Comparative Study of Three NNRTI-Sparing HAART Regimens

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.