HIV Infections
Conditions
Keywords
HIV, antiretroviral therapy naive, Integrase inhibitor, HIV/AIDS, treatment naïve
Brief summary
A prospective, randomized, open-label pilot study to assess virologic suppression and immunologic recovery associated with a two-drug antiretroviral regimen of Raltegravir and the protease inhibitor lopinavir/ritonavir (LPV/r) and a three drug regimen with Raltegravir and two nRTIs (emtricitabine/tenofovir) in HIV-1 infected treatment-naïve subjects. Immunology Substudy added to determine the kinetics of recovery of CD4 T cells and subpopulations (regulatory T cell \[T regs\], TH-17 and TH1) after treatment initiation with Raltegravir based regimens and their relationship with functional CD8 T cells and if Raltegravir containing therapies leads to decreases in markers of gut microbial translocation and of cellular and soluble markers of immune activation.
Detailed description
A009 is a prospective, randomized, open-label pilot study to assess virologic suppression and immune recovery rates associated with a two-drug potent antiretroviral regimen of raltegravir and the protease inhibitor lopinavir/ritonavir and a three-drug regimen with raltegravir and two nRTIs (emtricitabine/tenofovir) in treatment-naïve subjects. HIV-1-infected subjects who are antiretroviral drug-naïve and have plasma HIV-1 RNA levels ≥5000 copies/ml obtained within 30 days prior to study entry will be randomized 1:1 to Raltegravir 400 mg BID + LPV 400 mg/RTV 100 mg BID (Arm A) or Raltegravir 400 mg BID + FTC 200 mg/TDF 300 mg QD (Arm B). Subjects will have measurements of HIV-1 RNA and CD4+ and CD8+ T-cell counts at pre-entry and entry. The average of these measurements will be used to establish their baseline values. Following entry, subjects will have plasma HIV-1 RNA samples drawn at days 2, 4, 8 and at weeks 2, 4, 8, 16, 24, 32, 40 and 48 and at virologic failure. CD38 expression on CD4+/CD8+ cells and CD38/HLA-DR activation antigen on CD4+ and CD8+ cells and subsets T-cell percentage will be done at entry, day 8 and weeks 4, 8, 24 and at virologic failure by advanced flow cytometry.
Interventions
DRUGRaltegravir & Lopinavir/ritonavir
Two drug regimen of an integrase inhibitor and ritonavir boosted protease inhibitor
DRUGRaltegravir and emtricitabine/tenofovir
Three drug regimen of an integrase inhibitor and a fixed dose combination of a non-nucleoside/nucleotide inhibitors
Sponsors
Margaret A. Fischl, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Documented HIV Infection * Genotypic resistance without major resistance mutations within 30 days * Antiretroviral drug-naïve * Screening HIV-1 RNA ≥5000 * Women of reproductive potential * Negative pregnancy test within 48 hours
Exclusion criteria
* Acute or recent HIV-1 infection * Currently breast feeding * Use of immunomodulators * Evidence of major resistance mutations * HBsAg positive * Acute hepatitis of any etiology or clinically significant liver disease * Current imprisonment or involuntary incarceration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Confirmed Virologic Failure | weeks | time to confirmed viologic failure at 24 weeks (up to 48 weeks) |
| Time to Virologic Failure | week 24 (up to 48 weeks) | time to virologic failure at week 24 (up to 48 weeks) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Study Medication Toxicity-related Discontinuation . | 48 weeks | grade 3 and grade 4 symptoms and laboratory study treatment limiting toxicity |
| Weeks to HIV-1 RNA <200 Copies/ml | from date of treatment start to first week documented viral suppression | time to viral suppression noted as week on study treatment to attain HIV-1 RNA \< 200 copies/ml |
| Change From Baseline CD4+ and CD8+ Cell Counts | Baseline, Weeks 16 and 24 | mean change in CD4+ and CD8+ T-lymphocytes counts from baseline (defined as the average of pre-entry and entry values) at weeks 16 and 24 in the two treatment arms |
| Study Medication Tolerability | date started study treatment to first week documented change study treatment up to week 48 | study treatment tolerability as measured by number of subjects receiving study treatment who either discontinued or changed any component of study treatment |
Countries
United States
Participant flow
Recruitment details
Patients were randomly assigned to receive one of two regimens Raltegravir (Isentress, Merck & Company) 400 mg twice daily with either Lopinavir/ritonavir (Kaletra, Abbott Laboratories) 200 mg/100 mg twice daily or with emtricitabine/tenofovir (Truvada, Gilead Sciences) 200 mg/100 mg twice daily.
Pre-assignment details
Participants with acute or recent HIV-1 infection, major resistance-associated mutation on any genotype performed at any time prior to study entry, serious illness requiring systemic treatment and/or hospitalization within 7 days of study entry, HBsAg positivity, acute hepatitis of any etiology, clinically significant liver disease were excluded
Participants by arm
| Arm | Count |
|---|---|
| Raltegravir & Lopinavir/Ritonavir Raltegravir 400 mg tablet every 12 hours for 48 & Lopinavir/ritonavir 400 mg/100 mg capsules every 12 hours for 48 weeks
Raltegravir and Lopinavir/ritonavir: 400 mg BID for 48 weeks 400mg/100 mg BID for 48 weeks | 21 |
| Raltegravir & Emtricitabine/Tenofovir Raltegravir 400 mg tablet every 12 hours for 48 weeks & emtricitabine 200mg/ tenofovir 300 mg tab once daily for 48 weeks
Raltegravir, emtricitabine, tenofovir: 400 mg BID for 48 weeks 200 mg QD for 48 weeks 300 mg QD for 48 | 23 |
| Total | 44 |
Baseline characteristics
| Characteristic | Raltegravir & Lopinavir/Ritonavir | Raltegravir & Emtricitabine/Tenofovir | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 23 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 15 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 7 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 16 Participants | 28 Participants |
| Region of Enrollment United States | 21 participants | 23 participants | 44 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 18 Participants | 22 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 21 | 0 / 23 |
| serious Total, serious adverse events | 4 / 21 | 0 / 23 |
Outcome results
Primary
Time to Confirmed Virologic Failure
time to confirmed viologic failure at 24 weeks (up to 48 weeks)
Time frame: weeks
Population: descriptive
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Time to Confirmed Virologic Failure | 28 weeks |
| Raltegravir & Emtricitabine/Tenofovir | Time to Confirmed Virologic Failure | 29 weeks |
Primary
Time to Virologic Failure
time to virologic failure at week 24 (up to 48 weeks)
Time frame: week 24 (up to 48 weeks)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Time to Virologic Failure | 3.2296 weeks | Standard Deviation 0.1596 |
| Raltegravir & Emtricitabine/Tenofovir | Time to Virologic Failure | 2.9952 weeks | Standard Deviation 0.1812 |
Secondary
Change From Baseline CD4+ and CD8+ Cell Counts
mean change in CD4+ and CD8+ T-lymphocytes counts from baseline (defined as the average of pre-entry and entry values) at weeks 16 and 24 in the two treatment arms
Time frame: Baseline, Weeks 16 and 24
Population: Change from baseline compared between arms using repeated measures analysis of covariance. Linear mixed models used to accomplish these analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Change From Baseline CD4+ and CD8+ Cell Counts | week 16 CD4 cells | 516.34 cells/mm3 | Standard Error 76.52 |
| Raltegravir & Lopinavir/Ritonavir | Change From Baseline CD4+ and CD8+ Cell Counts | week 24 CD4 cells | 521.31 cells/mm3 | Standard Error 76.52 |
| Raltegravir & Emtricitabine/Tenofovir | Change From Baseline CD4+ and CD8+ Cell Counts | week 16 CD4 cells | 452.11 cells/mm3 | Standard Error 92.48 |
| Raltegravir & Emtricitabine/Tenofovir | Change From Baseline CD4+ and CD8+ Cell Counts | week 24 CD4 cells | 482.36 cells/mm3 | Standard Error 93.32 |
Secondary
Study Medication Tolerability
study treatment tolerability as measured by number of subjects receiving study treatment who either discontinued or changed any component of study treatment
Time frame: date started study treatment to first week documented change study treatment up to week 48
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Study Medication Tolerability | 1 participants |
| Raltegravir & Emtricitabine/Tenofovir | Study Medication Tolerability | 0 participants |
Secondary
Study Medication Toxicity-related Discontinuation .
grade 3 and grade 4 symptoms and laboratory study treatment limiting toxicity
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Study Medication Toxicity-related Discontinuation . | 1 participants |
| Raltegravir & Emtricitabine/Tenofovir | Study Medication Toxicity-related Discontinuation . | 0 participants |
Secondary
Weeks to HIV-1 RNA <200 Copies/ml
time to viral suppression noted as week on study treatment to attain HIV-1 RNA \< 200 copies/ml
Time frame: from date of treatment start to first week documented viral suppression
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Raltegravir & Lopinavir/Ritonavir | Weeks to HIV-1 RNA <200 Copies/ml | week to <200 Copies/ml | 28 week to viral supresssion |
| Raltegravir & Lopinavir/Ritonavir | Weeks to HIV-1 RNA <200 Copies/ml | week to <50 Copies/ml | 56 week to viral supresssion |
| Raltegravir & Emtricitabine/Tenofovir | Weeks to HIV-1 RNA <200 Copies/ml | week to <200 Copies/ml | 28 week to viral supresssion |
| Raltegravir & Emtricitabine/Tenofovir | Weeks to HIV-1 RNA <200 Copies/ml | week to <50 Copies/ml | 56 week to viral supresssion |