"The Once A Day Protease Inhibitor Regimens"

• CD4 cell count change from baseline during treatment. [ Time Frame: 24, 48 and 96 weeks. ] [ Designated as safety issue: Yes ]
• Development of drug resistance and mutational patterns in patients who have virologic failure on the study regimens. [ Time Frame: At time of virological failure. ] [ Designated as safety issue: Yes ]
• Occurrence of adverse events and safety of each regimen. [ Time Frame: During the entire study. ] [ Designated as safety issue: Yes ]
• Clinical disease progression, including death, for each strategy arm. [ Time Frame: During the entire study. ] [ Designated as safety issue: Yes ]
• Differences regarding adherence between the two treatment arms. [ Time Frame: 24, 48 and 96 weeks. ] [ Designated as safety issue: Yes ]
• Changes of body appearance occurred in both arms. [ Time Frame: 24, 48 and 96 weeks. ] [ Designated as safety issue: Yes ]

• CD4 cell count change from baseline during treatment.
• Development of drug resistance and mutational patterns in patients who have virologic failure on the study regimens.
• Occurrence of adverse events and safety of each regimen.
• Clinical disease progression, including death, for each strategy arm.
• Differences regarding adherence between the two treatment arms.
• Changes of body appearance occurred in both arms.

Atazanavir (ATV) and fosamprenavir (fAPV) are new protease inhibitors that can be administered once-a-day and boosted with ritonavir (r). Prior studies have demonstrated that both are effective in treatment of ARV-naïve HIV-infected people. This study was designed to demonstrate if a HAART regimen containing ATV/r is not inferior to a HAART regimen containing fAPV/r, in ARV-naïve patients over a 96-week period.

This is a phase IV, single center, randomized, open label, 2-arm clinical trial in ARV therapy-naïve patients with HIV-1 RNA >1,000 copes/mL and CD4 cell count <350 cells/mm3. Patients will be randomized to receive tenofovir and emtricitabine plus either ATV (300mg qd) and ritonavir (100mg qd) or fAPV (1400mg qd) and ritonavir (200mg qd).

Over the past decade, there have been significant advances toward fighting the progression of HIV disease. Current treatment strategies consist of utilization of potent combination antiretroviral therapy to suppress HIV replication below detectable limits limiting the potential for the emergence of resistant viruses, boosting CD4 cell counts and thereby delaying disease progression. Treatment of HIV-1 infection with Highly Active Antiretroviral Therapy (HAART) regimens containing a protease inhibitor (PI) and two nucleoside reverse transcriptase inhibitor (NRTIs) has been shown to prolong survival and decrease disease progression. Despite these potent antiretroviral agents, current available therapies continue to fail in some patients. Poor adherence to complex treatment regimens remains a significant cause of suboptimal viral suppression leading to emerge of resistant virus. Atazanavir and fosamprenavir were recently FDA approved protease inhibitors. The efficacy and safety profile of these two drugs have been established in clinical trials enrolling antiretroviral therapy naïve and protease inhibitor experienced patients. Atazanavir and fosamprenavir are the only protease inhibitors approved for a once a day regimen and this may set a new standard for treatment of antiretroviral therapy naïve HIV infected patients. Adherence to the medicines, a key component of treatment success, could be significantly improved by using these once daily regimens. However, no head-to-head trials comparing the safety and efficacy of fosamprenavir and atazanavir have been published. This prospective, randomized, open label 2-arm study will compare these two protease inhibitors for therapy of antiretroviral treatment-naïve HIV-infected patients. Patients who are successfully screened for eligibility will be randomized to receive tenofovir and emtricitabine plus either atazanavir (300mg qd) and ritonavir (100mg qd) or fosamprenavir (1400mg qd) and ritonavir (200mg qd). Participants will undergo assessment on day 1 and attend study visits at weeks 6, 12 and every 3 months until the completion of the study on week 96. "Antiretroviral Medication Self-Report" and "3-Day HIV Medication Self-Report" questionnaires will be applied at weeks 6, 12 and every 3 month, thereafter, until week 96. "Changes in Body Appearance" questionnaire will be applied at baseline and weeks 24, 48, 72, and 96.

• HIV Infections
• Antiretroviral Therapy

• Drug: ritonavir-boosted atazanavir
  100 mg ritonavir plus 300 mg atazanavir in combination with tenofovir-emtricitabine fixed dose combination given once daily.
• Drug: ritonavir-boosted fosamprenavir
  100 mg ritonavir plus 1,400 mg fosamprenavir in combination with tenofovir-emtricitabine fixed dose combination given once daily.

• Active Comparator: Atazanavir
  Intervention: Drug: ritonavir-boosted atazanavir
• Active Comparator: Fosamprenavir
  Intervention: Drug: ritonavir-boosted fosamprenavir

• Holmes A, Lucke J, Maghidman S, Fernandez-Bussy S, Barnett B, Arduino R. Tenofovir associated nephrotoxicity is dose-dependent ritonavir administration a co-factor? XVI International AIDS Conference. Toronto, Canada. August 13-18, 2006. Abstract TUPE0085.
• Bell TK, Holmes A, McCormack OE, Barnett BJ, Arduino RC. Changing Genotypic Resistance Patterns and Demographics of Antiretroviral-Naïve HIV Patients in Houston: 1999-2006. 44th Annual Meeting of the Infectious Diseases Society of America (IDSA). Toronto, Canada. October 12-15, 2006. Abstract 975.
• Holmes A, Bell T, Barnett B, Arduino R. Emerging resistance mutations in once-daily ritonavir-boosted protease inhibitor-containing antiretroviral regimens. 44th Annual Meeting of the Infectious Diseases Society of America (IDSA). Toronto, Canada. October 12-15, 2006. Abstract 973.
• Murphy RL, Sanne I, Cahn P, Phanuphak P, Percival L, Kelleher T, Giordano M. Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS. 2003 Dec 5;17(18):2603-14.
• Sax PE. Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Atazanavir in treatment-experienced patients. AIDS Clin Care. 2003 Sep;15(9):78.
• Bayes M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2003 Jul-Aug;25(6):483-506.
• Goldsmith DR, Perry CM. Atazanavir. Drugs. 2003;63(16):1679-93; discussion 1694-5. Review.
• Rodriguez-French A, Boghossian J, Gray GE, Nadler JP, Quinones AR, Sepulveda GE, Millard JM, Wannamaker PG. The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):22-32.
• [No authors listed] SOLO trial results released. AIDS Patient Care STDS. 2003 Feb;17(2):95. No abstract available.
• Falcoz C, Jenkins JM, Bye C, Hardman TC, Kenney KB, Studenberg S, Fuder H, Prince WT. Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers. J Clin Pharmacol. 2002 Aug;42(8):887-98.
• Vierling P, Greiner J. Prodrugs of HIV protease inhibitors. Curr Pharm Des. 2003;9(22):1755-70. Review.
• Mannheimer SB, Matts J, Telzak E, Chesney M, Child C, Wu AW, Friedland G; Terry Beirn Community Programs for Clinical Research on AIDS. Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence. AIDS Care. 2005 Jan;17(1):10-22.

Inclusion Criteria:

• 18 years of age or older.
• Patient agrees to participate in the study by giving written informed consent.
• Documentation of HIV infection.
• No prior treatment with any anti-retroviral agent.
• CD4 cell count < 350 cells x mm3 or with an AIDS defining condition.
• Viral load > 1,000 copies/mL

Exclusion Criteria:

• Less than 18 years old.
• Current pregnancy or breastfeeding.
• Any previous antiretroviral regimen.
• Severe hepatic impairment that precludes the use of either study drug. This will be defined as any laboratory value of Grade 3 or 4 on the ACTG scale.
• Use of any contra-indicated medication as defined in the package insert for each drug.
• Any condition that, in the judgment of the investigator, precludes successful participation in the study.