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

• Medroxyprogesterone Acetate (MPA) Pharmacokinetic Parameter (PK) Area Under the Concentration-time Curve (AUC0-12weeks) [ Time Frame: Day 0, Weeks 2, 4, 6, 8, 10 and 12 ] [ Designated as safety issue: Yes ]
  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.
  
  
• AUC0-12hour for LPV at Baseline (Day 0) Before DMPA Administration and at Week 4 (Four Weeks After DMPA Administration) [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  

• Percentage of Participants With Progesterone Levels Less Than the Lower Limit of Quantification (LLQ). [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• MPA PK Parameter Minimum Plasma Concentration (Cmin) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• MPA PK Parameter Maximum Plasma Concentration (Cmax) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• MPA PK Parameter Time to Cmax (Tmax) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• MPA PK Parameter Clearance (CL/F) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• MPA PK Parameter Half-Life (T1/2) Determined Based on MPA Levels. [ Time Frame: 0, 2, 4, 6, 8, 10, and 12 weeks ] [ Designated as safety issue: Yes ]
  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.
  
  
• LPV PK Parameter Cmin. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• LPV PK Parameter Cmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• LPV PK Parameter Tmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• LPV PK Parameter CL/F. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• LPV PK Parameter T1/2. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Ritonavir (RTV) PK Parameter AUC0-12h. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• RTV PK Parameter Cmin. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• RTV PK Parameter Cmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• RTV PK Parameter Tmax. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• RTV PK Parameter CL/F. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• RTV PK Parameter T1/2. [ Time Frame: Day 0 and Week 4 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Percentage of Participants With Menstrual Irregularities of Grade 1 and Higher Deemed Possibly, Probably or Definitely Related to Study Treatment. [ Time Frame: From day 0 to week 12 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL. [ Time Frame: Day 0, Weeks 2, 4, 8, and 12 ] [ Designated as safety issue: Yes ]
  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.
  
  
• Cell Mediated Immunity (CMI) to HIV and the Common Opportunistic Agent Varicella-zoster Virus (VZV) Using the Enzyme-linked Immunospot (ELISPOT) Assay. [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
  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.
  
  
• CMI to HIV and the Common Opportunistic Agent VZV Using the Lymphocyte Proliferation Assay (LPA). [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
  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.
  
  
• Regulatory T Cells (Tregs) at Baseline, Week 4 and Week 12 Using Flow Cytometry in Freshly Thawed PBMCs. [ Time Frame: Day 0, Weeks 4 and 12 ] [ Designated as safety issue: No ]
  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.
  
  

The primary study objective was addressed by calculating the Area Under the Concentration-Time Curve (AUC) from week 0 (prior to DMPA injection) to week 12 (twelve weeks after DMPA injection) in our study participants.

DMPA was supplied and administered as part of the protocol, however Kaletra was not. It was required that participants already be on a Kaletra based regimen prior to entering the study, as described in the eligibility criteria.

Arm A of AIDS Clinical Trial Group (ACTG) A5093, which consisted of 14 participants who were administered DMPA without Kaletra, was used as reference data.