Comparative Study of Three NNRTI-Sparing HAART Regimens

• Time from virologic failure defined as the time from study entry to the first of two consecutive HIV-1 RNA levels [ Time Frame: At or after Week 16 and before Week 24 or after study Week 24 ] [ Designated as safety issue: No ]
• Time to discontinuation of the RAL or PI component of randomized treatment for toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

• Time to virologic failure defined as the time from randomization to the first of two consecutive HIV-1 RNA levels [ Time Frame: At or after Week 16 and before Week 24 or after study Week 24 ] [ Designated as safety issue: No ]
• Discontinuation of the RAL or PI component of randomized treatment for toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]

• Occurrence of new Grade 2, 3, or 4 sign or symptom or Grade 3 or 4 laboratory toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Time to loss of virologic response [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Presence of mutations associated with PI, NRTI, or RAL resistance [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Number of drug classes with evidence of resistance [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• CD4 counts and CD4 count changes from baseline [ Time Frame: At Weeks 4, 24, 48, 96, and 144 ] [ Designated as safety issue: No ]
• Time from study entry to death or AIDS defining condition, or certain targeted serious non-AIDS defining events. See protocol for more detail. [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Targeted serious non-AIDS defining events including CDC category B [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Changes in fasting total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, cardiovascular risk, waist circumference and waist-to-height ratio, and self-reported rates of body shape changes [ Time Frame: At baseline and Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]
• Self-reported adherence [ Time Frame: At Weeks 4, 24, 48, 96, and 144 ] [ Designated as safety issue: No ]
• Pregnancy outcomes [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

• Occurrence of new Grade 2, 3, or 4 sign or symptom, or Grade 3 or 4 laboratory toxicity [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Time to loss of virologic response [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Presence of mutations associated with PI, NRTI, or RAL resistance [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• Number of drug classes with evidence of resistance [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
• CD4 counts and CD4 count changes from baseline [ Time Frame: At Weeks 4, 24, 48, 96, and 144 ] [ Designated as safety issue: No ]
• Death or AIDS defining condition [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Targeted serious non-AIDS defining events including CDC category B [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
• Changes from baseline in fasting total cholesterol, HDL cholesterol, triglycerides, glucose, Framingham 10-year risk, and self-reported rates of body shape changes in the three study regimens [ Time Frame: At Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]
• Risk behavior defined as the number of unprotected insertive or receptive anal or vaginal intercourse without the use of a condom in the preceding month [ Time Frame: At Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]
• Perception of infectiousness [ Time Frame: At Weeks 48, 96, and 144 ] [ Designated as safety issue: No ]
• Self-reported adherence [ Time Frame: At Weeks 4, 24, 48, 96, and 144 ] [ Designated as safety issue: No ]
• Pregnancy outcomes [ Time Frame: Throughout study ] [ Designated as safety issue: No ]

The U.S. Department of Health and Human Services (HHS) guidelines recommend that HIV infected patients who have never received anti-HIV therapy be treated with a triple drug regimen. The most commonly prescribed and successful regimen contains the medication efavirenz (EFV). However, this regimen has been shown to cause undesirable side effects for some patients and is therefore not an option. Alternative regimens are needed for these patients.

This study will look at how well different combinations of anti-HIV drugs work to decrease the amount of HIV in the blood (viral load) of and allow immune system recovery in people who have never received anti-HIV therapy. This study will also examine drug tolerability and safety for the various drug combinations.

Of the five anti-HIV drug classes, three are recommended as first-line regimens for patients who have never received anti-HIV treatment before (treatment naive): nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). The U.S. Department of Health and Human Services (HHS) guidelines recommend that treatment-naive HIV infected patients be treated with a triple drug regimen that includes 2 NRTIs + 1 NNRTI or 2 NRTIs + 1 PI as their initial treatment regimen.

According to data, an efavirenz (EFV)-containing regimen (2 NRTIs + 1 NNRTI, with EFVas the NNRTI) requires fewer pills for the patient, has mild and few side effects, and is more effective in reducing viral load than other regimens, making it the preferred choice for most patients. However, for some patients, an EFV-containing regimen is not possible due to dangerous side effects, acquired NNRTI-resistant HIV virus, or other undesirable effects. For these patients, it is necessary to find alternative regimens with comparable safety and efficacy. This study will examine how well different combinations of anti-HIV drugs work, including safety and drug tolerability for various combinations.

This is a phase III, prospective, randomized study. Participants will be randomly assigned to one of three different groups (treatment arms)—A, B, or C —each representing a different drug combination regimen, none of which will contain an NNRTI.

Arm A: Atazanavir (ATV) + Ritonavir (RTV) + Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)

Arm B: Raltegravir (RAL) + FTC/TDF

Arm C: Darunavir (DRV) + RTV + FTC/TDF

The duration of this study will be between 96 and 192 weeks, depending on when the participant enrolls. There will be a total of 1,800 participants, 600 per treatment arm. Screening and pre-entry evaluations must occur prior to the participant starting any study medication, treatments, or interventions. Participants will be randomly assigned to their treatment groups at the entry visit and must begin treatment within 72 hours of randomization. Participants will be told which group they are in and what medications they will be administered. The study drugs will be distributed at entry. All drugs are provided by the study with the exception of RTV, which will have to be obtained through the participant's primary care physician (Group A or C). If a participant is unable to tolerate any of the study medications during the course of the study then their doctor can switch them to another regimen.

During the study, participants will be asked to return to the clinic at Weeks 4, 8, 16, 24, 36, and 48 and then every 16 weeks until the end of the study. They will also be contacted by telephone during Week 2 to check on their status. Visits will last about 1 hour. At most visits, participants will have a physical exam and will answer questions about any medications they may be taking. Additionally, participants will complete questionnaires addressing their smoking and alcohol habits, will have blood drawn, and will be asked to give urine samples. At some visits, participants will have to come to the clinic without having eaten for 8 hours. If the participant is female and able to become pregnant, a pregnancy test may be given at any visit if pregnancy is suspected.

In the first 10 participant at each imaging site, the flow-mediated vasodilation (FMD) test, which measures cardiovascular risk, will be completed twice. This test will be performed on Week 24.

Some participants of A5257 will be asked to participate in an optional metabolic substudy of A5257. This substudy will take place at only some study sites and may last up to 144 weeks, including time on A5257. The primary focus of this substudy is to examine carotid artery intima-media thickness (CIMT) as it relates to both RTV- and RAL-containing regimens. Randomization, stratification, treatment assignments, and study visits will be as per A5257.

• Drug: Emtricitabine/tenofovir disoproxil fumarate
  A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs)
  Other Name: TDF/FTC
• Drug: Raltegravir
  An integrase inhibitor
  Other Name: RAL
• Drug: Darunavir
  A protease inhibitor (PI)
  Other Name: DRV
• Drug: Ritonavir
  A protease inhibitor (PI)
  Other Name: RTV
• Drug: Atazanavir
  A protease inhibitor (PI)
  Other Name: ATZ

• Experimental: Group A
  Participants will be administered emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), ritonavir (RTV), and atazanavir (ATV) to be taken orally, once daily for the entire duration of the study
  Interventions:

  • Drug: Emtricitabine/tenofovir disoproxil fumarate
  • Drug: Ritonavir
  • Drug: Atazanavir
• Experimental: Group B
  Participants will be administered FTC/TDF orally, once daily, and raltegravir (RAL) orally, twice daily, for the entire duration of the study
  Interventions:

  • Drug: Emtricitabine/tenofovir disoproxil fumarate
  • Drug: Raltegravir
• Experimental: Group C
  Participants will be administered FTC/TDF, darunavir (DRV), and RTV, orally, once daily for the entire duration of the study
  Interventions:

  • Drug: Emtricitabine/tenofovir disoproxil fumarate
  • Drug: Darunavir
  • Drug: Ritonavir

• Bartlett JA, Chen SS, Quinn JB. Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview. HIV Clin Trials. 2007 Jul-Aug;8(4):221-6. Review.
• Duvivier C, Ghosn J, Assoumou L, Soulié C, Peytavin G, Calvez V, Génin MA, Molina JM, Bouchaud O, Katlama C, Costagliola D; ANRS 121 study group. Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother. 2008 Oct;62(4):797-808. Epub 2008 Jul 18.
• Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33.
• Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55.

Inclusion Criteria:

• HIV infected
• No evidence of any exclusionary mutations defined as any major NRTI or PI resistance-associated mutation on any genotype or evidence of significant NRTI or PI resistance on any phenotype performed at any time prior to study entry. NNRTI-associated resistance mutations are not excluded. More information on this criterion can be found in the study protocol.
• No prior anti-HIV therapy. More information on this criterion can be found in the study protocol.
• Viral load is 1000 copies/mL or higher, as measured within 90 days prior to study entry
• Certain laboratory values obtained within 60 days prior to study entry
• Ability to obtain RTV by prescription
• Completed cardiovascular risk assessment. More information on this criterion can be found in the study protocol.
• Must agree to use acceptable forms of contraception while receiving study drugs and for 6 weeks after stopping the medications. More information on this criterion is available in the protocol.
• Negative pregnancy test within 72 hours before initiating antiretroviral medication
• Participating in research at any AIDS Clinical Trial Group (ACTG) clinical research site or select International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group sites
• Ability and willingness of subject or legal guardian/representative to give written informed consent

Exclusion Criteria:

• Use of immunomodulators, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Those using stable physiologic glucocorticoid doses, a short course of pharmacologic glucocorticoid, corticosteroids for acute therapy treating an opportunistic infection, inhaled or topical corticosteroids, or granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) will not be excluded.
• Known allergy or sensitivity to study drugs or their ingredients. A history of sulfa allergy is not excluded.
• Any condition that, in the opinion of the investigator, would compromise the participant's ability to participate in the study
• Serious illness requiring systemic treatment and/or hospitalization until participant either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 7 days prior to study entry
• Requirement for any current medications that are prohibited with any study drugs
• Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness
• Any prior use of entecavir for treatment of hepatitis B for greater than 8 weeks while the participant was known to be HIV infected
• Presence of decompensated cirrhosis
• Pregnant or breastfeeding

• National Institute of Allergy and Infectious Diseases (NIAID)
• Bristol-Myers Squibb
• Gilead Sciences
• Merck
• Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA