Trial Outcomes & Findings for Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women (NCT NCT01296152)

NCT ID: NCT01296152

Last Updated: 2015-12-22

Results Overview

This evaluates the effect of lopinavir/ritonavir (LPV/r) on pharmacokinetic parameter AUC of MPA by looking at the MPA AUC from day 0 to week 12. AUC0-12weeks was calculated using single MPA concentrations sampled immediately prior to DMPA administration on day 0, and at 2, 4, 6, 8, 10 and 12 weeks after administration of the single DMPA dose.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 25 participants
• Primary outcome timeframe: Day 0, Weeks 2, 4, 6, 8, 10 and 12
• Results posted on: 2015-12-22

Participant Flow

Twenty-five HIV-1 infected women, ages 15 to 47 years, were recruited at 13 U.S. Clinical Research Sites and U.S. National Institute of Allergy and Infectious Diseases and National Institute of Child Health and Human Development-funded International Maternal Pediatric Adolescent AIDS Clinical Trial sites between June 1, 2011 and July 26, 2012.

Eligible participants: pre-menopausal HIV-1 infected females, >=13 years, plasma HIV-1 RNA <=400 copies/mL and cluster of differentiation 4 (CD4+) count >= 200 cells/mm^3 within 30 days prior to entry. Last menstrual period <=35 days prior to entry. If >35 days, follicle stimulating hormone (FSH) must have been <=40 Milli-International units/mL.

Participant milestones

Measure	Depo-medroxyprogesterone Acetate (DMPA) At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. depo-medroxyprogesterone acetate: At study entry/ Day 0, participants will receive Depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. Depo-medroxyprogesterone Acetate
Overall Study STARTED	25
Overall Study COMPLETED	24
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Measure	Depo-medroxyprogesterone Acetate (DMPA) At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. depo-medroxyprogesterone acetate: At study entry/ Day 0, participants will receive Depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. Depo-medroxyprogesterone Acetate
Overall Study Unwilling to adhere to study requirement	1

Baseline Characteristics

Pharmacokinetic Interactions Between DMPA and LPV/r Among HIV-Infected Women

Baseline characteristics by cohort

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=25 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. depo-medroxyprogesterone acetate: At study entry/ Day 0, participants will receive Depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose. Depo-medroxyprogesterone Acetate
Age, Categorical <=18 years	3 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	22 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	31 years n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Race/Ethnicity, Customized White Non-Hispanic	3 participants n=5 Participants
Race/Ethnicity, Customized Black Non-Hispanic	15 participants n=5 Participants
Race/Ethnicity, Customized Hispanic (Regardless of Race)	6 participants n=5 Participants
Race/Ethnicity, Customized American Indian, Alaskan Native	1 participants n=5 Participants
Region of Enrollment United States	25 participants n=5 Participants

PRIMARY outcome

Timeframe: Day 0, Weeks 2, 4, 6, 8, 10 and 12

Population: One participant was excluded from all PK analyses for taking a prohibited medication with potential to interfere with PK assessments. For another participant who missed week 10 and 12 visits, a modelling approach was used to estimate the week 12 MPA level.

This evaluates the effect of lopinavir/ritonavir (LPV/r) on pharmacokinetic parameter AUC of MPA by looking at the MPA AUC from day 0 to week 12. AUC0-12weeks was calculated using single MPA concentrations sampled immediately prior to DMPA administration on day 0, and at 2, 4, 6, 8, 10 and 12 weeks after administration of the single DMPA dose.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Medroxyprogesterone Acetate (MPA) Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-12weeks)	18.08 ng*wk/mL Interval 5.91 to 32.33

PRIMARY outcome

Timeframe: Day 0 and Week 4

Population: All participants eligible for the first primary PK outcome measure (MPA AUC0-12weeks) were included in this second primary outcome measure looking at LPV AUC0-12hours at Day 0 and week 4.

This evaluates the effect of DMPA on LPV PK parameter AUC by comparing PK AUCs of LPV from 0 to 12 hours obtained at study Day 0 (before DMPA was administered) with PK AUCs of LPV from 0 to 12 hours at study Week 4 (4 weeks after DMPA was administered). Blood samples were drawn for LPV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration) LPV AUC0-12hour at day 0 (without DMPA)	98046.46 ng*h/mL Interval 38347.88 to 158899.17
AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration) LPV AUC0-12hour at week 4 (with DMPA)	97948.29 ng*h/mL Interval 56489.42 to 192989.17

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: All 24 participants included in the primary analyses were eligible for this secondary objective, however participants occasionally missed the progesterone draw (see N for each week in table below).

This evaluates the suppression of ovulation due to the potential PK interaction between DMPA and LPV/r. The LLQ of progesterone is 0.5ng/mL. The threshold for suppression of ovulation is 5ng/mL.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 0 (N=24)	50.0 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 2 (N=23)	87.0 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 4 (N=24)	95.8 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 6 (N=24)	95.8 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 8 (N=24)	95.8 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 10 (N=20)	95.0 Percent of Participants
Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). Pct with Progesterone<LLQ at Week 12 (N=23)	95.7 Percent of Participants

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of MPA AUC.

This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmin based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
MPA PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on MPA Levels.	0.47 ng/mL Interval 0.03 to 1.43

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of MPA AUC.

This evaluates the effect of LPV/r on the secondary MPA PK parameter Cmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
MPA PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on MPA Levels.	2.88 ng/mL Interval 0.84 to 5.88

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of MPA AUC.

This evaluates the effect of LPV/r on the secondary MPA PK parameter Tmax based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
MPA PK Parameter Time to Cmax (Tmax) Determined Based on MPA Levels.	4.00 week Interval 2.0 to 12.0

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of MPA AUC.

This evaluates the effect of LPV/r on the secondary MPA PK parameter CL/F based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
MPA PK Parameter Clearance (CL/F) Determined Based on MPA Levels.	8297.35 L/week Interval 4639.14 to 25385.74

SECONDARY outcome

Timeframe: 0, 2, 4, 6, 8, 10, and 12 weeks

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of MPA AUC. A minimum of three observations in the elimination phase was required to determine T1/2 and therefore results are presented for 22 participants.

This evaluates the effect of LPV/r on the secondary MPA PK parameter T1/2 based on MPA levels measured at weeks 0, 2, 4, 6, 8, 10, and 12.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=22 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
MPA PK Parameter Half-Life (T1/2) Determined Based on MPA Levels.	3.37 week Interval 1.11 to 508.53

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the secondary LPV PK parameter Cmin obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
LPV PK Parameter Cmin. LPV Cmin day 0	5630.00 ng/mL Interval 25.0 to 10600.0
LPV PK Parameter Cmin. LPV Cmin week 4	5700.00 ng/mL Interval 3630.0 to 13900.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the secondary LPV PK parameter Cmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
LPV PK Parameter Cmax. LPV Cmax week 4	10950.00 ng/mL Interval 6290.0 to 18700.0
LPV PK Parameter Cmax. LPV Cmax day 0	10750.00 ng/mL Interval 4760.0 to 16000.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the secondary LPV PK parameter Tmax obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
LPV PK Parameter Tmax. LPV Tmax day 0	3.00 hour Interval 1.0 to 8.0
LPV PK Parameter Tmax. LPV Tmax week 4	3.00 hour Interval 1.0 to 8.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the secondary LPV PK parameter CL/F obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
LPV PK Parameter CL/F. LPV CL/F day 0	4.08 L/hour Interval 2.52 to 10.43
LPV PK Parameter CL/F. LPV CL/F week 4	4.08 L/hour Interval 2.02 to 7.08

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants who took DMPA with LPV/r and were eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the secondary LPV PK parameter T1/2 obtained from both sampling periods, before DMPA injection at study day 0 and four weeks after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
LPV PK Parameter T1/2. LPV T1/2 day 0	11.76 hour Interval 1.6 to 33.67
LPV PK Parameter T1/2. LPV T1/2 week 4	12.64 hour Interval 5.15 to 63.98

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the PK parameter AUC0-12h of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4. Blood samples were drawn for RTV concentration levels at time zero (before LPV/r dosing) and at 30 minutes and 1, 2, 3, 4, 5, 6, 8 and 10 hours after LPV/r dosing at day 0 and week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Ritonavir (RTV) PK Parameter AUC0-12h. RTV AUC0-12h day 0	5176.79 ng*h/mL Interval 1605.05 to 9858.86
Ritonavir (RTV) PK Parameter AUC0-12h. RTV AUC0-12h week 4	5014.73 ng*h/mL Interval 2325.59 to 10011.32

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the PK parameter Cmin of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
RTV PK Parameter Cmin. RTV Cmin day 0	181.00 ng/mL Interval 25.0 to 527.0
RTV PK Parameter Cmin. RTV Cmin week 4	194.50 ng/mL Interval 68.9 to 486.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the PK parameter Cmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
RTV PK Parameter Cmax. RTV Cmax day 0	884.00 ng/mL Interval 224.0 to 2070.0
RTV PK Parameter Cmax. RTV Cmax week 4	726.00 ng/mL Interval 268.0 to 1950.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the PK parameter Tmax of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
RTV PK Parameter Tmax. RTV Tmax day 0	3.00 hour Interval 1.0 to 12.0
RTV PK Parameter Tmax. RTV Tmax week 4	3.00 hour Interval 1.0 to 6.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC.

This evaluates the effect of MPA on the PK parameter CL/F of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
RTV PK Parameter CL/F. RTV CL/F day 0	19.32 L/hour Interval 10.14 to 62.3
RTV PK Parameter CL/F. RTV CL/F week 4	19.94 L/hour Interval 9.99 to 43.0

SECONDARY outcome

Timeframe: Day 0 and Week 4

Population: The analysis population is the 24 A5283 participants eligible for the primary PK outcome of LPV AUC. For one participant at day 0, T1/2 results were not estimated.

This evaluates the effect of MPA on the PK parameter T1/2 of RTV obtained from both sampling periods, before DMPA injection at study day 0 and after DMPA injection at study week 4.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
RTV PK Parameter T1/2. RTV T1/2 day 0 (N=23)	4.56 hour Interval 1.28 to 22.59
RTV PK Parameter T1/2. RTV T1/2 week 4	6.32 hour Interval 2.23 to 10.62

SECONDARY outcome

Timeframe: From day 0 to week 12

Population: This analysis focuses on the 24 participants eligible for the PK analyses.

This evaluates toxicity and safety of concomitant medication of DMPA and LPV/r, focusing specifically on the adverse event (AE) menstrual irregularities with abnormal vaginal bleeding. The AEs were graded by the clinicians according to the Division of AIDS (DAIDS) AE Grading Table (see references in the Protocol Section) as follows: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening, Grade 5=Death. Relationship to study treatment was determined by the study's co-chairs.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Percentage of Participants With Menstrual Irregularities of Grade 1 and Higher Deemed Possibly, Probably or Definitely Related to Study Treatment.	25 Percent of Participants

SECONDARY outcome

Timeframe: Day 0, Weeks 2, 4, 8, and 12

Population: All 24 participants included in the primary analyses were eligible for this secondary objective, however participants occasionally missed the HIV-1 RNA draw (see N for each week in table below).

This evaluates the short-term impact of MPA on virologic suppression in participants taking LPV/r who have received a dose of DMPA by measuring percentage of participants with HIV-1 RNA levels <400 copies/mL at day 0 (prior to DMPA injection) and at weeks 2, 4, 8 and 12 (after DMPA injection). An FDA-approved HIV-1 RNA assay with a lower limit of detection of 75 copies/mL or less was required and the same HIV-1 RNA assay was required to be performed for each participant across all study visits. The Roche COBAS AmpliPrep/TaqMan HIV-1 and Abbott RealTime HIV-1 tests were used.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=24 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. Pct with HIV RNA<400 at Week 0 (N=24)	100 Percent of Participants
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. Pct with HIV RNA<400 at Week 2 (N=24)	100 Percent of Participants
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. Pct with HIV RNA<400 at Week 4 (N=23)	100 Percent of Participants
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. Pct with HIV RNA<400 at Week 8 (N=24)	100 Percent of Participants
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. Pct with HIV RNA<400 at Week 12 (N=23)	87 Percent of Participants

SECONDARY outcome

Timeframe: Day 0, Weeks 4 and 12

Population: All 24 participants included in the primary analyses were eligible for this secondary objective. 22 participants with available data were analyzed.

This evaluates the effect of MPA on CMI to HIV and VZV at baseline before DMPA (day 0) and after DMPA (weeks 4 and 12) . Cytokines are interferon-gamma (IFN-gamma) and interleukin 2 (IL-2), and Stimuli are HIV and VZV. Summary of adjusted ELISPOT assay results is in spot forming cells (SFC)/10^6 peripheral blood mononuclear cells (PBMC) by study weeks 0, 4 and 12. The outcome measures of IFN-gamma and IL-2 measured for HIV and VZV are presented here together to provide all results pertaining to the same objective in a single data table.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=22 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*HIV Week 0 (N=22)	82.50 SFC/10^6 PBMC Interval 4.0 to 152.0
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*HIV Week 4 (N=21)	46.50 SFC/10^6 PBMC Interval 13.0 to 130.5
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*HIV Week 12 (N=20)	57.75 SFC/10^6 PBMC Interval 3.75 to 156.5
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*VZV Week 0 (N=20)	2.75 SFC/10^6 PBMC Interval 1.0 to 12.0
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*VZV Week 4 (N=20)	2.00 SFC/10^6 PBMC Interval 1.0 to 13.25
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IFN-gamma*VZV Week 12 (N=19)	6.50 SFC/10^6 PBMC Interval 1.0 to 19.5
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*HIV Week 0 (N=22)	5.00 SFC/10^6 PBMC Interval 1.0 to 11.5
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*HIV Week 4 (N=21)	4.50 SFC/10^6 PBMC Interval 2.0 to 21.0
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*HIV Week 12 (N=20)	1.75 SFC/10^6 PBMC Interval 1.0 to 5.5
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*VZV Week 0 (N=20)	3.25 SFC/10^6 PBMC Interval 1.0 to 16.25
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*VZV Week 4 (N=20)	2.50 SFC/10^6 PBMC Interval 1.0 to 10.0
Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. IL-2*VZV Week 12 (N=19)	5.50 SFC/10^6 PBMC Interval 1.0 to 21.5

SECONDARY outcome

Timeframe: Day 0, Weeks 4 and 12

Population: All 24 participants included in the primary analyses were eligible for this secondary objective. 22 participants with available data were analyzed.

This evaluates the effect of MPA on CMI to HIV and VZV. This outcome was measured at Baseline Before DMPA (Day 0) and After DMPA (Weeks 4 and 12) using the Lymphocyte Proliferation Assay (LPA). The data table shows a summary of LPA assay results by study week with stimuli HIV and VZV. Proliferation results are reported as a stimulation index (SI) which represents the ratio of the stimulated counts per minute to unstimulated control counts per minute.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=22 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). HIV SI Week 0 (N=18)	50.62 SI Ratio Interval 5.36 to 74.13
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). HIV SI Week 4 (N=17)	21.39 SI Ratio Interval 6.99 to 50.51
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). HIV SI Week 12 (N=14)	54.66 SI Ratio Interval 5.24 to 121.13
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). VZV SI Week 0 (N=22)	22.38 SI Ratio Interval 3.05 to 66.98
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). VZV SI Week 4 (N=22)	17.73 SI Ratio Interval 4.55 to 115.22
CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). VZV SI Week 12 (N=21)	23.28 SI Ratio Interval 5.02 to 148.86

SECONDARY outcome

Timeframe: Day 0, Weeks 4 and 12

Population: All 24 participants included in the primary analyses were eligible for this secondary objective. 21 participants with available data were analyzed.

This evaluates the effect of MPA on Tregs at baseline (Day 0), week 4 and week 12 using flow cytometry in freshly thawed PBMCs. A summary of CD4+ and cluster of differentiation 8 (CD8+) anchored T-cell subsets by study week, in percent that express the marker of interest, is presented here together to provide all results pertaining to this objective in a single data table.

Outcome measures

Measure	Depo-medroxyprogesterone Acetate (DMPA) n=21 Participants At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+FOXP3+ Week 0	1.26 Percent CD4/CD8 cells expressing marker Interval 0.8 to 2.73
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+FOXP3+ Week 4	1.30 Percent CD4/CD8 cells expressing marker Interval 0.9 to 1.46
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+FOXP3+ Week 12	1.29 Percent CD4/CD8 cells expressing marker Interval 1.01 to 1.8
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD25+FOXP3+ Week 0	0.41 Percent CD4/CD8 cells expressing marker Interval 0.17 to 0.8
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD25+FOXP3+ Week 4	0.24 Percent CD4/CD8 cells expressing marker Interval 0.11 to 0.62
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD25+FOXP3+ Week 12	0.33 Percent CD4/CD8 cells expressing marker Interval 0.13 to 0.45
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD39+ Week 0	10.10 Percent CD4/CD8 cells expressing marker Interval 5.95 to 15.9
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD39+ Week 4	10.10 Percent CD4/CD8 cells expressing marker Interval 6.31 to 13.2
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+CD39+ Week 12	11.60 Percent CD4/CD8 cells expressing marker Interval 7.65 to 16.5
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+TGFB+ Week 0	4.32 Percent CD4/CD8 cells expressing marker Interval 2.66 to 6.02
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+TGFB+ Week 4	3.62 Percent CD4/CD8 cells expressing marker Interval 1.93 to 7.96
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+TGFB+ Week 12	3.08 Percent CD4/CD8 cells expressing marker Interval 2.3 to 5.62
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+IL10+ Week 0	4.66 Percent CD4/CD8 cells expressing marker Interval 3.52 to 6.16
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+IL10+ Week 4	6.01 Percent CD4/CD8 cells expressing marker Interval 3.41 to 7.68
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+IL10+ Week 12	5.64 Percent CD4/CD8 cells expressing marker Interval 3.56 to 8.43
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+IL35+ Week 0	1.86 Percent CD4/CD8 cells expressing marker Interval 1.22 to 3.36
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+Interleukin35+(IL35+) Week 4	1.59 Percent CD4/CD8 cells expressing marker Interval 0.93 to 3.19
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD4+IL35+ Week 12	1.35 Percent CD4/CD8 cells expressing marker Interval 0.78 to 2.08
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+FOXP3+ Week 0	0.85 Percent CD4/CD8 cells expressing marker Interval 0.54 to 1.04
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+FOXP3+ Week 4	0.91 Percent CD4/CD8 cells expressing marker Interval 0.68 to 1.49
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+FOXP3+ Week 12	0.74 Percent CD4/CD8 cells expressing marker Interval 0.67 to 1.43
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD25+FOXP3+ Week 0	0.07 Percent CD4/CD8 cells expressing marker Interval 0.03 to 0.19
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD25+FOXP3+ Week 4	0.06 Percent CD4/CD8 cells expressing marker Interval 0.03 to 0.27
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD25+FOXP3+ Week 12	0.08 Percent CD4/CD8 cells expressing marker Interval 0.01 to 0.26
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD39+ Week 0	3.38 Percent CD4/CD8 cells expressing marker Interval 2.53 to 4.52
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD39+ Week 4	4.20 Percent CD4/CD8 cells expressing marker Interval 2.37 to 4.89
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+CD39+ Week 12	3.12 Percent CD4/CD8 cells expressing marker Interval 2.31 to 5.2
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+TGFB+ Week 0	1.26 Percent CD4/CD8 cells expressing marker Interval 0.74 to 1.9
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+TGFB+ Week 4	1.22 Percent CD4/CD8 cells expressing marker Interval 0.76 to 2.02
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+TGFB+ Week 12	1.18 Percent CD4/CD8 cells expressing marker Interval 0.6 to 1.66
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL10+ Week 0	1.46 Percent CD4/CD8 cells expressing marker Interval 1.1 to 1.87
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL10+ Week 4	1.53 Percent CD4/CD8 cells expressing marker Interval 1.13 to 2.6
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL10+ Week 12	1.45 Percent CD4/CD8 cells expressing marker Interval 1.1 to 2.21
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL35+ Week 0	1.22 Percent CD4/CD8 cells expressing marker Interval 0.87 to 1.61
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL35+ Week 4	1.52 Percent CD4/CD8 cells expressing marker Interval 0.53 to 1.99
Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. CD8+IL35+ Week 12	0.89 Percent CD4/CD8 cells expressing marker Interval 0.65 to 1.83

Adverse Events

Arm A

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Arm A n=25 participants at risk At study entry/ Day 0, subjects will receive depo-medroxyprogesterone (DMPA) 150mg administered intramuscularly (IM) as a single-dose.
General disorders Chills	8.0% 2/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Investigations Weight increased	8.0% 2/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Nervous system disorders Dizziness	8.0% 2/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Nervous system disorders Headache	12.0% 3/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Psychiatric disorders Irritability	8.0% 2/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Reproductive system and breast disorders Menorrhagia	16.0% 4/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Reproductive system and breast disorders Metrorrhagia	20.0% 5/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Reproductive system and breast disorders Vaginal haemorrhage	12.0% 3/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.
Skin and subcutaneous tissue disorders Erythema	8.0% 2/25 • From Day 0 to Week 12. The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS expedited adverse events (EAE) Manual was used for this study. Study agents requiring expedited reporting were: DMPA and LPV/r. The DAIDS AE Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used to grade the severity of events.

Additional Information

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Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place