Trial Outcomes & Findings for Safety and Effectiveness of Low-Dose Methotrexate for Reducing Inflammation in HIV-Infected Adults on ARV Medications (NCT NCT01949116)

NCT ID: NCT01949116

Last Updated: 2021-11-01

Results Overview

Number of participants who experienced any one of the following safety milestones: * Entry CD4+ T-cell count less than 700 cells/mm\^3, confirmed CD4+ decline greater than 33% of baseline AND to less than 350 cells/mm\^3 * Entry CD4+ T-cell count greater than or equal to 700 cells/mm\^3, a confirmed CD4+ decline greater than 50% of baseline * Confirmed HIV-1 RNA Level Greater Than 200 Copies/mL in the Absence of an Interruption in ART * New or recurrent CDC category C AIDS-indicator condition * Evidence of HIV-associated infection including CMV end-organ disease, varicella zoster, EBV related clinical disease * Requirement for LDMTX discontinuation for confirmed Grade 3 or higher toxicity * Lymphoproliferative malignancies * Pulmonary toxicity which is defined as Grade 3 or 4 dyspnea, cough, shortness of breath which in the opinion of the local investigator is related to the study drug but not related to other clinical causes such as asthma, influenza, etc.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

176 participants

Primary outcome timeframe

From study entry to week 36

Results posted on

2021-11-01

Participant Flow

Total of 176 participants randomized to A5314 - 86 in LDMTX, 90 in Placebo. The first participant enrolled on January 31, 2014; the last participant enrolled on March 31, 2016. A range of 2 to 25 participants per site enrolled across 22 clinical research sites during study accrual.

Participant milestones

Participant milestones
Measure	Low-dose Methotrexate (LDMTX) From study entry through Week 1, participants received 5 mg of LDMTX once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to LDMTX, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of LDMTX, all participants continued taking folic acid for an additional 4 weeks. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo From study entry through Week 1, participants received 5 mg of placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of placebo, all participants continued taking folic acid for an additional 4 weeks. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Study STARTED	86	90
Overall Study COMPLETED	78	84
Overall Study NOT COMPLETED	8	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Low-dose Methotrexate (LDMTX) From study entry through Week 1, participants received 5 mg of LDMTX once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to LDMTX, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of LDMTX, all participants continued taking folic acid for an additional 4 weeks. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo From study entry through Week 1, participants received 5 mg of placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation were re-evaluated at the following study visit. In addition to placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of placebo, all participants continued taking folic acid for an additional 4 weeks. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Overall Study Death	2	0
Overall Study Lost to Follow-up	1	3
Overall Study Withdrawal by Subject	5	3

Baseline Characteristics

Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Low-dose Methotrexate (LDMTX) n=86 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=90 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Total n=176 Participants Total of all reporting groups
Age, Continuous	55 years n=86 Participants	53 years n=90 Participants	54 years n=176 Participants
Sex: Female, Male Female	8 Participants n=86 Participants	9 Participants n=90 Participants	17 Participants n=176 Participants
Sex: Female, Male Male	78 Participants n=86 Participants	81 Participants n=90 Participants	159 Participants n=176 Participants
Region of Enrollment United States	86 Participants n=86 Participants	90 Participants n=90 Participants	176 Participants n=176 Participants
Current Statin Use Current Statin Use	51 Participants n=86 Participants	52 Participants n=90 Participants	103 Participants n=176 Participants
Current Statin Use No Current Statin Use	35 Participants n=86 Participants	38 Participants n=90 Participants	73 Participants n=176 Participants
Smoking Status Current Smoker	28 Participants n=86 Participants	40 Participants n=90 Participants	68 Participants n=176 Participants
Smoking Status Current non-smoker	58 Participants n=86 Participants	50 Participants n=90 Participants	108 Participants n=176 Participants
Type of CVD Risk CAD, CVD, or PAD	20 Participants n=86 Participants	12 Participants n=90 Participants	32 Participants n=176 Participants
Type of CVD Risk Controlled type 2 diabetes mellitus	19 Participants n=86 Participants	20 Participants n=90 Participants	39 Participants n=176 Participants
Type of CVD Risk Smoking/hypertension/dyslipidemia/hsCRP >= 2mg/L	47 Participants n=86 Participants	58 Participants n=90 Participants	105 Participants n=176 Participants
10 year ASCVD risk	10.1 Percent risk of ASCVD n=47 Participants • Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.	7.9 Percent risk of ASCVD n=58 Participants • Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.	8.7 Percent risk of ASCVD n=105 Participants • Participants with any risk of CAD, CVD, PAD, or controlled type 2 diabetes mellitus are excluded from the ASCVD risk calculation.
CD4+ cell count	689 cells/mm^3 n=86 Participants	729 cells/mm^3 n=90 Participants	726 cells/mm^3 n=176 Participants
HIV-1 RNA Detectable	2 Participants n=86 Participants	4 Participants n=90 Participants	6 Participants n=176 Participants
HIV-1 RNA Below Assay Limit of Detection	84 Participants n=86 Participants	84 Participants n=90 Participants	168 Participants n=176 Participants
HIV-1 RNA Missing	0 Participants n=86 Participants	2 Participants n=90 Participants	2 Participants n=176 Participants
Brachial Artery FMD	3.54 Percent Dilation n=86 Participants • 3 participants in the placebo group have either unsatisfactory scans or did not meet protocol requirements at the time of the FMD assessment.	3.41 Percent Dilation n=87 Participants • 3 participants in the placebo group have either unsatisfactory scans or did not meet protocol requirements at the time of the FMD assessment.	3.45 Percent Dilation n=173 Participants • 3 participants in the placebo group have either unsatisfactory scans or did not meet protocol requirements at the time of the FMD assessment.

PRIMARY outcome

Timeframe: From study entry to week 36

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=86 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=90 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Number of Participants Who Reached at Least One Safety Milestone Over the Duration of Study Follow-up (36 Weeks)	11 Participants	5 Participants

PRIMARY outcome

Timeframe: From Baseline to Week 24

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

Flow-mediated vasodilation is defined as the maximum FMD (%) calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter. Absolute change of FMD at week 24 is calculated from baseline FMD.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=80 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Primary Efficacy Endpoint of Change From Baseline to Week 24 in Brachial Artery Flow-mediated Vasodilation (FMD)	0.24 Percent Dilation Interval -0.4 to 0.88	0.15 Percent Dilation Interval -0.47 to 0.77

SECONDARY outcome

Timeframe: From Baseline to Week 12

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

The absolute change from baseline to week 24 FMD (%), defined as the maximum FMD calculated from reactive hyperemia (RH) 60 and RH 90 relative to resting artery diameter.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=75 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Change From Baseline to Week 12 in Brachial Artery FMD	0.32 Percent Dilation Interval -1.55 to 1.54	-0.06 Percent Dilation Interval -1.3 to 1.66

SECONDARY outcome

Timeframe: From Baseline to Week 12

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

The change in resting average diameter in millimeters of the brachial artery at week 12 from baseline.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=75 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Change From Baseline to Week 12 in Brachial Artery Resting Average Diameter	0.04 mm Interval -0.09 to 0.13	0.03 mm Interval -0.09 to 0.15

SECONDARY outcome

Timeframe: From Baseline to Week 24

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

The absolute change in resting average diameter in millimeters of the brachial artery at week 24 from baseline.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=80 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Change From Baseline to Week 24 in Brachial Artery Resting Average Diameter	0 mm Interval -0.11 to 0.13	0.01 mm Interval -0.1 to 0.12

SECONDARY outcome

Timeframe: From Baseline to Week 24

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

The absolute change in RH flow rate in cc/min of the brachial artery at week 24 from baseline.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=76 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Change From Baseline to Week 24 in Reactive Hyperemic (RH) Flow Rate	-11.40 cc/min Interval -97.46 to 161.64	13.76 cc/min Interval -135.11 to 107.73

SECONDARY outcome

Timeframe: From Baseline to Week 24

Population: Intent-to-treat (ITT) population consists of all eligible participants who were randomized for the study.

The absolute change in peak RH flow velocity in cm/s of the brachial artery at week 24 from baseline.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=74 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=76 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Change From Baseline to Week 24 in Peak Reactive Hyperemic (RH) Flow Velocity	-0.20 cm/s Interval -11.3 to 14.4	-0.83 cm/s Interval -16.8 to 16.88

SECONDARY outcome

Timeframe: From Baseline to week 24

Population: Adequately-dosed (AD) population included 129 participants who initiated study treatment with 24-week continuous dosing to at least 8 or more 15 mg doses of LDMTX/Placebo (59 in LDMTX, 70 in Placebo). 3 of these participants were not identified at the time of the specimen request for biomarker testing, other missing data are due to missed visits.

hsCRP is a marker of inflammation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10\^\[fold-change\] - 1) x 100%. One single hsCRP result at week 24 was above the limit of quantification, therefore excluded from analysis.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=55 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=69 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Percentage Change From Baseline to Week 24 in High-sensitivity C-reactive Protein (hsCRP)	-3.5 Percentage Change Interval -26.7 to 27.1	5.4 Percentage Change Interval -16.8 to 33.5

SECONDARY outcome

Timeframe: From Baseline to Week 24

IL-6 is a marker of systemic inflammation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10\^\[fold-change\] - 1) x 100%.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=59 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=70 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Percentage Change From Baseline to Week 24 in Interleukin-6 (IL-6)	13.4 Percentage Change Interval -1.3 to 30.3	21.3 Percentage Change Interval -0.2 to 47.4

SECONDARY outcome

Timeframe: From Baseline to Week 24

sCD163 is a marker of Macrophage activation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10\^\[fold-change\] - 1) x 100%.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=56 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=69 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Percentage Change From Baseline to Week 24 in Soluble CD 163 (sCD163)	2.7 Percentage Change Interval -4.2 to 10.1	7.5 Percentage Change Interval 0.6 to 15.0

SECONDARY outcome

Timeframe: From Baseline to Week 24

D-dimer (or D dimer) is a marker of coagulation activation. Change from baseline (Week 24 - baseline) was performed on the log10 scale and is thus presented as percentage change, i.e. (10\^\[fold-change\] - 1) x 100%.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=56 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=69 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Percentage Change From Baseline to Week 24 in D-Dimer	-1.5 Percentage Change Interval -10.6 to 8.5	9.9 Percentage Change Interval -3.3 to 24.9

SECONDARY outcome

Timeframe: From Baseline to Week 24

Three categories of monocyte levels are presented: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14dimCD16+). Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells that express the subset of interest.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=56 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=68 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Absolute Change From Baseline to Week 24 in Monocyte Levels Classical (CD14+CD16-)	-0.15 Percent of Expression in Parent Cell Interval -1.39 to 1.1	0.82 Percent of Expression in Parent Cell Interval -0.42 to 2.06
Absolute Change From Baseline to Week 24 in Monocyte Levels Intermediate (CD14+CD16+)	-0.07 Percent of Expression in Parent Cell Interval -0.77 to 0.62	-0.51 Percent of Expression in Parent Cell Interval -1.32 to 0.29
Absolute Change From Baseline to Week 24 in Monocyte Levels Non-classical (CD14dimCD16+)	0.21 Percent of Expression in Parent Cell Interval -0.66 to 1.08	-0.29 Percent of Expression in Parent Cell Interval -0.89 to 0.31

SECONDARY outcome

Timeframe: From Baseline to Week 24

The adhesion and activation indices of interest are the percentages of CD38+HLADR+ expressions in both parent CD4+ and CD8+ T cells. Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells (either CD4+ or CD8+) that express CD38+HLADR+ cells.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=56 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=68 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Absolute Change From Baseline to Week 24 in Adhesion and Activation Indices (CD3+CD4+) CD38+HLADR+	-0.27 Percent of Expression in Parent Cell Interval -0.58 to 0.04	0.22 Percent of Expression in Parent Cell Interval -0.06 to 0.5
Absolute Change From Baseline to Week 24 in Adhesion and Activation Indices (CD3+CD8+) CD38+HLADR+	-1.50 Percent of Expression in Parent Cell Interval -2.06 to -0.95	0.90 Percent of Expression in Parent Cell Interval -0.35 to 2.15

SECONDARY outcome

Timeframe: From Baseline to Week 24

CX3CR1+ is a cellular marker of immune activation. The outcome measured is the percentages of CX3CR1+ expressions in both parent CD4+ and CD8+ T cells. Absolute change from baseline (Week 24 - baseline) was analyzed on the measured scale, which is the percent of parent cells (either CD4+ or CD8+) that express CX3CR1+ cells.

Outcome measures

Outcome measures
Measure	Low-dose Methotrexate (LDMTX) n=56 Participants From study entry through Week 1, participants will receive 5 mg of LDMTX once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to LDMTX, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after LDMTX is discontinued, either at Week 24 or earlier, for any reason. LDMTX: LDMTX 5 mg: one 5-mg capsule by mouth once weekly LDMTX 10 mg: two 5-mg capsules by mouth once weekly LDMTX 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day	Placebo n=68 Participants From study entry through Week 1, participants will receive 5 mg of placebo once a week. For participants who are clinically stable at the Week 1 study visit, the dose will be increased to 10 mg once a week through Week 12. For participants who are clinically stable at the Week 12 study visit, the dose will be increased to 15 mg once a week through Week 24. In addition to placebo, all participants will also receive 1 mg of folic acid once a day from study entry through 4 weeks after placebo is discontinued, either at Week 24 or earlier, for any reason. Placebo: Placebo 5 mg: one 5-mg capsule by mouth once weekly Placebo 10 mg: two 5-mg capsules by mouth once weekly Placebo 15 mg: three 5-mg capsules by mouth once weekly Folic acid: 1-mg tablet of folic acid by mouth once a day
Absolute Change From Baseline to Week 24 in Homing Molecule (CX3CR1+) Expression (CD3+CD4+) CX3CR1+	-0.30 Percent of Expression in Parent Cell Interval -0.8 to 0.2	0.03 Percent of Expression in Parent Cell Interval -0.55 to 0.6
Absolute Change From Baseline to Week 24 in Homing Molecule (CX3CR1+) Expression (CD3+CD8+) CX3CR1+	-0.83 Percent of Expression in Parent Cell Interval -2.76 to 1.11	0.39 Percent of Expression in Parent Cell Interval -1.13 to 1.92

Adverse Events

LDMTX

Serious events: 9 serious events

Other events: 81 other events

Deaths: 2 deaths

Placebo

Serious events: 8 serious events

Other events: 76 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

ACTG Clinicaltrials.gov Coordinator

ACTG Network Coordinating Center, Social and Scientific Systems, Inc.

Phone: (301) 628-3313

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	LDMTX n=86 participants at risk From study entry through Week 1, participants received either 5 mg of LDMTX once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation was re-evaluated at the following study visit. In addition to LDMTX, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of LDMTX, all participants continued taking folic acid for an additional 4 weeks.	Placebo n=90 participants at risk From study entry through Week 1, participants received either 5 mg of placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation was re-evaluated at the following study visit. In addition to placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of placebo, all participants continued taking folic acid for an additional 4 weeks.
Blood and lymphatic system disorders Neutropenia	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Cardiac disorders Acute myocardial infarction	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Cardiac disorders Coronary artery stenosis	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Gastrointestinal disorders Food poisoning	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
General disorders Chest pain	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
General disorders Pyrexia	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Infections and infestations Bronchitis	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Infections and infestations Gastroenteritis shigella	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Infections and infestations Pneumonia	2.3% 2/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Infections and infestations Pneumonia bacterial	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Infections and infestations Pneumonia pneumococcal	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Injury, poisoning and procedural complications Subdural haemorrhage	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Metabolism and nutrition disorders Hypophosphataemia	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Musculoskeletal and connective tissue disorders Tenosynovitis	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Carcinoma in situ	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Nervous system disorders Syncope	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Reproductive system and breast disorders Scrotal pain	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	1.1% 1/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.2% 1/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	0.00% 0/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.

Other adverse events
Measure	LDMTX n=86 participants at risk From study entry through Week 1, participants received either 5 mg of LDMTX once a week. For participants who were clinically stable at the Week 1 study visit, the dose of LDMTX was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of LDMTX was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation was re-evaluated at the following study visit. In addition to LDMTX, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of LDMTX, all participants continued taking folic acid for an additional 4 weeks.	Placebo n=90 participants at risk From study entry through Week 1, participants received either 5 mg of placebo once a week. For participants who were clinically stable at the Week 1 study visit, the dose of placebo was increased to 10 mg once a week through Week 12. For participants who were clinically stable at the Week 12 study visit, the dose of placebo was increased to 15 mg once a week through Week 24. Participants who did not meet the criteria for dose escalation was re-evaluated at the following study visit. In addition to placebo, all participants also received 1 mg of folic acid once a day from study entry throughout Week 24. After taking the final dose of placebo, all participants continued taking folic acid for an additional 4 weeks.
Gastrointestinal disorders Nausea	5.8% 5/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	2.2% 2/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
General disorders Fatigue	9.3% 8/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
General disorders Malaise	2.3% 2/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
General disorders Pyrexia	5.8% 5/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Alanine aminotransferase increased	11.6% 10/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	12.2% 11/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Aspartate aminotransferase increased	12.8% 11/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	16.7% 15/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood alkaline phosphatase increased	3.5% 3/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood bicarbonate decreased	14.0% 12/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	10.0% 9/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood bilirubin increased	14.0% 12/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	12.2% 11/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood cholesterol increased	43.0% 37/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	30.0% 27/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood creatinine increased	22.1% 19/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	13.3% 12/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood glucose decreased	14.0% 12/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	3.3% 3/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood glucose increased	44.2% 38/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	43.3% 39/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood potassium decreased	5.8% 5/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Blood sodium decreased	22.1% 19/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	15.6% 14/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Low density lipoprotein increased	24.4% 21/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	15.6% 14/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Investigations Neutrophil count decreased	8.1% 7/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	6.7% 6/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Musculoskeletal and connective tissue disorders Pain in extremity	5.8% 5/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	2.2% 2/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Respiratory, thoracic and mediastinal disorders Cough	11.6% 10/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	8.9% 8/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.0% 6/86 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.	5.6% 5/90 • Adverse Events (AEs) reported from study enrollment until study completion at 36 weeks. All serious adverse events, all AEs that led to a change in treatment, all signs and symptoms grade 2 or higher, all laboratory abnormalities grade 3 or higher and any of following targeted medical conditions: cardiovascular, hematologic, infectious, and neoplastic diseases (including mycobacterial infections, thrush, oral ulcers); hepatobilary, lymphoproliferative, renal, and pulmonary disorders; CDC category C AIDS conditions, regardless of grade.