Simplification to Abacavir/Lamivudine + Atazanavir Maintains Viral Suppression and Improves Bone and Renal Biomarkers in ASSURE, a Randomized, Open Label, Non-Inferiority Trial

Objective Simplification of antiretroviral therapy in patients with suppressed viremia may minimize long-term adverse effects. The study’s primary objective was to determine whether abacavir/lamivudine + atazanavir (ABC/3TC+ATV) was virologically non-inferior to tenofovir/emtricitabine + atazanavir/ritonavir (TDF/FTC+ATV/r) over 24 weeks in a population of virologically suppressed, HIV-1 infected patients. Design This open-label, multicenter, non-inferiority study enrolled antiretroviral experienced, HIV-infected adults currently receiving a regimen of TDF/FTC+ATV/r for ≥6 months with no history of virologic failure and whose HIV-1 RNA had been ≤75 copies/mL on 2 consecutive measurements including screening. Patients were randomized 1∶2 to continue current treatment or simplify to ABC/3TC+ATV. Methods The primary endpoint was the proportion of patients with HIV-RNA<50 copies/mL at Week 24 by the Time to Loss of Virologic Response (TLOVR) algorithm. Secondary endpoints included alternative measures of efficacy, adverse events (AEs), and fasting lipids. Exploratory endpoints included inflammatory, coagulation, bone, and renal biomarkers. Results After 24 weeks, ABC/3TC+ATV (n = 199) was non-inferior to TDF/FTC+ATV/r (n = 97) by both the primary analysis (87% in both groups) and all secondary efficacy analyses. Rates of grade 2–4 AEs were similar between the two groups (40% vs 37%, respectively), but an excess of hyperbilirubinemia made the rate of grade 3–4 laboratory abnormalities higher in the TDF/FTC+ATV/r group (30%) compared with the ABC/3TC+ATV group (13%). Lipid levels were stable except for HDL cholesterol, which increased significantly in the ABC/3TC+ATV group. Bone and renal biomarkers improved significantly between baseline and Week 24 in patients taking ABC/3TC+ATV, and the difference between groups was significant at Week 24. No significant changes occurred in any inflammatory or coagulation biomarker within or between treatment groups. Conclusions After 24 weeks, simplification to ABC/3TC+ATV from TDF/FTC+ATV/r maintained viral suppression was well-tolerated, and led to improvements in bone and renal biomarkers and HDL cholesterol. Trial Registration ClinicalTrials.gov NCT01102972 GlaxoSmithKline Clinical Study Register #113734


LIST OF ABBREVIATIONS
The need to find alternative treatment strategies that do not require the use of RTV is of continued interest among clinicians who perceive this as an unmet patient need. Data from this study will support this simplification strategy as a long term treatment option for subjects and clinicians who prefer a RTV-sparing regimen.
The benefit to patients would be a simplified and cost effective treatment regimen, with potentially fewer adverse effects and potential reduction in drug-drug interactions. The risks to this approach are potentially lower ATV trough levels that may lead to resistance development and the unknown long-term impact of switching Tenofovir/Emtricitabine (TDF/FTC) for Abacavir/Lamivudine (ABC/3TC). However, this risk to patients may be small and mitigated due to the expected low rate of virologic failure observed following this strategy, the ability to change to an alternative treatment regimen quickly at a relatively low level of viral replication, the expected emergence of mutation pattern(s) readily rescued by other current available PIs, and the shorter study duration.
Potential risks of using this simplification study design are that some subjects may experience viral rebound and potentially develop resistance mutations rendering the simplification regimen less effective. However, subjects randomized to the simplification arm who experience viral rebound will have the opportunity to switch to an alternative regimen at the time of confirmed virologic failure. Overall the risk of virologic failure in the RTV-sparing arm is small and readily manageable compared to the benefit of protection from long-term complications of RTV-containing therapy such as hyperlipidemia, insulin resistance, lipoatrophy, and gastrointestinal intolerance and associated complexities for Human Immunodeficiency Virus (HIV)-infected patients with other co-morbidities.
The long-term implications of this strategy are currently unknown, but any risk is likely to be small given the short-term exposure to resistant virus and that ATV-resistant virus has been documented in vitro to be susceptible to alternative PIs. This is a phase IV, prospective, randomized, open-label, multicenter, non-inferiority study of the safety, efficacy, and tolerability of ATV + ABC/3TC once daily compared to ATV/RTV + TDF/FTC once daily for 48 weeks in HIV-1 infected, HLA-B*5701negative subjects who are currently receiving a stable regimen of ATV/RTV + TDF/FTC once daily and are virologically suppressed (plasma HIV-1 RNA 75 c/mL).
A minimum of 300 subjects meeting eligibility criteria will be stratified by initial antiretroviral regimen received (ATV/RTV + TDF/FTC as initial regimen OR as first or second switch regimen) and randomized 2:1 to receive one of the following antiretroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm B: (Continuation)
ATV/RTV 300 mg/100 mg once daily + TDF/FTC 300 mg/200 mg once daily Subjects who enter the Screening period of this study must continue receiving their ATV/RTV + TDF/FTC regimen up to, but not including, the Baseline visit (Day 1). Subjects will begin randomized treatment on Day 1.
This study consists of a 35 day Screening period, a 48 week Treatment period (Day 1 through Week 48) and a Follow-up period (contact approximately 2-4 weeks after the Week 48 visit or Withdrawal visit).

Protocol-Defined Virologic Failure
Virologic failure is defined as plasma HIV-1 RNA rebound ≥400 c/mL. Virologic failure in this study must be confirmed: A subject is considered a suspected virologic failure after the first HIV-1 RNA measurement of ≥400 c/mL.
If the repeat HIV-1 RNA measurement performed at least 28 days later is again 400 c/mL, the subject is considered a confirmed virologic failure.

Algorithm for Management of Virologic Failure
Subjects who meet the definition for confirmed virologic failure with an HIV-1 RNA measurement 400 but <2000 c/mL may continue in the study at the discretion of the investigator and after consultation with the Sponsor, and choose one of the two following management options: 1. Continue randomized treatment regimen

Change to a new antiretroviral regimen
If a subject switches to a new antiretroviral regimen, any regimen may be chosen. The Sponsor will provide the following study drugs for the purpose of constructing a new treatment regimen: ATV, RTV, ABC/3TC, TDF/FTC, 3TC/Zidovudine (ZDV) or Fosamprenavir (FPV).

Withdrawal Criteria for Subjects with Confirmed Virologic Failure
Subject must be withdrawn from the study for either of the following situations: Subject has an HIV-1 RNA measurement 2000 c/mL at the confirmatory visit for virologic failure Subject has two consecutive HIV-1 RNA measurements 2000 c/mL at any time Note: A subject with an HIV-1 RNA 2000 c/mL at the time of suspected virologic failure need not be withdrawn as long as the repeat (confirmatory) HIV-1 RNA is <2000 c/mL.

Suspected Abacavir Hypersensitivity Reaction
Subjects who experience a suspected abacavir hypersensitivity reaction (ABC HSR) must discontinue abacavir and may chose from one of the following two options to remain on study: 1. Substitute zidovudine/lamivudine (ZDV/3TC) for ABC/3TC. ZDV/3TC will be provided by the Sponsor.
2. Substitute TDF/FTC for ABC/3TC and change back to original regimen of ATV/RTV + TDF/FTC. TDF/FTC and ATV/RTV will be provided by the Sponsor.

Declining Renal Function
Creatinine clearance <50 mL/min For subjects who experience progression to an estimated creatinine clearance (CrCl) (calculated by Cockroft-Gault equation) to <50 mL/min judged by the investigator to be attributed to study medication, the offending agent(s) must be discontinued. No dosereduction of the offending agent(s) will be allowed.
For subjects who experience progression to an estimated creatinine clearance (CrCl) (calculated by Cockroft-Gault equation) to <50 mL/min judged by the investigator to be NOT study drug-related, the investigator will choose from one of the following two management options for study medications: 1. Discontinue study medication(s) and switch to another agent in the same class and remain on study.
2. Dose reduce study medication (s) as indicated in prescribing information and remain on study.

Proximal Renal Tubule Dysfunction
Subjects who meet clinical and/or laboratory criteria for proximal renal tubule dysfunction (PRTD) must be withdrawn from study.

Primary Endpoint:
The primary endpoint is to determine the proportion of subjects who maintain plasma HIV-1 RNA <50 c/mL at 24 weeks by the Time to Loss Of Virologic Response (TLOVR) algorithm.

Secondary Endpoints:
The secondary efficacy endpoints are to determine the following: proportion of subjects with plasma HIV-1 RNA <50 c/mL at 48 weeks, proportion with plasma HIV-1 RNA <400 c/mL at 24 and 48 weeks, change from Baseline in HIV-1 RNA and CD4+ cell count, time to virologic failure, and identification of genotypic and phenotypic resistance in virus from subjects with virologic failure.
The secondary safety endpoints are to evaluate the change from Baseline in fasting lipid profiles (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides) and incidence of Grade 2 to 4 AEs and all serious adverse events (SAE)s.

Background
There are over twenty Food and Drug Administration (FDA) approved antiretroviral agents available with which to construct a highly active antiretroviral therapy (HAART) regimen which has proven to reduce morbidity and mortality in individuals with human immunodeficiency virus infection (HIV) or acquired immunodeficiency syndrome (AIDS) [Palella, 1998]. The current standard of therapy is a combination of at least three antiretrovirals consisting of two nucleoside/nucleotide (NRTI) analogues plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor [DHHS, 2009]. Among the available agents, atazanavir (ATV) boosted with ritonavir (RTV) + tenofovir/emtricitabine (TDF/FTC) is currently a preferred initial regimen for antiretroviral-naïve patients to reduce viral load and improve CD4 lymphocyte counts.
Low-dose RTV is commonly added to PI-based regimens to provide pharmacokinetic enhancement of the parent PI and to reduce the risk of drug resistance. However, RTV is also associated with adverse effects including gastrointestinal upset and lipid and metabolic alterations that may increase future cardiovascular risk. In addition, RTV is a perpetrator of cytochrome P450-mediated drug interactions which can limit the use of other concomitant drugs [Norvir Package Insert, 2010;Reyataz Package Insert, 2010]. The addition of RTV to PIs not co-formulated with RTV adds to the patient's pill burden and is associated with extra medication costs. Therefore, there is continued interest among clinicians to find alternative treatment strategies that do not require the use of RTV but continue to offer the potency and high virologic resistance barrier of protease inhibitors.
Treatment induction with a highly potent combination regimen followed by simplification is one strategy that has demonstrated comparable safety and efficacy outcomes in several studies [Gatell, 2007;Delfraissy, 2008;Squires, 2010a;Squires, 2010b]. Regimen induction with a RTV-boosted PI provides rapid initial virologic suppression reducing risk for development of viral resistance while subsequent simplification optimizes tolerability and adherence, minimizes short and long-term toxicity, and may reduce drug-drug interactions.
The SWAN study was a multicenter, randomized, open-label trial of 419 patients on a stable, virologically suppressive, PI-based regimen for a mean of 40.3 months who were randomized 2:1 to either switch to an ATV-containing regimen with unchanged NRTIs or remain on the initial non-ATV PI-based regimen. ATV was administered without RTV except in approximately 9% of subjects whose NRTIs included TDF, in which case ATV was given with low-dose RTV due to the pharmacokinetic interaction of ATV and TDF which requires that when using ATV in combination with TDF it must be boosted by RTV [Gatell, 2007]. In a post-hoc analysis among 153 subjects who were initially stable on a virologically suppressive, Lopinavir (LPV)/RTV based regimen, 82 (53%) switched to an unboosted ATV-based regimen, 18 (12%) switched to an ATV/RTV based regimen, and the remaining 53 subjects (34.5%) continued on the original LPV/RTV based regimen. At Week 48, the rates of viral rebound were comparable; 11% in the combined ATV arm and 9% in the LPV/RTV arm [Gatell, 2006]. Rates of treatment failure for any reason, which included viral rebound, failure to receive the randomized treatment, or discontinuation of study therapy were similar in both groups (26% of patients on LPV/RTV versus 28% on ATV). In addition, subjects switched to ATV had a reduction in new onset gastrointestinal symptoms, improvements in lipid parameters, and a lower usage of lipid lowering agents compared to subjects remaining on the LPV/RTV arm [Gatell, 2006]. This post-hoc analysis demonstrated that subjects switching from a stable, virologically suppressive, LPV/RTV based regimen to a RTV-boosted or RTVsparing ATV based regimen maintained similar virologic control with fewer lipid abnormalities and better gastrointestinal tolerability.
The ARIES study was a 144-week, phase IIIB, randomized, open-label, multi-center study in 419 randomized patients who had achieved virologic suppression during the initial 36-week induction phase. In the induction phase, patients received ATV/RTV + abacavir sulfate/lamivudine (ABC/3TC) over 36 weeks and those achieving virologic suppression were subsequently randomized (1:1) to a simplification regimen of ATV + ABC/3TC or remained on the induction regimen and then followed for 108 weeks. At week 84 (48 weeks from the start of randomization), 86% of patients randomized to the simplification arm vs. 81% of patients remaining on the induction arm maintained virologic suppression to HIV-1 RNA <50 copies/mL (c/mL) [Squires, 2010a]. Virologic failure occurred in 0.5% of patients in the simplification arm compared to 3% of patients in the induction arm through 84 weeks. Results were similar among patients with entry viral loads above and below 100,000 c/mL. Patients on the simplification regimen had less hyperbilirubinemia and a reduction in total cholesterol and triglycerides. At week 120 (84 weeks from start of randomization), virologic efficacy was sustained between groups resulting in 84% of ATV + ABC/3TC versus 83% of ATV/RTV + ABC/3TC subjects maintaining suppression to <50 c/mL [Squires, 2010b]. No differences in response rates by baseline viral load were observed between groups. The overall rate of virologic failure was 2% and comparable between groups. Subjects in the simplification arm continued to demonstrate favorable lipid benefits and maintained bilirubin reductions through 120 weeks.
ABC/3TC is a dual nucleoside combination that is also commonly used with RTVboosted ATV, but may also be used with unboosted ATV in appropriate patient populations. Recent data have shown that the combination of unboosted ATV plus ABC/3TC effectively maintains virologic suppression (plasma HIV-1 RNA <50 c/mL) after initial induction with RTV-boosting of ATV in HIV-infected patients [Delfraissy, 2008;Squires, 2010b]. In addition, ABC/3TC has a well-established safety profile and relatively few drug interactions [EPZICOM ® Package Insert, 2009].
The current study will evaluate whether subjects receiving a RTV-containing regimen of ATV/RTV + TDF/FTC who have achieved virologic suppression can safely simplify to a RTV-sparing regimen of ATV + ABC/3TC and maintain virologic suppression through 48 weeks.
This study will also evaluate changes in neurocognition (via a computerized test battery), and cardiovascular, renal and bone biomarkers as exploratory endpoints. As the life expectancy of HIV-1 infected patients continues to improve, long-term consequences of chronic HIV-infection and potentially specific antiretroviral therapies is of active research interest. Additionally, this study will increase our knowledge regarding the incidence of clinically suspected abacavir hypersensitivity reaction (ABC HSR) after excluding patients who carry the HLA-B*5701 allele.

Rationale
Protease inhibitor (PI)-based therapies containing low-dose RTV have demonstrated favourable efficacy, safety, and barrier to resistance among antiretroviral naïve and treatment experienced patients. However, RTV is associated with long-term gastrointestinal and metabolic toxicities, added pill burden and cost.
ATV is the only currently licensed PI that can be safely administered with or without RTV. Several trials [Delfraissy, 2008;Gatell, 2007;Squires, 2010a;Squires, 2010b] investigating an induction-simplification treatment strategy to achieve rapid initial viral load reduction with RTV-boosted ATV followed by simplification to unboosted ATV have demonstrated comparable efficacy. Although there are limited published data utilizing this strategy in clinical practice, a RTV-sparing strategy with ATV has shown improvement in lipids, bilirubin, low rate of virologic failure, and patient acceptance based on improved tolerability and fewer side effects [Santos, 2009;Pavie, 2009;Giuntini, 2010].
The need to find alternative treatment strategies that do not require the use of RTV is of continued interest among clinicians who perceive this as an unmet patient need. Data from this study will support this simplification strategy as a long term treatment option for subjects and clinicians who prefer a RTV-sparing regimen.
The benefit to patients would be a simplified and cost effective treatment regimen, with potentially fewer adverse effects and potential reduction in drug-drug interactions. The risks to this approach are potentially lower ATV trough levels that may lead to resistance development and the unknown long-term impact of switching TDF/FTC for ABC/3TC. However, this risk to patients may be small and mitigated due to the expected low rate of virologic failure observed following this strategy [Squires, 2010a;Squires, 2010b;Delfraissy, 2008], the ability to change to an alternative treatment regimen quickly at a relatively low level of viral replication, the expected emergence of mutation pattern(s) readily rescued by other current available PIs, and the shorter study duration.
Potential risks of using this simplification study design are that some subjects may experience viral rebound and potentially develop resistance mutations rendering the simplification regimen less effective [Malan, 2006;McGrath, 2006]. However, subjects randomized to the simplification arm who experience viral rebound will have the opportunity to switch to an alternative regimen at the time of confirmed virologic failure.
Overall the risk of virologic failure in the RTV-sparing arm is small and readily manageable compared to the benefit of protection from long-term complications of RTVcontaining therapy such as hyperlipidemia, insulin resistance, lipoatrophy, and gastrointestinal intolerance and associated complexities for HIV-infected patients with other co-morbidities.
The long-term implications of this strategy are currently unknown, but any risk is likely to be small given the short-term exposure to resistant virus and that ATV-resistant virus has been documented in vitro to be susceptible to alternative PIs.
Additionally, there is a small risk for subjects that are simplified to the ABC/3TC regimen to experience a suspected ABC HSR reaction. However, all subjects enrolled in this study will be HLA-B*5701 negative and therefore the risk for ABC HSR will be substantially reduced as evidenced by data in other HLA-B*5701 negative subjects receiving ABC-containing regimens in the ARIES and PREDICT-1 studies [Squires, 2010a;].

Primary Objective
To demonstrate that ATV + ABC/3TC is virologically noninferior to ATV/RTV + TDF/FTC over 24 weeks in a population of virologically suppressed HIV-1 infected subjects

Secondary Objectives
To compare the safety, tolerability, and virologic efficacy between ATV + ABC/3TC and ATV/RTV + TDF/FTC over 24 and 48 weeks To compare the immunologic response to ATV + ABC/3TC versus ATV/RTV + TDF/FTC over 24 and 48 weeks To evaluate clinical and laboratory adverse events (AEs) in subjects on ATV + ABC/3TC compared to those remaining on their Baseline regimen of ATV/RTV + TDF/FTC over 24 and 48 weeks To evaluate genotypic and phenotypic resistance patterns in subjects who experience virologic failure over 24 and 48 weeks

Exploratory Objectives
To compare neurocognitive changes between ATV + ABC/3TC and ATV/RTV + TDF/FTC over 24 and 48 weeks To compare changes in various serum cardiovascular, bone, and renal biomarkers between ATV + ABC/3TC and ATV/RTV + TDF/FTC over 24 and 48 weeks

Study Design
This is a phase IV, prospective, randomized, open-label, multicenter, non-inferiority study of the safety, efficacy, and tolerability of ATV + ABC/3TC once daily compared to ATV/RTV + TDF/FTC once daily for 48 weeks in HIV-1 infected, HLA-B*5701negative subjects who are currently receiving a stable regimen of ATV/RTV + TDF/FTC once daily and are virologically suppressed (plasma HIV-1 RNA 75 c/mL).
ATV/RTV + TDF/FTC once daily must be the subject's initial, or first or second switch regimen. However, regimen switches must not have been due to virologic failure.
A minimum of 300 subjects meeting eligibility criteria will be stratified by initial antiretroviral regimen received (ATV/RTV + TDF/FTC as initial regimen OR as the first or second switch regimen) and randomized 2:1 to receive one of the following antiretroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm A: (Simplification)
ATV 400 mg once daily + ABC/3TC 600 mg/300 mg once daily Study participation is considered complete when a subject has completed study procedures through Week 48.
Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

Protocol-Definition of Virologic Failure
Virologic failure is defined as plasma HIV-1 RNA rebound ≥400 c/mL.
Virologic failure in this study must be confirmed: A subject is considered a suspected virologic failure after the first HIV-1 RNA measurement of ≥400 c/mL.
If the repeat HIV-1 RNA measurement performed at least 28 days later is again 400 c/mL, the subject is considered a confirmed virologic failure.

Algorithm for Virologic Failure Management
Subjects who meet the definition for confirmed virologic failure with an HIV-1 RNA measurement 400 but <2000 c/mL may continue in the study at the discretion of the investigator and after consultation with the Sponsor, and choose one of the following two management options: 1. Continue randomized treatment regimen.

Change to a new antiretroviral regimen
If a subject switches to a new antiretroviral regimen, any regimen may be chosen. The Sponsor will provide the following study drugs for the purpose of constructing a new treatment regimen: ATV, RTV, ABC/3TC, TDF/FTC, Zidovudine (ZDV)/3TC or Fosamprenavir (FPV).

Withdrawal Criteria for Subjects with Confirmed Virologic Failure
Subject must be withdrawn from the study for either of the following situations: Subject has an HIV-1 RNA measurement 2000 c/mL at the confirmatory visit for virologic failure (see Section 3.2) Subject has two consecutive HIV-1 RNA measurements 2000 c/mL at any time Note: A subject with an HIV-1 RNA 2000 c/mL at the time of suspected virologic failure need not be withdrawn as long as the repeat (confirmatory) HIV-1 RNA is <2000 c/mL.

Discussion of Design
The current study is designed to evaluate whether virologically-suppressed subjects receiving ATV/RTV + TDF/FTC maintain virologic efficacy comparable to subjects who are simplified to ATV + ABC/3TC over 48 weeks. A simplification strategy is being investigated given the results from the ARIES trial demonstrating the safety and efficacy of switching virologically suppressed subjects from RTV-boosted ATV + ABC/3TC to unboosted ATV + ABC/3TC over 144 weeks [Squires, 2010a]. This strategy is also attractive given the potential to avoid the typical cumulative adverse effects of RTV as well as avoiding the known interaction between ATV and TDF which requires the use of RTV [Reyataz Package Insert, 2010].
An open-label instead of a placebo-matched study design was chosen since a placebomatched design would add to the pill burden of both treatment regimens. A placebomatched design would require that subjects randomized to the unboosted ATV treatment arm receive an additional RTV-placebo while subjects randomized to boosted ATV receive an additional ATV-placebo. RTV is associated with taste disturbances and other gastrointestinal adverse effects that would be difficult to match with a placebo in subjects accustomed to receiving RTV. Further, a placebo-matched design may be unnecessary since the primary objective is based on a virologic outcome. However, the absence of placebo-matching may be a potential source of bias in this study.
Utilizing the ABC/3TC fixed-dose combination (FDC) tablet as the NRTI backbone, this open-label, randomized, multicenter study will compare the safety and efficacy of ATV + ABC/3TC administered once daily to continuation of ATV/RTV + TDF/FTC once daily for 48 weeks in HIV-infected, HLA-B*5701 negative subjects who were initially suppressed on a combination of ATV/RTV + TDF/FTC once daily.

Number of Subjects
Approximately 300 HLA-B*5701 negative, adult HIV-1 infected patients will be randomized at approximately 40 sites within North America.

Inclusion Criteria
Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Adults 18 years of age.
2. Receiving a once-daily regimen of ATV/RTV (300 mg/100 mg) + TDF/FTC (300 mg/200 mg) for at least 6 months prior to the first day of Screening.
ATV/RTV+TDF/FTC must be the subject's initial regimen or first or second switch regimen.
Initial regimen is defined as the first regimen received by a previously antiretroviral naïve subject Any change of antiretroviral therapy, whether of a single drug or multiple drugs simultaneously, is considered a regimen switch.
Subjects must not have switched due to virologic failure.
If ATV/RTV + TDF/FTC is a subject's first or second switch regimen, then the subject may only have received the following prior regimens: a. Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); or, b. Child-bearing potential, has a negative pregnancy test at Screening (serum -Human chorionic gonadotropins (HCG) and Baseline (urine -HCG) and agrees to one of the following methods of contraception (any contraception method must be used consistently and correctly, i.e., in accordance with both the approved product label and the instructions of a physician): Complete abstinence from sexual intercourse from 2 weeks prior to administration of the Investigational Products, throughout the study, and for at least 2 weeks after discontinuation of all study medications Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide). Hormonal contraception will not be considered adequate for inclusion into this study.
Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year.
Sterilization (female subject or male partner of female subject).
All subjects participating in the study should be counselled on the practice of safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide).

Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study: 1. Evidence of virologic failure at any time defined as two consecutive plasma HIV-1 RNA levels ≥200 c/mL after initial suppression to HIV-1 RNA 75 c/mL.  [Cockroft, 1976]. A single repeat is allowed to determine eligibility.
10. Verified Grade 4 laboratory abnormality at Screening unless the Investigator can provide a compelling explanation (e.g. elevated Creatine Phosphokinase (CPK) due to exercise) for the laboratory result(s) and has the assent of the Sponsor. A single repeat is allowed to determine eligibility.
11. Any other laboratory abnormality or medical condition at Screening, which, in the opinion of the investigator, would preclude the subject's participation in the study (e.g. elevated liver function tests (LFTs) or pancreatitis, etc).
12. Immunization within 30 days prior to first dose of Investigational Product.
13. Any exposure to treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, or interferons) or receipt of an HIV-1 immunotherapeutic vaccine within 90 days prior to Screening. Subjects using inhaled corticosteroids or short-course systemic corticosteroids ( 14 days) are eligible for enrollment.
14. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 90 days prior to Screening, or an anticipated need for these agents within the study period.
15. Treatment within 30 days prior to first dose of Investigational Product for or an anticipated need during the study of any medications which can have interactions with the study medications, TDF, FTC, ABC, 3TC, ATV and/or RTV, as described in current product labelling (e.g. use of proton pump inhibitors with ATV).

Any previous abacavir-containing regimen
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the Investigational Product that may impact subject eligibility is provided in each specific product label.

Subject Withdrawal from Study
A subject must be withdrawn from the study when: A subject becomes Hepatitis B positive (+ HbsAg).
Subject requires the use of any prohibited study medication, unless explicit approval is given by the Sponsor in consultation with the Investigator (see Prohibited Medications, Section 5.7.2).
A subject is significantly non-compliant with the requirements of the protocol (based upon the discretion of the investigator).
A subject becomes pregnant (see Pregnancy, Section 6.4.8).
A subject has an adverse experience that would, in the investigator's judgment, make continued participation in the study an unacceptable risk.
Subject experiences a toxicity that meets the criteria for withdrawal (see Toxicity Management, Section 6.4.4) Subjects who become prisoners or become involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
Subject has a plasma HIV-1 RNA 2000 c/mL at the confirmatory virologic failure timepoint.
Subject has two consecutive HIV-1 RNA measurements 2000 c/mL at any time.
The Sponsor discontinues the study.
A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, withdraw the subject from participating in this study at any time.

Management of Withdrawn Subjects
If a subject is withdrawn from the study for any reason, the investigator must make every effort to perform the evaluations noted in the Time and Events table (see Section 6.1).
All data from the withdrawal visit should be recorded, as they comprise an essential evaluation that should be done prior to discharging any subject from the study.
If a subject is withdrawn from the study due to an AE (See Section 6.4.5.1) or serious adverse event (SAE) (See Section 6.4.5.2), the procedures stated in Section 6.4.5 (AEs and SAEs) must be followed and the AE must be followed-up until resolution.
Withdrawn subjects will not be replaced.

Investigational Product
The contents of the label will be in accordance with all applicable regulatory requirements.
Under normal conditions of handling and administration, Investigational Product is not expected to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from the Sponsor upon request.
Investigational Product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the Investigational Product will be limited to the investigator and authorized site staff. Investigational Product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.
TDF/FTC will be provided as a fixed dose combination tablet (Truvada) which contains 300 mg of TDF (as tenofovir disoproxil fumarate) and 200 mg of FTC. The tablets are film-coated, blue capsule-shaped and debossed with "GILEAD" on one side and with "701" on the other side. TDF/FTC is packaged in bottles of 30 with child-resistant closures.
ABC/3TC will be provided as a fixed dose combination tablet (EPZICOM ® ), which contains 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC. The tablets are film-coated, orange with a modified-capsule-shape and imprinted with GS FC2 and the other side plain. ABC/3TC is packaged in bottles of 30 with child-resistant closures.
ATV (Reyataz) will be provided as commercially available 200 mg and 300 mg oral capsules.

Permitted Alternative Regimens
The Sponsor will provide ATV, RTV, ABC/3TC, TDF/FTC, ZDV/3TC or FPV in the event an alternative regimen is required per protocol. For renal toxicity, reimbursement will be offered for appropriate treatment (e.g. non fixed-dose tablets). All antiretroviral agents in the alternative regimen should be administered and stored in accordance with the current approved product labeling.

Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization schedule. Subjects will be stratified by initial antiretroviral regimen received (ATV/RTV + TDF/FTC as initial regimen OR as first or second switch regimen) and randomized 2:1 to receive one of the following anti-retroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm B: (Continuation)
ATV/RTV 300 mg/100 mg once daily + TDF/FTC 300 mg/200 mg once daily If a subject is eligible for randomization, the investigator (or designee) will call RAMOS (Registration and Medication Ordering System) and the subject will be assigned a randomization number. The randomization code is on file with the Sponsor and with RAMOS.
Training on the use of RAMOS and detailed user worksheets will be provided by the Sponsor prior to study start.
Randomization numbers are unique and may not be reassigned to another study subject.

Blinding
There will be no blinding. This is an open-label study.

Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of Investigational Product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to the Sponsor, when applicable. Product accountability records must be maintained throughout the course of the study.
The Principal Investigator or authorized designee must sign for receipt and final disposition of all Investigational Products. To track Investigational Product receipt and return at the site level, signed and dated shipping and return forms must be maintained at the site. All Investigational Products will be handled and stored in accordance with the product label or information provided by the sponsor.
Within each subject's electronic case report form (eCRF), the name and total daily dose of each Investigational Product will be recorded. Start and stop dates of each Investigational Product must be recorded on this page. Date of resumption of original protocol dose and the date/reason for any permanent Investigational Product discontinuation will also be recorded.
Separate from the eCRF, sites will maintain a separate Investigational Product Accountability Log for each study drug to include the following: At the end of the study and at appropriate intervals during the study, all unused Investigational Product must be returned to the Sponsor according to procedures dictated by the study monitor or destroyed at the site and adequately documented. Monitors will regularly access pharmacy/dispensing records. Cases of suspected negligence will be investigated.

Permitted Medications and Non-Drug Therapies
Concomitant medications should be administered only as medically necessary during the study. Chemoprophylaxis for HIV-associated conditions is encouraged, if appropriate, at the discretion of the subject and his/her physician. All concomitant medications, blood products, and vaccines taken during the study will be recorded in the eCRF with dates of administration.
Hematological supportive therapy with Granulocyte Colony-Stimulating Factor (G-CSF) or erythropoietin will be permitted. Subjects being treated with G-CSF or erythropoietin at the time of Screening or Baseline will be allowed to participate in the study.
Because non-HIV vaccines may cause a temporary increase in the level of HIV-1 plasma RNA, it is recommended that a vaccine, if necessary, be given during or immediately after a scheduled visit after all laboratory tests have been drawn. This approach will minimize the risk of non-specific increases in the level of HIV-1 plasma RNA at the next scheduled assessment.
Subjects with confirmed virologic failure who are eligible to switch to an alternative antiretroviral regimen should administer medically necessary concomitant medications or non-drug therapies in accordance with recommendations from the current approved antiretroviral product label.

Prohibited Medications and Non-Drug Therapies
HIV immunotherapeutic vaccines are not permitted at any time during the study.
Other experimental agents, antiretroviral drugs, immunomodulators, cytotoxic chemotherapy, or radiation therapy may not be administered.
Refer to current prescribing information regarding medications that are prohibited for use with Investigational Products and substituted products contained in this study.

Treatment after the End of the Study
The Sponsor will not provide treatment after completion of the study.

Treatment of Investigational Product Overdose
An overdose is any dose greater than those described below for each study medication.
For the purposes of this study, an overdose is not an adverse event (AE, Section 6.4.5.1 unless it is accompanied by a clinical manifestation associated with the overdose. If the clinical manifestation presents with serious criteria, the event is a serious adverse event (SAE, Section 6.4.5.2).
If an overdose occurs and is associated with an adverse event requiring action, all study medications should be temporarily discontinued until the adverse event resolves. The investigator should use clinical judgement in treating overdose, as the Sponsor is unable to recommend specific treatment.

STUDY ASSESSMENTS AND PROCEDURES
Written informed consent must be obtained from each potentially eligible subject (or his/her legal representative) by study site personnel prior to the initiation of any Screening procedures as outlined in this protocol. The consent form must have been approved by the Institutional Review Board / Independent Ethics Committee (IRB/IEC). After signing an informed consent, subjects will complete Screening assessments to determine subject eligibility.
Each subject being screened for study enrollment evaluation will be assigned a subject number. This number will be given sequentially in chronological order of subject presentation according to a numeric roster provided by the Sponsor.
Subjects who qualify must return no more than 35 days from the day of the Screening visit to begin study treatment. Subjects not meeting all inclusion and exclusion criteria at initial screen may be re-screened once at the discretion of the investigator after consultation with the Sponsor. A subject, who is randomized into the trial and subsequently withdraws from the study for any reason, may not be re-screened.
A single repeat test per analyte is allowed during the Screening period. However, a repeat plasma HIV-1 RNA measurement is not allowed if the initial Screening value is >75 c/mL.
x a. W/D -Study withdrawal. Withdrawal evaluations performed if subject discontinues prematurely from the study. b. F/U -Study follow-up. Subjects will be contacted approximately 2-4 weeks after Week 48 or W/D by telephone for follow-up visit. If resolution of on-going AE(s) or confirmation of virologic failure is required the subject will return to the clinic for follow-up visit. c. Smoking history will be used to calculate Framingham cardiovascular risk score which includes assessment of age, gender, total cholesterol, HDL, SBP, BP lowering medication use and smoking use. d. Only SAEs related to study participation will be collected between obtaining written informed consent and administration of Investigational Products on Day 1. e. A confirmatory HIV-1 RNA should be scheduled at least 28 days after a plasma HIV-1 RNA 400 c/mL result for confirmation of virologic failure. f. Fasting is required (no food in previous 6-8 hours) except for the early W/D visit. g. Required for females of childbearing potential only. Serum pregnancy test to be performed at Screening, Week 48 and Early Withdrawl; Urine pregnancy test to be performed at Baseline. Pregnancy test may be performed at the discretion of the investigator if pregnancy is suspected at any time during the trial. h. PGx sample collection may be performed at any time starting at Baseline although it should be performed at the earliest time point possible. i. Confirmation of virologic failure. Subjects should be asked about potential compliance issues, illness or recent immunizations. It is recommended that subjects be adherent to study medications for at least 28 days before returning for a confirmatory HIV-1 RNA. j. A pre-baseline neurocognitive test is required to ensure that the subject is familiar with the testing modality. This test will be performed on the same day as the baseline test. k. This value can be recorded at any time during the study using the subject's medical history

Primary Endpoint
Proportion of subjects who maintain plasma HIV-1 RNA <50 c/mL at 24 weeks by time to loss of virologic response (TLOVR) algorithm

Secondary Efficacy Endpoints
Proportion of subjects with plasma HIV-1 RNA <50 c/mL at 48 weeks Proportion of subjects with plasma HIV-1 RNA <400 c/mL at 24 and 48 weeks Change from Baseline in HIV-1 RNA and CD4+ cell count Time to virologic failure Identification of genotypic and phenotypic resistance in virus from subjects with virologic failure

Efficacy Evaluations
Efficacy assessments will consist of the following investigations: Plasma for quantitative HIV-1 RNA will be collected at Baseline and Weeks 2,4,12,24,36,48, withdrawal (W/D) and, if necessary, follow-up visit.

Safety Evaluations
Safety assessments will consist of the following investigations: Clinical evaluations of adverse events will be made at Baseline and Weeks 2,4,12,24,36,48, W/D, when confirming virologic failure and at follow-up.
Vital signs (BP and HR) will be assessed at Baseline and Weeks 24, 48 and W/D.
Serum chemistry and hematology will be performed at Baseline and Weeks 2,4,12,24,36,48 and W/D. Evaluations may occur at the post-treatment follow-up if necessary for resolution of an ongoing laboratory adverse event.
Fasting lipid and fasting glucose evaluations will be made at Baseline and Weeks 4, 24, 48, and W/D.
HLA-B*5701 and Hepatitis C status will be assessed at Screening only.
Framingham cardiovascular risk assessment will be performed at Baseline and Weeks 24, 48 and W/D.

Clinical Laboratory Assessments
Hematology, clinical chemistry, urine chemistry analytes and additional parameters to be tested as per the time and events Changes from Baseline in various cardiovascular, bone, and renal biomarkers, which may or may not include markers such as high sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), D-dimer, serum procollagen type 1 N-propeptide (P1NP), serum bone specific alkaline phosphatase (BSAP), serum parathyroid hormone (PTH), serum c-telopeptide (CTx), osteocalcin, vitamin D 1,25-OH, and beta-2 microglobulin

Exploratory Evaluations
Exploratory assessments will consist of the following investigations: The pre-Baseline nadir CD4+ cell count will be collected. This may be collected at any time during the study.
Neurocognitive assessment via computerized questionnaire will be assessed at Baseline and Weeks 24, 48 and W/D.
A pre-baseline neurocognitive assessment is required to ensure that the subject is familiar with the testing modality. The pre-baseline assessment will be performed on the same day as the baseline assessment. The pre-baseline assessment data will not be collected.
Blood or urine samples for biomarker assessments will be collected at Baseline and Weeks 24, 48 and W/D.

General Toxicity Management
Adverse events that occur during the trial should be evaluated by the investigator and graded according to the modified Division of AIDS toxicity scales (see Appendix 3: DAIDS Division of Aids Table for Grading the Severity of Adult and Pediatric Adverse Events for laboratory test abnormalities and clinical toxicity).
The adverse event profiles for the combinations used in this study have not yet been fully defined. Trial medication may be interrupted at the discretion of the investigator and according to the severity of the adverse event. No dose reductions of any study medication will be allowed with the exception of declining creatinine clearance as indicated in product information.
Decisions regarding sequential reintroduction of study drugs or temporary interruption of one or more but not all drugs within the ART regimen should be made with the understanding that these changes may result in incomplete viral suppression and selection of resistant virus. Guidance is provided below on study medication interruptions based on the severity of the study medications-related adverse event. All changes in the Investigational Product regimen must be accurately recorded in the subject's eCRF.

Grade 1 or Grade 2 Toxicity/Adverse Event
Subjects who develop a Grade 1 or Grade 2 AE or toxicity may continue IP at the discretion of the investigator. (NOTEplease refer to Specific Toxicities for exceptions to this guideline in Section 6.4.4). Subjects who choose to withdraw from study due to a Grade 1 or 2 AE should have study withdrawal and follow-up evaluations completed.

Grade 3 Toxicity/Adverse Event
Subjects who develop a Grade 3 AE or toxicity should be managed as follows: 1. If the investigator has compelling evidence that the Grade 3 AE or toxicity has not been caused by IP, dosing may continue, after discussion with the Sponsor.
2. Subjects who develop a Grade 3 AE or toxicity, which the investigator considers related or possibly related to IP, should have all IP withheld and be rechecked each week until the adverse event returns to Grade 2. Once the AE is Grade 2, IP may be re-started at full dose at the discretion of the investigator. (Please refer to Section 6.4.4.5 for exception with hyperbilirubinemia and hypertriglyceridemia).

NOTE:
In the event of a discontinuation of ABC/3TC for any reason, re-initiation of this drug should be undertaken with caution. Health care providers should obtain a complete history of the events surrounding the discontinuation of ABC/3TC. If there are symptoms consistent with a hypersensitivity reaction, ABC should not be reinitiated, regardless of a subject's HLA-B*5701 status. If there is no evidence of a prior reaction, the subject may restart treatment with ABC/3TC. The subject and health care provider should be aware of the possibility of a rapid-onset hypersensitivity reaction upon re-initiation of ABC, which may be life-threatening, and the subject should be able to, if necessary, receive prompt medical evaluation (refer to Section 6.4.4.1).
3. Should the same Grade 3 AE recur within 28 days in the same subject, IP must be permanently discontinued and the subject withdrawn from study if the investigator considers the AE related to IP. If the AE recurs after 28 days, the above management scheme should be followed. Subjects experiencing Grade 3 AEs requiring permanent discontinuation of IP should be followed weekly until resolution of the AE and encouraged to have withdrawal study evaluations completed. A follow-up visit should be performed 2-4 weeks after the last dose of IP.
Subjects with Grade 3 asymptomatic laboratory abnormalities should be investigated for all potential non-drug related causes, and may continue therapy if the investigator has compelling evidence that the toxicity is not related to IP, following discussion with the Sponsor.

Grade 4 Toxicity/Adverse Event
Subjects who develop a Grade 4 AE or toxicity should have all IP permanently discontinued. However, if the investigator has compelling evidence that the AE is not causally related to the Investigational Product (s), dosing may continue after discussion with and assent from the Sponsor. Subjects experiencing Grade 4 AEs requiring permanent discontinuation of IP should be followed weekly until resolution of the AE and encouraged to complete the withdrawal study evaluation. A follow-up visit should be performed 2-4 weeks after the last dose of IP. (Please refer to Section 6.4.4.5 for exception with hyperbilirubinemia).
Subjects with Grade 4 asymptomatic laboratory abnormalities should be investigated for all potential non-drug related causes, and may continue therapy if the investigator has compelling evidence that the toxicity is not related to IP.
A follow-up visit should be performed 2-4 weeks after the last dose of IP if laboratory abnormalities are ongoing at the time of treatment completion.

Abacavir Hypersensitivity Reaction
All hypersensitivity reactions to abacavir will be considered and reported as SAEs regardless of severity (refer to Section 6.4.

Risk Factors for Abacavir Hypersensitivity Reaction
Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to ABC. In the prospective study CNA106030 (PREDICT-1), the use of such pre-therapy Screening for the HLA-B*5701 allele and subsequently avoiding ABC in HLA-B*5701 positive patients, reduced the incidence of clinically suspected ABC HSR from 7.8% (66 of 847) to 3.4% (27 of 803) (p<0.0001). Based on this study, it is estimated that 48% to 61% of patients with the HLA-B*5701 allele will develop a hypersensitivity reaction during the course of abacavir treatment compared with 0% to 4% of patients who do not have the HLA-B*5701 allele . While the PREDICT-1 study population was predominantly white, the association between HLA-B*5701 and ABC HSR appears to be generalisable across racial groups [Saag, 2008;Sun, 2007].
In any patient treated with ABC, the clinical diagnosis of suspected HSR must remain the basis of clinical decision making. Even in the absence of the HLA-B*5701 allele, it is important to permanently discontinue ABC and not rechallenge with ABC (i.e., ZIAGEN ® , TRIZIVIR, EPZICOM ® or KIVEXA ® ) if a HSR cannot be ruled out on clinical grounds, due to the potential for a severe or even fatal reaction.

Clinical Description of the Hypersensitivity Reaction
The abacavir hypersensitivity reaction is characterised by the appearance of symptoms indicating multi-organ involvement. The majority of patients have fever and/or rash as part of the syndrome; however reactions have occurred without rash or fever.
Symptoms can occur at any time during treatment with abacavir, but usually appear within the first six weeks of initiation of treatment (median time to onset 11 days). The symptoms worsen with continued therapy and can be life threatening. These symptoms usually resolve shortly after discontinuation of abacavir.
Frequently observed signs and symptoms include fever, rash, malaise or fatigue, gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain and respiratory symptoms such as dyspnea, sore throat, or cough. Other signs and symptoms include myalgia, arthralgia, oedema, pharyngitis, headache, paresthesia or myolysis.
Abnormal chest x-ray findings may also be present (predominantly infiltrates, which can be localised).
Laboratory abnormalities may include elevated liver function tests (such as hepatic transaminases), increased creatine phosphokinase or creatinine levels, and lymphopenia.
Anaphylaxis, hypotension, liver failure, renal failure, adult respiratory distress syndrome or respiratory failure may occur.
Some patients with hypersensitivity were initially thought to have respiratory disease (pneumonia, bronchitis, pharyngitis), a flu-like illness, gastroenteritis or reactions to other medications. This delay in diagnosis of hypersensitivity has resulted in abacavir being continued or re-introduced, leading to a more severe hypersensitivity reaction or death. Therefore, the diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of these diseases.
Restarting any abacavir-containing product following hypersensitivity reaction results in a prompt return of symptoms within hours. This recurrence of the hypersensitivity reaction may be more severe than on initial presentation, and may include lifethreatening hypotension and death.

Clinical Management of Hypersensitivity Reactions
Patients developing signs or symptoms of hypersensitivity MUST contact their doctor immediately for advice.
If a hypersensitivity reaction is diagnosed, the abacavir-containing product MUST be discontinued immediately, regardless of a subject's HLA-B*5701 status. The patient should be asked to return all unused supplies of the abacavir-containing product for disposal to prevent an accidental re-challenge.

An abacavir containing medicinal product (ZIAGEN , TRIZIVIR , EPZICOM ® or KIVEXA), MUST NEVER be administered following a hypersensitivity reaction, as more severe symptoms will recur within hours and may include life-threatening hypotension and death.
To avoid a delay in diagnosis and minimize the risk of a life-threatening hypersensitivity reaction, the abacavir-containing product should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible (respiratory diseases, flu-like illness, gastroenteritis or reactions to other medications) and regardless of a subject's HLA-B*5701 status.
Symptomatic support for abacavir hypersensitivity may be indicated. This should include, for example, administration of intravenous fluids to patients who develop hypotension. Antihistamines or corticosteroids have been used in cases of abacavir hypersensitivity, however there are no clinical data demonstrating the benefit of these in the management of the reaction.
Laboratory and other investigations which may be useful in the evaluation and treatment of abacavir hypersensitivity include, but may not be limited to, measurement of ALT, AST, creatine phosphokinase, serum creatinine and white blood cell differential count and chest x-ray, if respiratory symptoms are present.

Special considerations following an interruption of abacavir therapy
If therapy with abacavir has been discontinued and restarting therapy is under consideration, the reason for discontinuation should be evaluated to ensure that the patient did not have symptoms of a hypersensitivity reaction, regardless of a subject's HLA-B*5701 status. If hypersensitivity reaction cannot be ruled out, no medicinal product containing abacavir (ZIAGEN , TRIZIVIR , EPZICOM ® or KIVEXA) should be restarted.
There have been infrequent reports of hypersensitivity reaction following reintroduction of an abacavir-containing product where the interruption was preceded by a single key symptom of hypersensitivity (rash, fever, malaise/fatigue, gastrointestinal symptoms or a respiratory symptom). If a decision is made to restart any abacavir-containing product in these patients, this should be done only under direct medical supervision.
On very rare occasions hypersensitivity reactions have been reported in patients who have re-started therapy, and who had no preceding symptoms of a hypersensitivity reaction. If a decision is made to re-start an abacavir-containing product, this must be done only if medical care can be accessed readily by the patient or others.

With reference to this protocol section and the 'Subject Information and Consent Form' investigators must ensure that patients are fully informed regarding the following information on the hypersensitivity reaction:
Patients must be made aware of the possibility of a hypersensitivity reaction to abacavir that may result in a life threatening reaction or death.
Patients must be made aware that not all people who experience ABC HSR will be HLA-B*5701 positive. Therefore, patients who are HLA-B*5701 negative and who develop signs or symptoms consistent with a possible HSR to ABC MUST STILL CONTACT their doctor IMMEDIATELY.
Patients who are hypersensitive to abacavir should be reminded that they must never take any abacavir containing medicinal product (ZIAGEN , TRIZIVIR , EPZICOM ® or KIVEXA) again, regardless of their HLA-B*5701 status.
In order to avoid restarting the abacavir-containing product, patients who have experienced a hypersensitivity reaction should be asked to return the remaining tablets or oral solution to the pharmacy.
Patients who have stopped an abacavir-containing product for any reason, and particularly due to possible adverse reactions or illness, must be advised to contact their doctor before restarting.
Each patient should be reminded to read the Package Leaflet included in the pack.
Patients should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.

Reporting of Hypersensitivity Reactions
All cases of potential abacavir hypersensitivity should be reported as Serious Adverse Events (SAE) (see Section 6.4.5.2). In addition to reporting the case as an SAE, the site should immediately notify the Sponsor and within one week of the onset of the hypersensitivity reaction, complete the Abacavir Hypersensitivity Reaction (HSR) eCRF.

Therapy Management for Abacavir Hypersensitivity Reaction
Subjects who experience a suspected abacavir hypersensitivity reaction (ABC HSR) must discontinue abacavir and may chose from one of the following two options to remain on study: Substitute zidovudine/lamivudine (ZDV/3TC) for ABC/3TC. ZDV/3TC will be provided by the Sponsor.
Substitute TDF/FTC for ABC/3TC and change back to original regimen of ATV/RTV + TDF/FTC. TDF/FTC and ATV/RTV will be provided by the Sponsor.
Abacavir substitution is only allowed for ABC hypersensitivity reactions. No NNRTI or PI substitutions are allowed. Any change MUST be discussed with THE SPONSOR PRIOR TO THE CHANGE BEING MADE.

Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme
Serious skin reactions such as Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme have been reported very rarely in patients taking abacavircontaining products. These patients generally do not have the cluster of additional symptoms (e.g., gastrointestinal and respiratory) that characterize the abacavir hypersensitivity reaction, but they do have features typical of these serious skin reactions.
If a serious skin reaction develops, the abacavir-containing product should be discontinued, and the patient should not be rechallenged with any abacavir-containing medicinal product (ZIAGEN , TRIZIVIR , EPZICOM ® or KIVEXA).
As many products other than abacavir also cause these serious skin reactions, all other medicinal products that the patient is receiving should also be reviewed and discontinued as appropriate.

Rash Not Accompanied by Systemic Symptoms
Subjects receiving ABC who develop rash of any grade should be evaluated for the possibility of an HSR to abacavir or a serious skin reaction such as Stevens Johnson Syndrome, Toxic Epidermal Necrolysis or Erythema Multiforme and managed appropriately as outlined above. Rash may be caused by therapies in any of the major antiretroviral classes, or by other therapies commonly used as concurrent medications, such as cotrimoxazole. As it is not possible to provide an exhaustive list of products that may cause rash in this protocol, please consult the product information leaflets for other products for information relating to rash.
The following guidance is provided for clinical management of subjects who experience rash alone in the absence of accompanying diagnosis of ABC hypersensitivity, systemic or allergic symptoms or signs of mucosal or target lesions. The toxicity ratings must be used to appropriately grade cutaneous events when recording adverse events.
Study treatment should be managed as outlined in the following table.

Event
Action with Study Drug ATV + RTV ATV Grade 1 or 2 rash alone Therapy can continue Therapy can continue Grade 1 or 2 rash with symptoms indicating multi-organ involvement a Discontinue all Investigational Products and assess further. Therapy with ATV + RTV should not be reinitiated unless the investigator has compelling evidence that the rash is not caused by ATV + RTV Discontinue all Investigational Products and assess further. Therapy with ATV should not be reinitiated unless the investigator has compelling evidence that the rash is not caused by ATV Grade 3/4 rash alone or with symptoms indicating multi-organ involvement a Discontinue all Investigational Products and assess further (see below).
Discontinue all Investigational Products and assess further (see below). a Symptoms include: systemic symptoms (fever, GI symptoms including nausea, vomiting, diarrhea or abdominal pain) or allergic symptoms, or mucosal involvement, or severe tiredness, achiness or generally ill feeling.
Adjunctive treatment: For Grade 1 or 2 rash, antihistamines or topical corticosteroids may be prescribed. Systemic corticosteroids are not recommended for Grade 1 or 2 rash, as steroid therapy may mask the appearance of other symptoms leading to more serious systemic involvement.
Subjects who develop a Grade 3 (vesiculation, or moist desquamation, or ulceration) or 4 rash (exfoliation, mucosal involvement, or target lesions [erythema multiform]) or any evidence of Stevens-Johnson Syndrome should have all study drugs discontinued and assessed appropriately. If Grade 3 or 4 rash is accompanied by systemic symptoms, ATV and/or RTV should be permanently discontinued. Steroids may be used for treatment of the event.
Subjects should be evaluated and followed aggressively for one week or until symptoms resolve or change, even though study medications have been discontinued.
Refer to local EPZICOM ® , ATV and RTV prescribing information for complete information regarding management of rash.
The rash and any associated symptoms should be reported as adverse events (see Section 6.4.5.1) and appropriate toxicity ratings should be used to grade the events (See Appendix 2: DAIDS Toxicity Grading Scale).
If the aetiology of the rash can be definitively diagnosed as being due to a specific medical event or a concomitant medicinal product, routine management should be performed and documentation of the diagnosis provided.

Nausea and Vomiting
Although common, nausea following initiation of therapy with antiretroviral medications usually subsides or resolves during the first few weeks of treatment. Upper gastrointestinal adverse events may be reduced by taking medications with a meal, and by maintaining a steady oral intake, e.g., pretzels or other dry bread. Subjects who experience potentially treatment limiting nausea or vomiting should be treated with antiemetics. No dose reduction or escalation of Investigational Products will be allowed.

Diarrhea
Subjects with Grade 1 diarrhea may be treated as needed with oral antidiarrheal agents.

Hyperbilirubinemia
Any elevation in indirect bilirubin does not constitute a safety concern unless accompanied by >35% increase in direct bilirubin.
For isolated Grade 3 unconjugated hyperbilirubinemia attributed to ATV, ATV should be continued unless associated with jaundice or scleral icterus that presents an intolerable cosmetic concern to the subject.
For isolated Grade 3 unconjugated hyperbilirubinemia that cannot be attributed to ATV or a non-study drug-related cause, all study medications should be held pending evaluation of aetiology.
A grade 2 elevation in total bilirubin ( 2 x ULN with >35% direct bilirubin) and grade 2 elevation in ALT ( 3 x ULN) is a SAE suggestive of significant liver toxicity which meets the criteria for Hy's Law and requires rapid evaluation and notification to the Sponsor within 24 hours. If this should occur, subject should immediately stop the Investigational Product(s), have their liver chemistries repeated, be closely monitored, and referred to a Hepatology specialist for further evaluation. Any subject meeting the above criteria should not be retreated or rechallenged with the Investigational Product(s).

Hypertriglyceridemia/Hypercholesterolemia
Please see the Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group [Dubé, 2003] for full discussion of management of hyperlipidemia in the context of HIV therapy.

Anemia/Neutropenia
Transfusions and erythropoietin may be used to manage anemia. Neutropenia may be managed with G-CSF or GM-CSF, at the discretion of the investigator.

Lactic Acidosis/Severe Hepatomegaly with Steatosis
The relevance of asymptomatic lactic acid elevations is unclear, and lactates are not part of the routine safety evaluations or monitoring for this study. Should an investigator suspect the occurrence of lactic acidosis in any subject, THE SPONSOR SHOULD BE CONSULTED. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination in the treatment of HIV infection. A majority of these cases have been in women. This syndrome is felt to be secondary to mitochondrial toxicity induced by the inhibitory effect of N(t)RTIs on DNA polymerase gamma, a key enzyme needed for mitochondrial DNA synthesis. Current knowledge regarding this syndrome is incomplete. Obesity and prolonged N(t)RTI exposure may be risk factors. Symptoms of lactic acidosis frequently involve non-specific symptoms such as fatigue, weakness, and fever, but in the majority of cases also involve symptoms suggestive of hepatic dysfunction such as nausea, vomiting, abdominal or epigastric discomfort, abdominal distension, hepatomegaly, and new onset elevated liver enzymes. Caution should be exercised when administering EPZICOM ® , Truvada or COMBIVIR to any subject and particularly to those with known risk factors for liver disease. Treatment with EPZICOM ® , Truvada or COMBIVIR should be suspended in any subject who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity and THE SPONSOR SHOULD BE CONSULTED.

Pancreatitis
Cases of pancreatitis have occurred rarely in subjects treated with ABC, 3TC, TDF and ZDV. However it is not clear whether these cases were due to the medicinal products or to the underlying HIV disease. Treatment with EPZICOM ® , Truvada or COMBIVIR should be stopped immediately if clinical signs, symptoms or laboratory abnormalities suggestive of pancreatitis occur.

Creatine Phosphokinase (CPK) Elevation
A Grade 3 or higher elevation in CPK should result in a repeat assessment within 2-4 weeks to ensure the result is transient or due to exercise and will not require a change in study treatment. A history regarding physical activity or exercise preceding the CPK evaluation should be obtained. Grade 4 elevations in CPK should have a repeat assessment after the subject has abstained from exercise for >24 hours. For persistent Grade 4 CPK elevations that are considered possibly or probably related to the IP, IP should be discontinued and the subject withdrawn from the study.

Nephrotoxicity
In addition to the Division of AIDS toxicity grading scale for serum creatinine, the National Kidney Foundation criteria for staging chronic kidney disease should be used to grade renal toxicity [National Kidney Foundation, 2002].

Decline in Renal Function
The Cockroft-Gault equation for estimating creatinine clearance (CrCl) will be used to determine changes in dosing for both TDF/FTC and ABC/3TC in the event of declining renal function.
For subjects who experience progression to an estimated CrCl (calculated by Cockroft-Gault equation) to <50 mL/min judged by the investigator to be attributed to study medication, the offending agent(s) must be discontinued. No dose-reduction of the offending agent(s) will be allowed.
For subjects who experience progression to an estimated CrCl (calculated by Cockroft-Gault equation) to <50 mL/min to be NOT study drug-related, the investigator will choose from one of the following two management options for study medications: 1. Discontinue study medication(s) and switch to another agent in the same class and remain on study.
2. Dose reduce study medication (s) as indicated in prescribing information and remain on study.
*Note: The Sponsor will provide ATV, RTV, ABC/3TC, TDF/FTC, 3TC/ZDV or FPV for the purpose of constructing an alternative treatment regimen for decline in renal function. Reimbursement will be offered for the cost associated with use of any agent not provided by the Sponsor.

Proximal Renal Tubule Dysfunction
Proximal Renal Tubule Dysfunction (PRTD) is defined as: Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum phosphorus <2.0 mg/dL Either of the above accompanied by any two of the following: Low serum potassium (<3 mEq/L) Low serum bicarbonate (<19 mEq/L) Quantification of urine protein and urine glucose will not be routinely performed at each visit, therefore PRTD will be evaluated based upon investigators clinical judgment and assessment of initial chemistry findings to determine if further work-up is required for PRTD. If PRTD is suspected, the investigator should consult the Sponsor and conduct follow-up investigations per clinical practice.
Subjects meeting criteria for PRTD must return for a confirmatory assessment within 4 weeks. If PRTD is confirmed, subject must discontinue study.
PRTD is considered resolved when serum creatinine is 0.3 mg/dL above Baseline, serum phosphorus is 2.5 mg/dL, and serum bicarbonate is 19 mEq/L [Fisher, 2001].

Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include: Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition New conditions detected or diagnosed after Investigational Product administration even though it may have been present prior to the start of the study Signs, symptoms, or the clinical sequelae of a suspected interaction Signs, symptoms, or the clinical sequelae of a suspected overdose of either Investigational Product or a concomitant medication (overdose per se will not be reported as an AE/SAE).
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE.
Events that do not meet the definition of an AE include: Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital) Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject's condition

Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose: h. All clinically suspected cases of ABC HSR in subjects receiving an ABC-containing product

Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from Baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject's condition, are not to be reported as AEs or SAEs.

Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs
The events or outcomes listed in the CDC Classification System for HIV-1 Infections (Appendix 3: CDC Classification System for HIV-1 Infections (1993) will be recorded on the HIV-Associated Conditions electronic case report form (eCRF) page if they occur. However, these individual events or outcomes, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these events or outcomes are not reported to the Sponsor as AEs and SAEs even though such event or outcome may meet the definition of an AE or SAE, unless the following conditions apply: the Investigator determines that the event or outcome qualifies as an SAE under part 'f' of the SAE definition (see Section 6.4.5.2 "Definition of a SAE"), or the event or outcome is in the Investigator's opinion of greater intensity, frequency or duration than expected for the individual subject, or death occurring for any reason during a study, including death due to a diseaserelated event, will always be reported promptly.
Lymphomas and invasive cervical carcinomas are excluded from this exemption; they must be reported as SAEs even if they are considered to be HIV related.

Pregnancy Testing
Women of childbearing potential must have a negative pregnancy test at Screening and Day 1 to be eligible for administration of IP. Pregnancy testing will also be conducted as per the Time and Events Table (See Section 6.1) and at anytime during the trial when pregnancy is suspected.

Action to be Taken if Pregnancy Occurs
Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to the Sponsor within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator's attention after the subject has completed the study and considered by the investigator as possibly related to the Investigational Product, must be promptly reported to the Sponsor.
The Sponsor's central safety department will also forward this information to the Antiretroviral Pregnancy Registry. The international registry is jointly sponsored by manufacturers or licensees of antiretroviral products. Additional information and a list of participating manufacturers/licensees are available from http://apregistry.com/index.htm.

Time Period for Collecting Pregnancy Information
Information on the occurrence of pregnancies in female subjects will be collected over the period starting at Screening and ending at the final follow-up visit. Only those pregnancies that occur following the first dose of IP will be reported to the Sponsor.
Follow-up information will only be collected for pregnancies occurring from Day 1 to the final follow-up visit.
In addition, the investigator must attempt to collect pregnancy information on any female partners of male study subjects who become pregnant while the subject is enrolled in the study. Pregnancy information must be reported to the Sponsor as described above.

Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.
AEs will be collected from the start of Investigational Product and until the follow up contact.
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., Investigational Product, protocolmandated procedures, invasive tests, or change in existing therapy) or related to a Sponsor concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to the Sponsor within 24 hours, as indicated in Section 6.4.10.

Prompt Reporting of Serious Adverse Events and Other Events
SAEs, pregnancies and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to the Sponsor as described in the following table once the investigator determines that the event meets the protocol definition for that event. Prompt notification of SAEs by the investigator to the Sponsor is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

Initial Reports
The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. The Sponsor will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and sponsor policy and are forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from the Sponsor will file it with the package insert and will notify the IRB/IEC, if appropriate according to local requirements.

Exploratory Biomarker Assessments
Blood and urine will be collected to perform various cardiovascular, bone and renal biomarker assessments at Baseline, Weeks 24, 48 and W/D. The assessments may or may not include markers such as high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), D-dimer, serum procollagen type 1 N-propeptide (P1NP), serum bone specific alkaline phosphatase (BSAP), serum parathyroid hormone (PTH), serum c-telopeptide (CTx), osteocalcin, vitamin D 1,25-OH, and beta-2 microglobulin. It is not anticipated that the Sponsor will provide the results of these assessments to the investigator.

Viral Genotyping and Phenotyping
Plasma samples will be prepared for storage at all study visits except Screening. Subjects experiencing virologic failure will also have samples drawn at the time the confirmatory sample is drawn for potential further analysis of the evolution of drug resistanceassociated mutation selection. Confirmed virologic failures will be genotyped and phenotyped using plasma samples collected at the point of first failure detection. The point of failure genotype and phenotype results will be provided to the relevant investigator on a per-subject basis when available. Additional analyses may be performed on these stored samples to better understand what factors can influence therapy response, such as clonal analysis of samples from subjects meeting virologic failure criteria.

HLA-B*5701 Determination
At the Screening visit, a 10 mL blood sample will be collected for HLA-B*5701 determination using deoxyribonucleic acid (DNA)-based methods by a suitably accredited clinical laboratory. All subjects must provide a blood sample for HLA-B*5701 determination, as subjects who are HLA-B*5701 positive may not participate in the study. HLA-B*5701 results will be provided to study sites to determine subject eligibility for the study. As HLA-B*5701 status has potential clinical implications, subjects will be provided with their HLA-B*5701 results.
A second 10 mL blood sample will be collected for potential pharmacogenetics research aimed at understanding variation in subject response to the antiretroviral therapies included in this study. Information regarding pharmacogenetic research is included in Appendix 4: Pharmacogenetics. The IEC/IRB and, where required, the applicable regulatory agency must approve the PGx assessments before these can be conducted at the site. The approval(s) must be in writing and will clearly specify approval of the PGx assessments (see Appendix 4: Pharmacogenetics). In some cases, approval of the PGx assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the PGx assessments is being deferred and the study, except for PGx assessments, can be initiated. When PGx assessments will not be approved, then the approval for the rest of the study will clearly indicate this and therefore, PGx assessments will not be conducted.

DATA MANAGEMENT
For this study subject data will be entered into electronic case report forms (eCRFs), transmitted electronically to the Sponsor and combined with data provided from other sources in a validated data system.
Management of clinical data will be performed in accordance with applicable Sponsor standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using the Medical Dictionary for Drug Regulatory Affairs (MedDRA) and an internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit trails) will be retained by the Sponsor, and copies will be sent to the investigator to maintain as the investigator copy. In all cases, subject initials will not be collected or transmitted to the Sponsor according to Sponsor policy.

Hypotheses
The primary hypothesis of interest is that treatment with ABC/3TC + ATV is not inferior to treatment with TDF/FTC + ATV/RTV in the proportion of subjects with plasma HIV-1 RNA <50 c/mL over 24 weeks in a population of virologically suppressed HIV-1 infected subjects.
The null hypothesis is that ABC/3TC + ATV arm is inferior to TDF/FTC + ATV/RTV arm in proportion of subjects with HIV-1 RNA <50 c/mL at Week 24. This null hypothesis is to be tested against the alternative that ABC/3TC + ATV is at least as good as (i.e., not inferior to) TDF/FTC + ATV/RTV in proportion of subjects with HIV-1 RNA <50 c/mL at Week 24. With a non-inferiority margin of 0.12, the null and alternative hypothesis can be written statistically as Ho: p 1p 2 -0.12, Ha: p 1p 2 > -0.12; where p 1, p 2 are the proportions of subjects with HIV-1 RNA <50 c/mL at Week 24 in ABC/3TC + ATV and TDF/FTC + ATV/RTV, respectively.

Study Design Considerations
This is a phase IV, randomized, open-label, multi-center study evaluating the efficacy, safety, and tolerability of the antiviral response between ATV + ABC/3TC and ATV/RTV + TDF/FTC for 48 weeks in HIV-1 infected, HLA-B*5701 negative subjects who were previously suppressed on ATV/RTV + TDF/FTC.

Sample Size Assumptions
A sample size of 300 subjects with a 2:1 randomization ratio in ABC/3TC + ATV to TDF/FTC + ATV/RTV will provide 90% power (one-sided, α=0.025) to establish noninferiority via a 95% confidence interval for the difference in proportions of subjects with HIV-1 RNA <50 c/mL at Week 24. This sample size calculation assumes a virologic response rate (proportions of subjects with HIV-1 RNA < 50 c/mL) of 89% in both treatment arms and a non-inferiority margin of 0.12.

Sample Size Sensitivity
The power of the study is affected by the assumptions of the proportion of virologic response in each treatment arm, type-I error, one or two sided test, and the non-inferiority margin. The non-inferiority margin has been set at 0.12 for the difference between treatment arms, and type-I error has been set at α=0.05, two sided (one sided α=0.025).
The choice of delta margin of 0.12 in comparing response rate is consistent with previous non-inferiority studies including studies to support regulatory submissions. Table 2 shows the sensitivity of the power change in the response rate assumptions with a total sample size of 300 subjects (200 in EPZICOM and 100 in Truvuda) using a noninferiority margin of 0.12, 1-sided alpha of 0.025.  Table 3 shows the sensitivity of the sample size change with varying response rates in order to achieve 90% based on a non-inferiority margin of 0.12 and 1-sided alpha of 0.025.

Sample Size Re-estimation
No sample size re-estimation is planned for this study.

Analysis Populations
Intent-to-treat (ITT) population The ITT population will consist of all enrolled subjects who are randomized in the study, regardless of what treatment is actually received or the eventual outcome of study participation. A modified ITT population, ITT-Exposed, that consists only of subjects who are in the ITT population and receive at least one dose of study drug, will be the primary population for efficacy analyses. If more than 5% of randomized subjects do not receive treatment, then additional sensitivity analyses may be carried out with the ITT population defining subjects who withdraw without receiving treatment as failures.

Safety Population
The safety population will consist of all randomized subjects with the exception of those with documented evidence of not having consumed any Investigational Product.

Virologic Failure Population
The virologic failure population will consist of all subjects who met the protocol defined virologic failure criteria.

Subpopulations
Sub-populations may be created as subsets of the ITT population for use in supporting safety or efficacy analyses. Sub-populations of interest may include (but are not limited to) per protocol population, Baseline HIV-1 RNA strata, Baseline CD4+ category, demographic category, age and ethnic origin categories or genotypic subgroups.

Analysis Data Sets
Observed Dataset The observed dataset contains all data collected while subjects are in the study. No missing values are imputed.

Primary Comparisons of Interest
For all study objectives, the primary comparison of interest will be between the two treatment arms: ABC/3TC + ATV and TDF/FTC + ATV/RTV. The treatment comparisons will be made at designated timepoints as specified in the defined endpoints.
For the primary efficacy endpoint, a two-sided 95% confidence interval (CI) approach will be used to test for non-inferiority between the two treatment arms as described further in the Primary Analysis Section 8.3.5.1.section below.

Interim Analysis
There are two planned analyses in this study: an interim analysis at Week 24 and a final analysis at Week 48. The Week 24 analysis is considered the primary analysis to establish non-inferiority.

Efficacy Analyses
All efficacy analysis will be performed based on the ITT-Exposed population.

Primary Analysis
The primary efficacy objective of the study is to establish the non-inferiority of the EPZICOM arm to the Truvada arm in proportion of subjects with plasma HIV-1 RNA <50 c/mL at Week 24.
Statistical hypothesis testing on the difference in the proportion of subjects with HIV-1 RNA <50 c/mL at Week 24 between the two treatment arms being -0.12 or less versus the alternative that the difference is > -0.12 will be performed at a one-sided 0.025 significance level. This is equivalent to constructing a two-sided 95% confidence interval on the difference in proportions and comparing the lower bound of the 95% CI to -0.12. The null hypothesis will be rejected and hence the non-inferiority will be established if the lower limit of the confidence interval for the difference (EPZICOM arm minus Truvada) in proportion of subjects with HIV-1 RNA <50 c/mL at Week 24 is > -0.12. However, if the lower limit of the 95% CI is ≤ -0.12, it cannot be ruled out that the EPZICOM arm is inferior to the Truvada arm. The Cochran-Mantel-Haenszel (CMH) test will be used in the analysis. Odds ratios, confidence intervals, and p-values will be computed: (1) stratifying by initial antiretroviral regimen received (ATV/RTV + TDF/FTC as initial regimen or ATV/RTV + TDF/FTC as first or second switch regimen), (2) stratifying by center, and (3) without stratification.

Secondary Analysis
The proportion of subjects with plasma HIV-1 RNA <400 c/mL and <50 c/mL will be calculated and summarized at each assessment week. TLOVR, Observed and M=F rates will be computed by treatment arm. The rates will be compared between treatment arms using the CMH test stratified by initial antiretroviral regimen received at the planned analysis timepoints.
Summary statistics for the measured values and change from Baseline in HIV-1 RNA will also be tabulated at each assessment week by treatment arm.
The immunologic response will be assessed with summary statistics for CD4+ and CD8+ cell count measured value and change from Baseline at each assessment week by treatment arm. These parameters may be compared between treatment arms using the Wilcoxon sum-rank test as exploratory analyses.
Time to loss of virologic response (TLOVR) will be analyzed using the Kaplan-Meier non-parametric method and plotted by treatment groups.

TLOVR algorithm:
For 1 and 2 below, all visits with no data will be discarded. In what follows, a visit means a visit with an observed viral load. Viral load data from all available visits, including offschedule visits will be included in the calculation.
If a subject has never achieved confirmed HIV-1 RNA levels <400 (50) c/mL (on two consecutive visits) before the following events, then this subject will be considered to have failed at time 0: Death Permanent discontinuation of study, study medication or any modifications of the regimen for any reason other than ABC HSR.
By the planned analysis week (Week 24 or 48).
For all subjects who had confirmed HIV-1 RNA levels <400 (50) c/mL, on two consecutive visits, the time of failure is the earliest time when any of the following specific event have occurred:

Death
Permanent discontinuation of study, study medication or any modifications of regimen for any reason other than ABC HSR Confirmed HIV-1 RNA levels 400 (50) c/mL (time to the first confirmed HIV-1 RNA 400 (50) c/mL) or HIV-1 RNA levels 400 (50) c/mL at one visit followed by loss to follow-up (including any discontinuation or just last visit) If the time of failure as defined above is immediately preceded by a single missing scheduled visit or multiple consecutive missing scheduled visits, then the time of failure is replaced by the first time of such missing visits.
Subjects who complete the planned analysis weeks (24, 48) of the study without experiencing a loss of virologic response will be right censored at that point.

Safety Analyses
All safety analyses will be based on the safety population.

Extent of Exposure
Extent of exposure will be summarized according to the cumulative number of days a subject was taking each Investigational Product and the maximum time the subject spent on any Investigational Product (i.e., the difference from the first day on any investigation product until the last day on any Investigational Product). Summary statistics for the extent of exposure to each specific Investigational Product will be provided.

Adverse Events
Adverse event data will be coded using the MedDRA coding dictionary and the resulting terms will be categorized by system organ class. A listing showing the relationship of AE, system organ class, group preferred terms and verbatim text will be presented. Adverse events (with onset on or after the first dose of Investigational Product or with onset before the first dose of Investigational Product but worsens during the study) will be tabulated by treatment arm for: All Grade 2-4 adverse events.
Treatment-related adverse events.
Adverse events leading to premature discontinuation from the study.

Serious adverse events.
Additionally, AEs will be tabulated by maximum intensity and action taken with respect to Investigational Product. The number and percent of subjects experiencing a treatment-limiting adverse event will also be presented by treatment arm.
A listing of deaths and SAEs that occur during the study will be generated. A listing of subjects who experience HSR will also be generated.
Exploratory statistical analyses of the AE data may be performed, as deemed appropriate. These analyses will be detailed in the reporting and analysis plan (RAP) for the study.

Clinical Laboratory Evaluations
Blood chemistry, haematology, and urine analytes will be summarized by treatment arm after conversion to standard units (as necessary). The laboratory data will be summarized as follows: Descriptive summary statistics will be presented by treatment arm and week for each laboratory parameter and change from Baseline.
Summary of toxicity shifts from Baseline: the maximum post-Baseline toxicity grade will be tabulated (count and percent) against the Baseline toxicity grade for each laboratory parameter by treatment arm.
Listing of laboratory data for subjects with at least one laboratory toxicity of Grade 3 or Grade 4 will be displayed by laboratory parameter, treatment arm, subject, and week.
Baseline is defined as the last pre-treatment value collected. Subjects must have both a Baseline and on-treatment measurement to be included in the change from Baseline analysis.

Viral Genotyping/Phenotyping Analyses
For the virologic failure population, only samples from subjects who meet the criteria for virologic failure and have genotypic or phenotypic resistance data will be included. As the absolute number of virologic failures is likely to be small, the statistical analyses will be mainly descriptive. Genotypic and phenotypic resistance data will be summarized by treatment arm at the time of virologic failure. Summaries of genotypic data will be based mainly on the mutations provided in the IAS USA Resistance Tables (based on the most current version). Correlation between phenotypic resistance, genotypic mutations, and HIV-1 RNA responses may be explored.

Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before subject enrolment begins.

Regulatory and Ethical Considerations, Including the Informed Consent Process
Prior to initiation of a study site, the Sponsor will obtain approval from the appropriate regulatory agency to conduct the study in accordance with applicable country-specific regulatory requirements, including those required under an US Investigational New Drug (IND).
The study will be conducted in accordance with all applicable regulatory requirements, [including an US IND].
The study will be conducted in accordance with Good Clinical Practice (GCP), all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to: Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and approval of study protocol and any subsequent amendments.

Subject informed consent.
Investigator reporting requirements.
The Sponsor will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the study.

Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and Sponsor procedures, monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Sponsor requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the eCRF will serve as the source document.
The Sponsor will monitor the study to ensure that the: Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.

Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor may conduct a quality assurance audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study.
In the event of an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss any findings/relevant issues.

Study and Site Closure
Upon completion or termination of the study, the monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and Sponsor Standard Operating Procedures.
The Sponsor reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe noncompliance. If the Sponsor determines that such action is required, the Sponsor will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, the Sponsor will provide advance notice to the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, the Sponsor will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. The Sponsor will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.

Records Retention
Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a Sponsor audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.
The Sponsor will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, Sponsor standard operating procedures, and/or institutional requirements.
The investigator must notify the Sponsor of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

Provision of Study Results to Investigators, Posting to the Clinical Trials Register and Publication
Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a Sponsor site or other mutuallyagreeable location.
The Sponsor will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.
The Sponsor will provide the investigator with the randomization codes for their site only after completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than 12 months after the last subject's last visit (LSLV) or sooner if required by legal agreement, local law or regulation. In addition, a manuscript will be submitted to a peer-reviewed journal for publication within 18 months of LSLV. When manuscript publication in a peer-reviewed journal is not feasible, further study information will be posted to the Sponsor's Clinical Study Register to supplement the results summary.
A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

Clinical Categories
The clinical categories of HIV infection are defined as follows:

Appendix 2: CogState
Research concerning cognition is still in its infancy. As we discover more about the subject, cognitive testing plays an increasingly important role -especially in clinical trials.
CogState ClinicalTrials tasks provide rapid, sensitive and valid measurement of distinct cognitive functions. The tasks use novel visual and verbal stimuli to ensure assessment is culture-neutral and not limited by a subject's level of education. All CogState tasks are designed for repeated administration with minimal practice or learning effects, making them ideal for use in clinical research trials.
A CogState ClinicalTrials test battery comprises a number of individual tasks -each designed to test a specific area of cognition. When a number of these individual tasks are put together to form a test battery, a more complete picture of a person's cognitive state can be garnered.
All CogState test batteries run on standard computer equipment and allow for non-expert administration. It is estimated that the battery used for this study should take approximately 15 minutes to complete.
CogState is fully compliant with FDA 21 CFR Part 11 and all quality and data systems have been audited successfully by independent consultants and global pharmaceutical companies.
Additional information and instruction will be provided in the Study Procedures Manual.
For further information, go to http://www.cogstate.com/.  The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor for that lab.       In a retrospective study in over 5,000 patients who initiated warfarin therapy, an algorithm that included both clinical and genetic factors was better correlated with the empirically determined stable warfarin maintenance dose for outliers (patients who did not respond to a standard 5 mg dose) than an algorithm that only included clinical factors.

Adult and
A key component to successful PGx research is the collection of samples during the conduct of clinical studies.
Collection of whole blood samples, even when no a priory hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in handling or response to any of the HIV medicines taken in this study.

Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to any of the HIV medicines used in this study. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with HIV medicines taken in this study that may be attributable to genetic variation of subjects, the following objectives may be investigated: Relationship between genetic variants and the pharmacokinetics and/or pharmacodynamics of HIV medicines taken in this study Relationship between genetic variants and safety and/or tolerability of HIV medicines taken in this study

Study Population
Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives treatment for HIV infection may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled.

Study Assessments and Procedures
In addition to any blood samples take for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labeled (or "coded") with a study specific number that can be traced or linked back to the subject by the Investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study.
If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or a set of studies) of the HIV therapies taken in this study has been completed and the study data reviewed.
In some cases, the samples may not be studied. e.g., no questions are raised about how people respond to the HIV therapies taken in this study.
Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or the Sponsor may destroy the samples sooner. The Sponsor or those working with the Sponsor (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form.
Subjects can request their sample to be destroyed at any time.

Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for PGx research withdraws from the clinical study for any reason other than lost to followup, the subject will be given the following options: The sample is retained for PGx research Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for any reason, the Investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by the Sponsor and maintain the documentation in the site study records. In either case, the Sponsor will only keep study information collected/generated up to that point.

Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the Investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by the Sponsor and maintain the documentation in the site study records.

Pharmacogenetics Analyses
Generally the Sponsor will utilize two approaches to explore genetic variation in drug response.
1. Specific sections of DNA may be selected from areas of the genome (e.g., candidate genes) known to encode the drug target, drug metabolizing enzymes, areas associated with mechanisms underlying adverse events, and those linked to study disease and, thus, linked to drug response.
In addition, continuing research may identify other enzymes, transporters, proteins, or receptors that may be involved in response to the HIV medicines taken in this study. The genes that may code for these proteins may also be studied.
2. Genome-wide scans involving a large numbers of polymorphic markers (e.g., single nucleotide polymorphisms or SNPs) located throughout the genome. This approach is often employed when potential genetic effects are not well understood.
Typically the methods used to identify markers that are associated with drug response are:

Hardy-Weinberg Equilibrium Testing
The genotypic frequencies of each polymorphism will be evaluated for conformity to those expected under normal conditions by employing Hardy-Weinberg Equilibrium testing.

Comparison of Demographic and Baseline Characteristics by Genotype
Differences in Baseline clinical characteristics and potential contributing covariates may be summarized and compared among genotype (or haplotype) subgroups.

Evaluation of Genotypic Effects
Analyses may be carried out to evaluate the degree of association between subject genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and safety). Where such genotypic tests are inappropriate (for example, where the number of marker genotypes is too large and/or the frequency of individual genotypes too small), allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker allele is the same in responders and non-responders.

Evaluation of Treatment by Genotype and Gene-Gene Interaction
In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the selected parameters, the possibility of a treatment group by genotype (haplotype or allele) interaction will also be explored. If appropriate, the joint effects of multiple markers (gene-gene interactions) may also be evaluated.

Linkage Disequilibrium
For pairs of polymorphisms, the degree to which alleles from the two sites are correlated (linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites within a gene are shown to be statistically associated with a response to IP, the degree of linkage disequilibrium will aid interpretation in that it will indicate the extent to which the two sites are exerting independent effects.

Multiple Comparisons and Multiplicity
An adjustment to observed p-values may be made to limit erroneous conclusions due to multiple tests when multiple markers are evaluated (especially in the case of a genome scan for association),

Power and Sample Size Considerations
The ability to detect differential drug response among genotypes at a polymorphic site depends on the total number of subjects genotyped and the frequency distribution of the different genotypes. Consequently, genotyping analyses are plausible for those polymorphic sites where the number of subjects comprising the genotypic groups is sufficiently large; however, these frequencies will not be known until sufficient samples have been collected and genotyping is complete.
Estimates of sample sizes required to demonstrate genotype effects vary considerably, depending on the assumptions made about allele frequency, genetic effect size, and mechanism of inheritance [Cardon, 2000]. In the work by Palmer and Cookson [Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300 cases and 600 controls would be needed to conduct a genetic association analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls would be needed to demonstrate an association.
Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002; and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic markers have been found to significantly associate with hypersensitivity reaction (abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample sizes typically encountered in Phase I and Phase II studies may be sufficient to identify clinically relevant genetic associations.

Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any blood being taken for PGx research.

Provision of Study Results and Confidentiality of Subject's PGx Data
The Sponsor may summarize the cumulative PGx research results in the clinical study report.
In general, the Sponsor does not inform the Investigator, subject, or anyone else (e.g., family members, study Investigators, primary care physicians, insurers, or employers) of the PGx research results that are not known to be relevant to the subject's medical care at the time of the study, because the information generated from PGx studies is preliminary in nature, and the significance and scientific validity of the results are undetermined at such an early stage of research, under any circumstances unless required by law.

Changes
The author list previously read: There are over twenty Food and Drug Administration (FDA) approved antiretroviral agents available with which to construct a highly active antiretroviral therapy (HAART) regimen which has proven to reduce morbidity and mortality in individuals with human immunodeficiency virus infection (HIV) or acquired immunodeficiency syndrome (AIDS) [Palella, 1998]. The current standard of therapy is a combination of at least three antiretrovirals consisting of two nucleoside/nucleotide (NRTI) analogues plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor [DHHS, 2009]. Among the available agents, atazanavir (ATV) boosted with ritonavir (RTV) + tenofovir/emtricitabine (TDF/FTC) is currently a preferred initial regimen for antiretroviral-naïve patients to reduce viral load and improve CD4 lymphocyte counts.
Low-dose RTV is commonly added to PI-based regimens to provide pharmacokinetic enhancement of the parent PI and to reduce the risk of drug resistance. However, RTV is also associated with adverse effects including gastrointestinal upset and lipid and metabolic alterations that may increase future cardiovascular risk. In addition, RTV is a perpetrator of cytochrome P450-mediated drug interactions which can limit the use of other concomitant drugs [Norvir, Package Insert, 2009;Reyataz, Package Insert, 2009]. The addition of RTV to PIs not co-formulated with RTV adds to the patient's pill burden and is associated with extra medication costs. Therefore, there is continued interest among clinicians to find alternative treatment strategies that do not require the use of RTV but continue to offer the potency and high virologic resistance barrier of protease inhibitors.
Treatment induction with a highly potent combination regimen followed by simplification is one strategy that has demonstrated comparable safety and efficacy outcomes in several studies [Gatell, 2007;Delfraissy, 2008;Squires, 2009]. Regimen induction with a RTV-boosted PI provides rapid initial virologic suppression reducing risk for development of viral resistance while subsequent simplification optimizes tolerability and adherence, minimizes short and long-term toxicity, and may reduce drugdrug interactions.
The SWAN study was a multicenter, randomized, open-label trial of 419 patients on a stable, virologically suppressive, PI-based regimen for a mean of 40.3 months who were randomized 2:1 to either switch to an ATV-containing regimen with unchanged NRTIs or remain on the initial non-ATV PI-based regimen. ATV was administered without RTV except in approximately 9% of subjects whose NRTIs included TDF, in which case ATV was given with low-dose RTV due to the pharmacokinetic interaction of ATV and TDF which requires that when using ATV in combination with TDF it must be boosted by RTV [Gatell, 2007]. In a post-hoc analysis among 153 subjects who were initially stable on a virologically suppressive, Lopinavir (LPV)/RTV based regimen, 82 (53%) switched to an unboosted ATV-based regimen, 18 (12%) switched to an ATV/RTV based regimen, and the remaining 53 subjects (34.5%) continued on the original LPV/RTV based regimen. At Week 48, the rates of viral rebound were comparable; 11% in the combined ATV arm and 9% in the LPV/RTV arm [Gatell, 2006]. Rates of treatment failure for any reason, which included viral rebound, failure to receive the randomized treatment, or discontinuation of study therapy were similar in both groups (26% of patients on LPV/RTV versus 28% on ATV). In addition, subjects switched to ATV had a reduction in new onset gastrointestinal symptoms, improvements in lipid parameters, and a lower usage of lipid lowering agents compared to subjects remaining on the LPV/RTV arm [Gatell, 2006]. This post-hoc analysis demonstrated that subjects switching from a stable, virologically suppressive, LPV/RTV based regimen to a RTV-boosted or RTVsparing ATV based regimen maintained similar virologic control with fewer lipid abnormalities and better gastrointestinal tolerability.
The ARIES study was a 144-week, phase IIIB, randomized, open-label, multi-center study in 419 randomized patients who had achieved virologic suppression during the initial 36-week induction phase. In the induction phase, patients received ATV/RTV + abacavir sulfate/lamivudine (ABC/3TC) over 36 weeks and those achieving virologic suppression were subsequently randomized (1:1) to a simplification regimen of ATV + ABC/3TC or remained on the induction regimen and then followed for 108 weeks. At week 84 (48 weeks from the start of randomization), 86% of patients randomized to the simplification arm vs. 81% of patients remaining on the induction arm maintained virologic suppression to HIV-1 RNA <50 copies/mL (c/mL) [Squires, 2009]. Virologic failure occurred in 0.5% of patients in the simplification arm compared to 3% of patients in the induction arm through 84 weeks. Results were similar among patients with entry viral loads above and below 100,000 c/mL. Patients on the simplification regimen had less hyperbilirubinemia and a reduction in total cholesterol and triglycerides.
ABC/3TC is a dual nucleoside combination that is also commonly used with RTVboosted ATV, but may also be used with unboosted ATV in appropriate patient populations. Recent data have shown that the combination of unboosted ATV plus ABC/3TC effectively maintains virologic suppression (plasma HIV-1 RNA <50 c/mL) after initial induction with RTV-boosting of ATV in HIV-infected patients [Delfraissy, 2008;Squires, 2009]. In addition, ABC/3TC has a well-established safety profile and relatively few drug interactions [EPZICOM ® Package Insert, 2009].
The current study will evaluate whether subjects receiving a RTV-containing regimen of ATV/RTV + TDF/FTC who have achieved virologic suppression can safely simplify to a RTV-sparing regimen of ATV + ABC/3TC and maintain virologic suppression through 48 weeks.
This study will also evaluate changes in neurocognition (via a computerized test battery), and cardiovascular, renal and bone biomarkers as exploratory endpoints. As the life expectancy of HIV-1 infected patients continues to improve, long-term consequences of chronic HIV-infection and potentially specific antiretroviral therapies is of active research interest. Additionally, this study will increase our knowledge regarding the incidence of clinically suspected abacavir hypersensitivity reaction (ABC HSR) after excluding patients who carry the HLA-B*5701 allele.

And now reads:
There are over twenty Food and Drug Administration (FDA) approved antiretroviral agents available with which to construct a highly active antiretroviral therapy (HAART) regimen which has proven to reduce morbidity and mortality in individuals with human immunodeficiency virus infection (HIV) or acquired immunodeficiency syndrome (AIDS) [Palella, 1998]. The current standard of therapy is a combination of at least three antiretrovirals consisting of two nucleoside/nucleotide (NRTI) analogues plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or an integrase inhibitor [DHHS, 2009]. Among the available agents, atazanavir (ATV) boosted with ritonavir (RTV) + tenofovir/emtricitabine (TDF/FTC) is currently a preferred initial regimen for antiretroviral-naïve patients to reduce viral load and improve CD4 lymphocyte counts.
Low-dose RTV is commonly added to PI-based regimens to provide pharmacokinetic enhancement of the parent PI and to reduce the risk of drug resistance. However, RTV is also associated with adverse effects including gastrointestinal upset and lipid and metabolic alterations that may increase future cardiovascular risk. In addition, RTV is a perpetrator of cytochrome P450-mediated drug interactions which can limit the use of other concomitant drugs [Norvir, Package Insert, 2010;Reyataz, Package Insert, 2010]. The addition of RTV to PIs not co-formulated with RTV adds to the patient's pill burden and is associated with extra medication costs. Therefore, there is continued interest among clinicians to find alternative treatment strategies that do not require the use of RTV but continue to offer the potency and high virologic resistance barrier of protease inhibitors.
Treatment induction with a highly potent combination regimen followed by simplification is one strategy that has demonstrated comparable safety and efficacy outcomes in several studies [Gatell, 2007;Delfraissy, 2008;Squires, 2010a;Squires, 2010b]. Regimen induction with a RTV-boosted PI provides rapid initial virologic suppression reducing risk for development of viral resistance while subsequent simplification optimizes tolerability and adherence, minimizes short and long-term toxicity, and may reduce drug-drug interactions.
The SWAN study was a multicenter, randomized, open-label trial of 419 patients on a stable, virologically suppressive, PI-based regimen for a mean of 40.3 months who were randomized 2:1 to either switch to an ATV-containing regimen with unchanged NRTIs or remain on the initial non-ATV PI-based regimen. ATV was administered without RTV except in approximately 9% of subjects whose NRTIs included TDF, in which case ATV was given with low-dose RTV due to the pharmacokinetic interaction of ATV and TDF which requires that when using ATV in combination with TDF it must be boosted by RTV [Gatell, 2007]. In a post-hoc analysis among 153 subjects who were initially stable on a virologically suppressive, Lopinavir (LPV)/RTV based regimen, 82 (53%) switched to an unboosted ATV-based regimen, 18 (12%) switched to an ATV/RTV based regimen, and the remaining 53 subjects (34.5%) continued on the original LPV/RTV based regimen. At Week 48, the rates of viral rebound were comparable; 11% in the combined ATV arm and 9% in the LPV/RTV arm [Gatell, 2006]. Rates of treatment failure for any reason, which included viral rebound, failure to receive the randomized treatment, or discontinuation of study therapy were similar in both groups (26% of patients on LPV/RTV versus 28% on ATV). In addition, subjects switched to ATV had a reduction in new onset gastrointestinal symptoms, improvements in lipid parameters, and a lower usage of lipid lowering agents compared to subjects remaining on the LPV/RTV arm [Gatell, 2006]. This post-hoc analysis demonstrated that subjects switching from a stable, virologically suppressive, LPV/RTV based regimen to a RTV-boosted or RTVsparing ATV based regimen maintained similar virologic control with fewer lipid abnormalities and better gastrointestinal tolerability.
The ARIES study was a 144-week, phase IIIB, randomized, open-label, multi-center study in 419 randomized patients who had achieved virologic suppression during the initial 36-week induction phase. In the induction phase, patients received ATV/RTV + abacavir sulfate/lamivudine (ABC/3TC) over 36 weeks and those achieving virologic suppression were subsequently randomized (1:1) to a simplification regimen of ATV + ABC/3TC or remained on the induction regimen and then followed for 108 weeks. At week 84 (48 weeks from the start of randomization), 86% of patients randomized to the simplification arm vs. 81% of patients remaining on the induction arm maintained virologic suppression to HIV-1 RNA <50 copies/mL (c/mL) [Squires, 2010a]. Virologic failure occurred in 0.5% of patients in the simplification arm compared to 3% of patients in the induction arm through 84 weeks. Results were similar among patients with entry viral loads above and below 100,000 c/mL. Patients on the simplification regimen had less hyperbilirubinemia and a reduction in total cholesterol and triglycerides. At week 120 (84 weeks from start of randomization), virologic efficacy was sustained between groups resulting in 84% of ATV + ABC/3TC versus 83% of ATV/RTV + ABC/3TC subjects maintaining suppression to <50 c/mL [Squires ,2010b]. No differences in response rates by baseline viral load were observed between groups. The overall rate of virologic failure was 2% and comparable between groups. Subjects in the simplification arm continued to demonstrate favorable lipid benefits and maintained bilirubin reductions through 120 weeks.
ABC/3TC is a dual nucleoside combination that is also commonly used with RTVboosted ATV, but may also be used with unboosted ATV in appropriate patient populations. Recent data have shown that the combination of unboosted ATV plus ABC/3TC effectively maintains virologic suppression (plasma HIV-1 RNA <50 c/mL) after initial induction with RTV-boosting of ATV in HIV-infected patients [Delfraissy, 2008;Squires, 2010b]. In addition, ABC/3TC has a well-established safety profile and relatively few drug interactions [EPZICOM ® Package Insert, 2009].
The current study will evaluate whether subjects receiving a RTV-containing regimen of ATV/RTV + TDF/FTC who have achieved virologic suppression can safely simplify to a RTV-sparing regimen of ATV + ABC/3TC and maintain virologic suppression through 48 weeks.
This study will also evaluate changes in neurocognition (via a computerized test battery), and cardiovascular, renal and bone biomarkers as exploratory endpoints. As the life expectancy of HIV-1 infected patients continues to improve, long-term consequences of chronic HIV-infection and potentially specific antiretroviral therapies is of active research interest. Additionally, this study will increase our knowledge regarding the incidence of clinically suspected abacavir hypersensitivity reaction (ABC HSR) after excluding patients who carry the HLA-B*5701 allele.

Section 1.2 (Rationale) previously read:
Protease inhibitor (PI)-based therapies containing low-dose RTV have demonstrated favourable efficacy, safety, and barrier to resistance among antiretroviral naïve and treatment experienced patients. However, RTV is associated with long-term gastrointestinal and metabolic toxicities, added pill burden and cost, and requires refrigeration.
ATV is the only currently licensed PI that can be safely administered with or without RTV. Several trials [Delfraissy, 2008;Gatell, 2007;Squires, 2009] investigating an induction-simplification treatment strategy to achieve rapid initial viral load reduction with RTV-boosted ATV followed by simplification to unboosted ATV have demonstrated comparable efficacy. Although there are limited published data utilizing this strategy in clinical practice, a RTV-sparing strategy with ATV has shown improvement in lipids, bilirubin, low rate of virologic failure, and patient acceptance based on improved tolerability and fewer side effects [Santos, 2009;Pavie, 2009;Giuntini, 2010].
The need to find alternative treatment strategies that do not require the use of RTV is of continued interest among clinicians who perceive this as an unmet patient need. Data from this study will support this simplification strategy as a long term treatment option for subjects and clinicians who prefer a RTV-sparing regimen.
The benefit to patients would be a simplified and cost effective treatment regimen, with potentially fewer adverse effects and no need for refrigeration. The risks to this approach are potentially lower ATV trough levels that may lead to resistance development and the unknown long-term impact of switching TDF/FTC for ABC/3TC. However, this risk to patients may be small and mitigated due to the expected low rate of virologic failure observed following this strategy [Squires, 2009;Delfraissy, 2008], the ability to change to an alternative treatment regimen quickly at a relatively low level of viral replication, the expected emergence of mutation pattern(s) readily rescued by other current available PIs, and the shorter study duration.
Potential risks of using this simplification study design are that some subjects may experience viral rebound and potentially develop resistance mutations rendering the simplification regimen less effective [Malan, 2006;McGrath, 2006]. However, subjects randomized to the simplification arm who experience viral rebound will have the opportunity to switch to an alternative regimen at the time of confirmed virologic failure.
Overall the risk of virologic failure in the RTV-sparing arm is small and readily manageable compared to the benefit of protection from long-term complications of RTVcontaining therapy such as hyperlipidemia, insulin resistance, lipoatrophy, and gastrointestinal intolerance and associated complexities for HIV-infected patients with other co-morbidities.
The long-term implications of this strategy are currently unknown, but any risk is likely to be small given the short-term exposure to resistant virus and that ATV-resistant virus has been documented in vitro to be susceptible to alternative PIs.
Additionally, there is a small risk for subjects that are simplified to the ABC/3TC regimen to experience a suspected ABC HSR reaction. However, all subjects enrolled in this study will be HLA-B*5701 negative and therefore the risk for ABC HSR will be substantially reduced as evidenced by data in other HLA-B*5701 negative subjects receiving ABC-containing regimens in the ARIES and PREDICT-1 studies [Squires, 2009;.

And now reads:
Protease inhibitor (PI)-based therapies containing low-dose RTV have demonstrated favourable efficacy, safety, and barrier to resistance among antiretroviral naïve and treatment experienced patients. However, RTV is associated with long-term gastrointestinal and metabolic toxicities, added pill burden and cost.
ATV is the only currently licensed PI that can be safely administered with or without RTV. Several trials [Delfraissy, 2008;Gatell, 2007;Squires, 2010a;Squires, 2010b] investigating an induction-simplification treatment strategy to achieve rapid initial viral load reduction with RTV-boosted ATV followed by simplification to unboosted ATV have demonstrated comparable efficacy. Although there are limited published data utilizing this strategy in clinical practice, a RTV-sparing strategy with ATV has shown improvement in lipids, bilirubin, low rate of virologic failure, and patient acceptance based on improved tolerability and fewer side effects [Santos, 2009;Pavie, 2009;Giuntini, 2010].
The need to find alternative treatment strategies that do not require the use of RTV is of continued interest among clinicians who perceive this as an unmet patient need. Data from this study will support this simplification strategy as a long term treatment option for subjects and clinicians who prefer a RTV-sparing regimen.
The benefit to patients would be a simplified and cost effective treatment regimen, with potentially fewer adverse effects and potential reduction in drug-drug interactions. The risks to this approach are potentially lower ATV trough levels that may lead to resistance development and the unknown long-term impact of switching TDF/FTC for ABC/3TC. However, this risk to patients may be small and mitigated due to the expected low rate of virologic failure observed following this strategy [Squires, 2010a;Squires, 2010b;Delfraissy, 2008], the ability to change to an alternative treatment regimen quickly at a relatively low level of viral replication, the expected emergence of mutation pattern(s) readily rescued by other current available PIs, and the shorter study duration.
Potential risks of using this simplification study design are that some subjects may experience viral rebound and potentially develop resistance mutations rendering the simplification regimen less effective [Malan, 2006;McGrath, 2006]. However, subjects randomized to the simplification arm who experience viral rebound will have the opportunity to switch to an alternative regimen at the time of confirmed virologic failure.
Overall the risk of virologic failure in the RTV-sparing arm is small and readily manageable compared to the benefit of protection from long-term complications of RTVcontaining therapy such as hyperlipidemia, insulin resistance, lipoatrophy, and gastrointestinal intolerance and associated complexities for HIV-infected patients with other co-morbidities.
The long-term implications of this strategy are currently unknown, but any risk is likely to be small given the short-term exposure to resistant virus and that ATV-resistant virus has been documented in vitro to be susceptible to alternative PIs.
Additionally, there is a small risk for subjects that are simplified to the ABC/3TC regimen to experience a suspected ABC HSR reaction. However, all subjects enrolled in this study will be HLA-B*5701 negative and therefore the risk for ABC HSR will be substantially reduced as evidenced by data in other HLA-B*5701 negative subjects receiving ABC-containing regimens in the ARIES and PREDICT-1 studies [Squires, 2010a;.

Section 3.1 (Study Design) previously read:
This is a phase IV, prospective, randomized, open-label, multicenter, non-inferiority study of the safety, efficacy, and tolerability of ATV + ABC/3TC once daily compared to ATV/RTV + TDF/FTC once daily for 48 weeks in HIV-1 infected, HLA-B*5701negative subjects who are currently receiving a stable regimen of ATV/RTV + TDF/FTC once daily and are virologically suppressed (plasma HIV-1 RNA <50 c/mL).
ATV/RTV + TDF/FTC once daily should be the subjects initial or first and only switch regimen. First switch is defined as changing from an initial regimen of any licensed NNRTI + TDF/FTC to ATV/RTV + TDF/FTC. The switch must not be due to virologic failure.
A minimum of 300 subjects meeting eligibility criteria will be stratified by initial antiretroviral regimen received (NNRTI + TDF/FTC or ATV/RTV + TDF/FTC) and randomized 2:1 to receive one of the following anti-retroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm B: (Continuation)
ATV/RTV 300 mg/100 mg once daily + TDF/FTC 300 mg/200 mg once daily Subjects who enter the Screening period of this study must continue receiving their ATV/RTV + TDF/FTC regimen up to, but not including, the Baseline visit (Day 1). Subjects will begin randomized treatment on Day 1.
This study consists of up to a 28-35 day Screening period, a 48 week Treatment period (Day 1 through Week 48) and a follow-up period (contact approximately 2-4 weeks after the Week 48 visit or Withdrawal visit).
Study participation is considered complete when a subject has completed study procedures through Week 48.
Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

And now reads:
This study consists of a 35 day Screening period, a 48 week Treatment period (Day 1 through Week 48) and a follow-up period (contact approximately 2-4 weeks after the Week 48 visit or Withdrawal visit).
Study participation is considered complete when a subject has completed study procedures through Week 48.
Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

Section 4.2 (Inclusion Criteria) previously read:
Subjects eligible for enrolment in the study must meet all of the following criteria: 1. Adults 18 years of age.
2. Receiving a once-daily regimen of ATV/RTV (300 mg/100 mg) + TDF/FTC (300 mg/200 mg) as his/her INITIAL or FIRST AND ONLY SWITCH regimen for at least 6 months prior to or by the first day of Screening.
First switch is defined as changing from an initial regimen of any licensed NNRTI + TDF/FTC to ATV/RTV + TDF/FTC.

Virologically suppressed on ATV/RTV + TDF/FTC
Virologically suppressed is defined as HIV-1 RNA <50 c/mL at 2 consecutive timepoints, one of which is at Screening and the other at least 28 days prior to Screening 4. A female is eligible to enter and participate in the study if she is of: a. Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); or, b. Child-bearing potential, has a negative pregnancy test at Screening (serum -Human chorionic gonadotropins (HCG) and Baseline (urine -HCG) and agrees to one of the following methods of contraception (any contraception method must be used consistently and correctly, i.e., in accordance with both the approved product label and the instructions of a physician): Complete abstinence from sexual intercourse from 2 weeks prior to administration of the Investigational Products, throughout the study, and for at least 2 weeks after discontinuation of all study medications Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide). Hormonal contraception will not be considered adequate for inclusion into this study.
Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year.
Sterilization (female subject or male partner of female subject).
14. Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 90 days prior to Screening, or an anticipated need for these agents within the study period.
15. Treatment within 30 days prior to first dose of Investigational Product for or an anticipated need during the study of any medications which can have interactions with the study medications, TDF, FTC, ABC, 3TC, ATV and/or RTV, as described in current product labelling (e.g. use of proton pump inhibitors with ATV).

Any previous abacavir-containing regimen
Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the Investigational Product that may impact subject eligibility is provided in each specific product label.

Section 4.4.1 (Subject Withdrawal from Study) previously read:
A subject must be withdrawn from the study when: A subject becomes Hepatitis B positive (+ HbsAg).
Subject requires the use of any prohibited study medication (see Prohibited Medications, Section 5.7.2).
A subject is significantly non-compliant with the requirements of the protocol (based upon the discretion of the investigator).
A subject becomes pregnant (see Pregnancy, Section 6.4.8).
A subject has an adverse experience that would, in the investigator's judgment, make continued participation in the study an unacceptable risk.
Subject experiences a toxicity that meets the criteria for withdrawal (see Toxicity Management, Section 6.4.4) Subjects who become prisoners or become involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
Subject has a plasma HIV-1 RNA 2000 c/mL at the confirmatory virologic failure timepoint.
Subject has two consecutive HIV-1 RNA measurements 2000 c/mL at any time.
The Sponsor discontinues the study.
A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, withdraw the subject from participating in this study at any time.

Management of Withdrawn Subjects
If a subject is withdrawn from the study for any reason, the investigator must make every effort to perform the evaluations noted in the Time and Events table (see Section 6.1).
All data from the withdrawal visit should be recorded, as they comprise an essential evaluation that should be done prior to discharging any subject from the study.
If a subject is withdrawn from the study due to an AE (See Section 6.4.5.1) or serious adverse event (SAE) (See Section 6.4.5.2), the procedures stated in Section 6.4.5 (AEs and SAEs) must be followed and the AE must be followed-up until resolution.
Withdrawn subjects will not be replaced.

And now reads:
A subject must be withdrawn from the study when: A subject becomes Hepatitis B positive (+ HbsAg).
Subject requires the use of any prohibited study medication, unless explicit approval is given by the Sponsor in consultation with the Investigator (see Prohibited Medications, Section 5.7.2).
A subject is significantly non-compliant with the requirements of the protocol (based upon the discretion of the investigator).
A subject becomes pregnant (see Pregnancy, Section 6.4.8).
A subject has an adverse experience that would, in the investigator's judgment, make continued participation in the study an unacceptable risk.
Subject experiences a toxicity that meets the criteria for withdrawal (see Toxicity Management, Section 6.4.4) Subjects who become prisoners or become involuntarily incarcerated for treatment of either a psychiatric or physical (e.g., infectious disease) illness.
Subject has a plasma HIV-1 RNA 2000 c/mL at the confirmatory virologic failure timepoint.
Subject has two consecutive HIV-1 RNA measurements 2000 c/mL at any time.
The Sponsor discontinues the study.
A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, withdraw the subject from participating in this study at any time.

Management of Withdrawn Subjects
If a subject is withdrawn from the study for any reason, the investigator must make every effort to perform the evaluations noted in the Time and Events table (see Section 6.1).
All data from the withdrawal visit should be recorded, as they comprise an essential evaluation that should be done prior to discharging any subject from the study.
If a subject is withdrawn from the study due to an AE (See Section 6.4.5.1) or serious adverse event (SAE) (See Section 6.4.5.2), the procedures stated in Section 6.4.5 (AEs and SAEs) must be followed and the AE must be followed-up until resolution.
Withdrawn subjects will not be replaced.

Section 5.3 (Treatment Assignment) previously read:
Subjects will be assigned to study treatment in accordance with the randomization schedule. Subjects will be stratified by initial antiretroviral regimen received (NNRTI + TDF/FTC or ATV/RTV + TDF/FTC) and randomized 2:1 to receive one of the following anti-retroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm B: (Continuation)
ATV/RTV 300 mg/100 mg once daily + TDF/FTC 300 mg/200 mg once daily If a subject is eligible for randomization, the investigator (or designee) will call RAMOS (Registration and Medication Ordering System) and the subject will be assigned a randomization number. The randomization code is on file with the Sponsor and with RAMOS.
Training on the use of RAMOS and detailed user worksheets will be provided by the Sponsor prior to study start.
Randomization numbers are unique and may not be reassigned to another study subject.

And now reads:
Subjects will be assigned to study treatment in accordance with the randomization schedule. Subjects will be stratified by initial antiretroviral regimen received (ATV/RTV + TDF/FTC as initial regimen OR as first or second switch regimen) and randomized 2:1 to receive one of the following anti-retroviral therapy (ART)-regimens below for 48 weeks. Subjects will have twice the chance to be randomized to the simplification arm than the continuation arm.

Treatment Arm B: (Continuation)
ATV/RTV 300 mg/100 mg once daily + TDF/FTC 300 mg/200 mg once daily If a subject is eligible for randomization, the investigator (or designee) will call RAMOS (Registration and Medication Ordering System) and the subject will be assigned a randomization number. The randomization code is on file with the Sponsor and with RAMOS.
Training on the use of RAMOS and detailed user worksheets will be provided by the Sponsor prior to study start.
Randomization numbers are unique and may not be reassigned to another study subject.

Section 6 (Study Assessments and Procedures) Previously read:
Written informed consent must be obtained from each potentially eligible subject (or his/her legal representative) by study site personnel prior to the initiation of any Screening procedures as outlined in this protocol. The consent form must have been approved by the Institutional Review Board / Independent Ethics Committee (IRB/IEC). After signing an informed consent, subjects will complete Screening assessments to determine subject eligibility.
Each subject being screened for study enrollment evaluation will be assigned a subject number. This number will be given sequentially in chronological order of subject presentation according to a numeric roster provided by the Sponsor.
Subjects who qualify must return within 28-35 days of the Screening visit to begin study treatment. Subjects not meeting all inclusion and exclusion criteria at initial screen may be re-screened at the discretion of the investigator after consultation with the Sponsor. A subject, who is randomized into the trial and subsequently withdraws from the study for any reason, may not be re-screened.
A single repeat test per analyte is allowed during the Screening period. However, a repeat plasma HIV-1 RNA measurement is not allowed if the initial Screening value is >50 c/mL.