HIV Infections
Conditions
Keywords
HIV treatment, Treatment-naive, Adult
Brief summary
CCTG 589 is a randomized, open-label, pilot study comparing the efficacy, safety and tolerability of RAL plus LPV/r to EFV plus TDF/FTC in HIV-infected, treatment-naïve subjects. Subjects will be ineligible if they have any evidence of drug resistant virus in the past or at the time of screening (if never previously tested). Those who are found to be eligible will be randomized 1:1 to initiate either LPV/r (400/100 mg) plus RAL (400mg), both given twice-daily, or fixed dose combination of EFV (600 mg), TDF (300 mg) and FTC (200 mg) given as once-daily Atripla® for 48 weeks. Hypotheses 1. The novel nucleoside-sparing combination of LPV/r + RAL will have a faster phase 1 viral decay rate compared to standard-of-care therapy with EFV/TDF/FTC in antiretroviral-naïve patients. 1. Faster phase 1 viral decay dynamics will be associated with improved longer-term (week 48) viral suppression. 2. Faster phase 1 viral decay dynamics will be associated with accelerated early (Day 0-14) clearance of cell-associated HIV DNA. 3. Faster phase 1 viral decay dynamics will be associated with greater early (baseline to week 12) CD4+ T-cell recovery. 2. The LPV/r + RAL arm will have greater decreases in early (baseline to week 4) CD4/CD8 T-cell immune activation and apoptosis which will be associated with greater late (week 12 to week 48) CD4+ T-cell recovery. 3. Subjects treated with LPV/r + RAL arm will have smaller changes in total cholesterol and triglycerides from baseline than those receiving EFV/TDF/FTC.
Detailed description
The purpose of this study is to determine how well a new anti-HIV drug combination (RAL plus LPV/r) taken twice a day decreases the amount of HIV found in participants' blood (viral load) compared to taking the once-a-day combination pill Atripla®. This study will also try to determine if the new combination has fewer side effects and is tolerated better than Atripla®. Another reason this study is being done is to see if this new drug combination helps participants' body's CD4 cells recover differently and will also look at how well participants' bodies absorbs these drugs and how safe these drugs are when given together.
Interventions
kaletra 2 tabs twice a day + Raltegravir 1 tab twice a day
DRUGAtripla
Atripla 1 tab once a day
Sponsors
California HIV/AIDS Research Program
Merck Sharp & Dohme LLC
Abbott
University of California, San Diego
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-1 infection. * Treatment naïve (defined as having never received any HIV antiretroviral agents in past). * CD4+ T-cell count greater than or equal to 50 cells/mm3 * HIV viral load greater than or equal to 5,000 copies/mL * Laboratory values obtained by screening laboratories within 30 days of entry: * Absolute neutrophil count (ANC) greater than 750/mm3. * Hemoglobin greater than 8.0 g/dL. * Platelet count greater than 50,000/mm3. * Calculated creatinine clearance (CrCl) \> 60 mL/min as estimated by the Cockcroft-Gault equation: * For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) = CrCl (mL/min) * For women, multiply the result by 0.85 = CrCl (mL/min) * AST (SGOT), ALT (SGPT), and alkaline phosphatase less than 5 x ULN. * Total bilirubin less than 2.5 x ULN. * Females of childbearing potential must have a negative serum pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period. * Men and women age greater than or equal to 18 years. * Ability to obtain prescription for HIV antiretroviral medications and to have required prescriptions filled prior to entry. * Ability and willingness of subject to give written informed consent
Exclusion criteria
* Pregnancy or breast-feeding * Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 30 days prior to study entry (day 0). * Acute therapy for serious infection or other serious medical illnesses (in the judgment of the site investigator) requiring systemic treatment and/or hospitalization within 14 days prior to study entry (day 0). * Evidence of HIV seroconversion within 6 months prior to study entry. * Evidence of any major HIV drug resistance-associated mutation on any genotype performed prior to study entry or at the time of screening. * History of chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable). * History of chronic active hepatitis B (defined as surface antigen positive and/or HBV DNA detectable). * Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements. * Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry. * Use of human growth hormone within 30 days prior to study entry. * Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Compare the Phase 1 Viral Decay Rates Between LPV/r + RAL vs. EFV/TDF/FTC Treatment Combinations. | Baseline, days 2, 7, 10, 14 | Repeated HIV RNA measured at different time points (baseline, days 2, 7, 10, 14) will be treated as the outcome variable in a linear mixed-effects model. The primary fixed effects will include time, treatment group, treatment group-by-time interaction; random effects will include both intercept and slope allowing each subject to have individual baseline viral load and viral decay (rate of decrease in viral load following initiation of antiretroviral therapy). The treatment group-by- time interaction term in the model will indicate the difference in viral decay rates between the two treatment groups. Baseline covariate adjustment will be included if necessary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral Suppression Efficacy at 48 Weeks | 48 weeks | To determine the antiviral efficacy of LPV/r + RAL compared to EFV/TDF/FTC after 48 weeks of treatment by achieving undetectable viral load |
| Compare Early Activated CD4+ T-cell Recovery Rates From Baseline to Week 4. | Baseline to Week 4 | To compare early (baseline to Week 4) activated CD4+ T-cell recovery rates between treatment regimens. |
| Compare Late Activated CD4+ T-cell Recovery Rates Between Treatment Regimens From Baseline to Week 48 | 48 weeks | To compare late (baseline to Week 48) activated CD4+ T-cell recovery rates between treatment regimens. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1 - Kaletra + Isentress Taken Twice Daily Kaletra (lopinavir/ritonavir 400/100 mg) + Isentress (Raltegravir 400 mg) twice-daily
Kaletra + Isentress: kaletra 2 tabs twice a day + Raltegravir 1 tab twice a day | 26 |
| 2 - Atripla Taken Once Daily Sustiva (EFV 600 mg), Viread (TDF 300 mg) and Emtriva (FTC 200 mg) taken as Atripla® once-daily
Atripla: Atripla 1 tab once a day | 25 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | randomized but did not do viral kinetics | 0 | 1 |
Baseline characteristics
| Characteristic | 1 - Kaletra + Isentress Taken Twice Daily | 2 - Atripla Taken Once Daily | Total |
|---|---|---|---|
| Age, Continuous | 40 years | 43 years | 43 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic | 12 Participants | 14 Participants | 26 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 14 Participants | 11 Participants | 25 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 21 Participants | 22 Participants | 43 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 25 Participants | 24 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 26 | 15 / 25 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 |
Outcome results
Primary
To Compare the Phase 1 Viral Decay Rates Between LPV/r + RAL vs. EFV/TDF/FTC Treatment Combinations.
Repeated HIV RNA measured at different time points (baseline, days 2, 7, 10, 14) will be treated as the outcome variable in a linear mixed-effects model. The primary fixed effects will include time, treatment group, treatment group-by-time interaction; random effects will include both intercept and slope allowing each subject to have individual baseline viral load and viral decay (rate of decrease in viral load following initiation of antiretroviral therapy). The treatment group-by- time interaction term in the model will indicate the difference in viral decay rates between the two treatment groups. Baseline covariate adjustment will be included if necessary.
Time frame: Baseline, days 2, 7, 10, 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1 - Kaletra + Isentress Taken Twice Daily | To Compare the Phase 1 Viral Decay Rates Between LPV/r + RAL vs. EFV/TDF/FTC Treatment Combinations. | 0.47 log(10)/day |
| 2 - Atripla Taken Once Daily | To Compare the Phase 1 Viral Decay Rates Between LPV/r + RAL vs. EFV/TDF/FTC Treatment Combinations. | 0.55 log(10)/day |
Secondary
Compare Early Activated CD4+ T-cell Recovery Rates From Baseline to Week 4.
To compare early (baseline to Week 4) activated CD4+ T-cell recovery rates between treatment regimens.
Time frame: Baseline to Week 4
Population: Participants who achieved viral suppression at week 24 and maintained it at week 48 were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 - Kaletra + Isentress Taken Twice Daily | Compare Early Activated CD4+ T-cell Recovery Rates From Baseline to Week 4. | -3.81 cells/mm^3 |
| 2 - Atripla Taken Once Daily | Compare Early Activated CD4+ T-cell Recovery Rates From Baseline to Week 4. | -1.18 cells/mm^3 |
Secondary
Compare Late Activated CD4+ T-cell Recovery Rates Between Treatment Regimens From Baseline to Week 48
To compare late (baseline to Week 48) activated CD4+ T-cell recovery rates between treatment regimens.
Time frame: 48 weeks
Population: Participants who achieved viral suppression at week 24 and maintained it at week 48 were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 1 - Kaletra + Isentress Taken Twice Daily | Compare Late Activated CD4+ T-cell Recovery Rates Between Treatment Regimens From Baseline to Week 48 | -2.24 cells/mm^3 |
| 2 - Atripla Taken Once Daily | Compare Late Activated CD4+ T-cell Recovery Rates Between Treatment Regimens From Baseline to Week 48 | -5.65 cells/mm^3 |
Secondary
Viral Suppression Efficacy at 48 Weeks
To determine the antiviral efficacy of LPV/r + RAL compared to EFV/TDF/FTC after 48 weeks of treatment by achieving undetectable viral load
Time frame: 48 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1 - Kaletra + Isentress Taken Twice Daily | Viral Suppression Efficacy at 48 Weeks | 86 percentage of participants |
| 2 - Atripla Taken Once Daily | Viral Suppression Efficacy at 48 Weeks | 87.5 percentage of participants |