Standard Antiretroviral v. Multi-class Therapy in Acutely HIV-1 Infected Antiretroviral-Naïve Subjects (ADARC 2007-01)

• DURATION: Subjects will participate for at least 60 weeks and up to 96 weeks if in the opinion of the investigator and patient that continued therapy is in the patient's best interest.
• SAMPLE SIZE: 36 subjects randomized 2:1 multi-class versus standard antiretroviral therapy.
• POPULATION: Acutely HIV-1-infected, antiretroviral (ARV) drug-naïve (≤ 7 days of ARV treatment at anytime prior to study entry*) men and women ≥ 18 years of age.
• REGIMEN: At entry subjects will be randomized to one of the following in a 1:2 ratio:

ARM A: FTC 200 mg/TDF 300 mg QD + darunavir 800 mg/ritonavir 100 mg QD

ARM B: FTC 200 mg/TDF 300 mg QD + darunavir 800mg/ritonavir 100 mg QD + Raltegravir 400 mg BID + Maraviroc 150 mg BID

The three primary objectives are:

• To assess whether a multi-class regimen could completely suppress virus replication in HIV infected individuals based on:

• Plasma HIV-1 RNA levels at 48 weeks
• Ultrasensitive < 50 copy assay
• 5 copy assay
• 1 copy assay
• Cell associated HIV-1RNA levels at week 48
• Proviral DNA
• Levels at week 48
• Decay rates from week 12 to week 48
• To determine whether multi-class antiviral therapy results in enhanced immune reconstitution in peripheral blood and gastrointestinal mucosa based on flow and immunohistochemistry.
• To assess tolerability of multi-class compact antiviral therapy to that of standard compact antiviral therapy.

Inclusion criteria

• Acute HIV-1 infection defined as:

• Negative ELISA/Western Blot or indeterminate Western Blot in the presence of HIV-1 RNA > 5,000 copies/ml.
• Positive HIV-1 serology with a detuned ELISA O.D. value below 0.5.
• A documented negative serology within 180 days of screening and a positive HIV-1 serology at screening
• Antiretroviral (ARV) drug-naïve (defined as ≤ 7 days of ARV treatment at any time prior to entry*).
• The only exceptions are:

• Use of antivirals as part of post-exposure prophylaxis (PEP) provided the subject did not acquire HIV-1 infection from the event that required PEP.
• Therapy with an investigational ARV drug that was not an NRTI, NNRTI, or PI.
• Laboratory values obtained within 30 days prior to study entry.

• Absolute neutrophil count (ANC) ≥ 500/mm3
• Hemoglobin ≥ 8.0 g/dL
• Platelet count ≥ 40,000/mm3
• AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 7.5 × ULN
• Total bilirubin ≤2.5 x ULN
• Calculated creatinine clearance ≥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) NOTE: A program to assist in calculations is available on the DMC web site at: http://www.fstrf.org/ACTG/ccc.html
• For women of reproductive potential, negative serum or urine pregnancy test within 48 hours prior to initiating study medications unless otherwise specified by product labeling.
• Female candidates of reproductive potential is defined as girls who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) or have not undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation).

Contraception requirements:

• Female candidates of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree that they will use at least one reliable method of contraception while receiving the protocol-specified drugs and for 6 weeks after stopping the medications.

Male Candidates:

• If you are a heterosexual male, you and your sexual partner must agree to use acceptable methods of birth control during the entire study.
• Acceptable methods of birth control include intrauterine device (IUD), diaphragm with spermicide, condoms or not having sex.
• Oral contraceptives alone are not an acceptablemethod of birth control.
• Men and women age ≥ 18 years.
• Ability and willingness of subject to give written informed consent.

Exclusion criteria

• Currently breast-feeding.
• Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. NOTE: Subjects receiving stable physiologic glucocorticoid doses, defined as prednisone ≤ 10 mg/day, will not be excluded.
• Known allergy/sensitivity to study drugs or their formulations.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Serious illness requiring systemic treatment and/or hospitalization until candidate either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 7 days prior to study entry.

NOTE: Oral candidiasis, vaginal candidiasis, mucocutaneous herpes simplex, and other minor illnesses (as judged by the site investigator) have no restriction.

• Clinically relevant cardiac conduction system disease. This includes severe first degree atrioventricular block (PR interval > 0.26 seconds), or second, or third-degree atrioventricular block.
• Requirement for any current medications that are prohibited with any study treatment.
• Evidence of major resistance-associated mutations on genotype performed within 14 days of day 1. Major resistance-associated mutations include: NRTI: K65R or inserts Q151M, M184V/I, PI: I50L/V, I84V, N88S.
• Viral population that is either dual tropic or X4 tropic using the Monogram assay (patients will be entered and be treated pending this result performed within 28 days of day 1).
• Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical (e.g., infectious disease) illness.
• Participation in any other clinical trial within 30 days prior to screening.
• Any other clinical conditions or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the requirements.