A Phase 2b, Double-Blind, Placebo-Controlled, Exploratory Randomized Trial to Determine the Bone, Immunologic, Virologic, and Neurocognitive Effects of a Novel Maraviroc-Containing Antiretroviral Regimen in Treatment-Naïve Patients Infected With R5-Tropic HIV-1
Brief SummaryThe main purpose of this study was to compare the effects on bones of the following two drug combinations: - maraviroc (MVC), emtricitabine (FTC), plus darunavir/ritonavir (DRV/r) - tenofovir (TDF) plus emtricitabine (FTC) plus darunavir/ritonavir (DRV/r) Additional study objectives were the following: - To see how the drug combinations affect the brain and kidneys. - To see how well the drug combinations lower the HIV viral load. - To see how safe the drug combinations are, how well people are able to take the study drug combinations, and how well their immune systems respond to the study drugs.
Detailed DescriptionThere are now several HIV treatment options for a person with HIV infection who has not yet been treated. Most people who receive treatment and take their medications as directed have a good result. This is usually determined by measuring the amount of HIV in the blood (viral load). The best response is when HIV cannot be found (less than 50 copies/mL) in the blood. However, it has recently become clear that some people with HIV who are receiving effective HIV drugs continue to have more health problems than people without HIV infection. Sometimes, there is damage to organs in the body, including bone, kidneys, and the brain.
PhasePhase 2 - takes the treatment one step further, assessing the activity of a particular therapy in a disease, often building upon leads from the Phase I trial. While patients are generally required to be previously untreated, participation in a Phase II trial doesn't usually preclude the patient from getting the standard treatment after they've received the investigational agent. At best they are allowed to get a new drug they wouldn't be able to get otherwise that may turn out to be better for their disease.
Inclusion and Exclusion Criteria
- HIV-1 infection
- No evidence of exclusionary resistance mutations defined as evidence of any major NRTI mutation according to the current IAS list of HIV-1 Resistance Mutations Associated with Drug Resistance, or any DRV RAMs (refer to the A5303 PSWP for a list of these mutations) on any genotype; or evidence of significant NRTI or DRV resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations were not exclusionary.
- ARV drug-naïve, defined as =10 days of ART at any time prior to study entry, except in the instances defined in section 4.1.3 of the protocol.
- R5-only tropism based on Trofile testing performed within 90 days prior to study entry.
- Screening HIV-1 RNA >1000 copies/mL obtained within 90 days prior to study entry by any FDA-approved test for quantifying HIV-1 RNA at any laboratory that has a CLIA certification or its equivalent.
- Known hepatitis C virus (HCV) antibody status (performed at any laboratory that had a CLIA certification or its equivalent).
- Certain laboratory values obtained within 60 days prior to study entry, as defined in section 4.1.7 of the protocol.
- For women of reproductive potential, negative serum or urine pregnancy test with a sensitivity of ≤25 mIU/mL within 72 hours prior to study entry.
- Female subjects of reproductive potential, who were participating in sexual activity that could lead to pregnancy, must agree to use at least one reliable method of contraception (as defined in section 18.104.22.168 of the protocol) while receiving the study drugs and for 6 weeks after stopping the medications.
- Female subjects who were not of reproductive potential or whose male partner(s) had azoospermia were eligible to take study drugs without the use of contraceptives.
- Ability and willingness of subject or legal guardian/representative to give written informed consent.
- Willingness to undergo neuropsychological testing.
- DXA scan performed after confirmation of the subject's eligibility by Trofile testing but no more than 4 weeks prior to randomization.
- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
- New use of hormonal therapies within 6 months prior to study entry. (Stable therapy for ≥6 months was permitted.)
- New use of oral contraceptive pills (OCPs) in the past 3 months. (Stable therapy for ≥3 months was permitted.)
- Any oral, intravenous, or inhaled steroids within 30 days prior to study entry. (Intranasal steroids and topical corticosteroids were allowed.)
- Known allergy/sensitivity to study drugs or their formulations. (A history of sulfa allergy was not an exclusionary condition.)
- Known hypersensitivity to soy lecithin.
- Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or was clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry. (Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) were not exclusionary conditions.)
- Requirement for any current medications that were prohibited with any study drugs. (Prohibited medications must be discontinued at least 30 days prior to entry. Refer to the A5303 PSWP for a list of prohibited medications.)
- The presence of decompensated cirrhosis.
- A history of or current, active HBV infection defined as positive hepatitis B surface antigen test (or positive HBV DNA in subjects with isolated HBcAb positivity, defined as negative HBsAg, negative HBsAb, and positive HBcAb) at screening.
- Current or prior use of biphosphonates, teriparatide, raloxifene, or denosumab.
- Weight >300 lbs (exceeds weight limit of DXA scanners).
- History after 18 years of age of fracture of the spine, hip, wrist, or other site thought to be related to osteoporosis or bone fragility.
- Currently breastfeeding.
- Any active psychiatric illness including schizophrenia, severe depression, or severe bipolar affective disorder that, in the opinion of the investigator, could confound the analysis of the neurological examination or neuropsychological test results.
- Active drug or alcohol abuse that, in the investigator's opinion, could prevent compliance with study procedures or confound the analysis of study endpoints.
- Active brain infection (except for HIV-1), fungal meningitis, toxoplasmosis, central nervous system (CNS) lymphoma, brain neoplasm, or space-occupying brain lesion requiring acute or chronic therapy.
- Harbor-UCLA Med. Ctr. CRS (603), Torrance, California, 90502
- UCLA CARE Center CRS (601), Los Angeles, California, 90095
- Ucsd, Avrc Crs (701), San Diego, California, 92103
- Stanford CRS (501), Palo Alto, California, 94304
- Ucsf Aids Crs (801), San Francisco, California, 94110
- University of Colorado Hospital CRS (6101), Aurora, Colorado, 80045
- Houston AIDS Research Team CRS (31473), Houston, Texas, 77030
- Washington U CRS (2101), St. Louis, Missouri, 63110
- Rush Univ. Med. Ctr. ACTG CRS (2702), Chicago, Illinois, 60612
- Northwestern University CRS (2701), Chicago, Illinois, 60611
- Vanderbilt Therapeutics CRS (3652), Nashville, Tennessee, 37232
- Alabama Therapeutics CRS (5801), Birmingham, Alabama, 35294
- Univ. of Cincinnati CRS (2401), Cincinnati, Ohio, 45267