB treatment status and outcome 
determination by treatment arm. 
4.8.3.1 
Week 8 Mycobacterial Culture Conversion  
 
Summary of participants who met the mycobacterial culture conversion outcome at week 8. Details 
will be provided in the table to show why participants did not meet the definition of mycobacterial 
culture conversion at week 8 outcome measure. 
 
Summary of numbers and proportions of participants with mycobacterial culture conversion at week 
8, with 95% CIs based on Wilson’s score method, by treatment arm [Objective 1.3.1]. 
 
Summary of numbers and proportions of participants with mycobacterial culture conversion at week 
8, with 95% CIs based on Wilson’s score method, by pooled Arms A/C and Arm B [Objective 1.3.1]. 
 
Kaplan-Meier plot of time to mycobacterial culture conversion, with 95% pointwise CIs, by treatment 
arm [Objective 1.3.1]. 
 
Kaplan-Meier plot of time to mycobacterial culture conversion, with 95% pointwise CIs, by pooled 
Arms A/C and Arm B [Objective 1.3.1]. 
4.8.3.2 
TB Treatment Failure 
 
Summary of numbers and proportions of participants with TB treatment failure at or after week 24, 
with 95% CIs based on Wilson’s score method, by treatment arm [Objective 1.3.1]. 
 
Summary of numbers and proportions of participants with TB treatment failure at or after week 24, 
with 95% CIs based on Wilson’s score method, by pooled Arms A/C and Arm B [Objective 1.3.1]. 
 
Summary of cases of TB treatment failure with TB diagnostics on the baseline sputum, TB outcome 
at time of TB treatment discontinuation, weeks from TB treatment discontinuation to TB treatment 
failure, and results from TB diagnostics on the sputum collected at time of TB treatment failure (i.e., 
AFB smear, culture, and DST) by treatment arm.  
4.8.3.3 
TB Relapse/Recurrence 
 
Summary of numbers and proportions of participants with TB relapse/recurrence by week 72, with 
95% CIs based on Wilson’s score method, by treatment arm [Objective 1.3.1]. 
 
Summary of numbers and proportions of participants with TB relapse/recurrence by week 72, with 
95% CIs based on Wilson’s score method, by pooled Arms A/C and Arm B [Objective 1.3.1]. 


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4.8.3.4 
TB Drug Resistance 
 
Summary of numbers and proportions of participants with TB drug resistance among cases of TB 
treatment failure or TB relapse/recurrence by week 72, with 95% CIs based on Wilson’s score 
method, by treatment arm [Objective 1.3.7]. 
 
Summary of drug-resistant TB among cases of TB treatment failure or TB relapse/recurrence noted, 
with TB diagnostics on the baseline sputum, TB outcome at time of TB treatment discontinuation, 
weeks from TB treatment discontinuation to TB treatment failure or TB relapse/recurrence, and 
results from TB diagnostics on the sputum collected at time of TB treatment failure or suspected TB 
relapse/recurrence (i.e., AFB smear, culture, and DST) by treatment arm.