Nevirapine or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir in Human Immunodeficiency Virus (HIV)-1-infected Treatment Naive Adults

Randomized, Open Label Study Evaluating the Lipid Profile Difference and Efficacy of a Combined Therapy Including Tenofovir, Emtricitabine + Atazanavir / r or NVP in Naive HIV - 1 Infected Patients.

Primary purpose of this study is to compare the efficacy and safety of two different nevirapine (Viramune) dosing regimens (once daily (QD) and twice daily (BID) application) and of atazanavir/ritonavir (Reyataz/Norvir), all on an emtricitabine/tenofovir disoproxil fumarate (DF) (Truvada) background. Patients will receive either nevirapine (NVP) 200 mg twice daily, or NVP 400 mg once daily , or ritonavir-boosted atazanavir (ATZ/r), all in combination with emtricitabine (FTC) and tenofovir DF (TDF).

All patients receiving NVP will start at 200 mg once daily for 2 weeks, because it has been demonstrated that this lead-in dosing regimen reduces the frequency of NVP-induced rash. At Visit 3 (Week 2), patients increase the NVP dose to either 200 mg twice daily or to 400 mg once daily. Patients receiving ATZ/r will be treated with ATZ 300 mg once daily, boosted by 100 mg ritonavir (RTV) once daily. Background antiretroviral therapy for all patients consists of one tablet of Truvada. Treatment duration is 48 weeks (primary endpoint) with an extension to 144 weeks. Patients may also participate in the metabolic sub-study, comparing NVP and ATZ/r for signs and symptoms of lipodystrophy and serum lipid/glycaemic abnormalities.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: nevirapine bid; Drug: nevirapine qd; Drug: atazanavir

• Study Type: Interventional
• Enrollment (Actual): 576
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina
    • 1100.1470.54004 Boehringer Ingelheim Investigational Site
  • Córdoba, Argentina
    • 1100.1470.54002 Boehringer Ingelheim Investigational Site
  • Mar del Plata, Argentina
    • 1100.1470.54003 Boehringer Ingelheim Investigational Site
  • Rosario, Argentina
    • 1100.1470.54001 Boehringer Ingelheim Investigational Site
• Germany
  • Berlin, Germany
    • 1100.1470.49001 Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • 1100.1470.49002 Boehringer Ingelheim Investigational Site
  • Bochum, Germany
    • 1100.1470.49003 Boehringer Ingelheim Investigational Site
  • Bonn, Germany
    • 1100.1470.49018 Boehringer Ingelheim Investigational Site
  • Düsseldorf, Germany
    • 1100.1470.49014 Boehringer Ingelheim Investigational Site
  • Erlangen, Germany
    • 1100.1470.49008 Boehringer Ingelheim Investigational Site
  • Frankfurt, Germany
    • 1100.1470.49035 Boehringer Ingelheim Investigational Site
  • Frankfurt am Main, Germany
    • 1100.1470.49036 Boehringer Ingelheim Investigational Site
  • Freiburg/Breisgau, Germany
    • 1100.1470.49033 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1100.1470.49016 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1100.1470.49031 Boehringer Ingelheim Investigational Site
  • Hamburg, Germany
    • 1100.1470.49037 Boehringer Ingelheim Investigational Site
  • Hannover, Germany
    • 1100.1470.49020 Boehringer Ingelheim Investigational Site
  • Magdeburg, Germany
    • 1100.1470.49038 Boehringer Ingelheim Investigational Site
  • München, Germany
    • 1100.1470.49034 Boehringer Ingelheim Investigational Site
  • Ulm, Germany
    • 1100.1470.49000 Boehringer Ingelheim Investigational Site
  • Würzburg, Germany
    • 1100.1470.49032 Boehringer Ingelheim Investigational Site
• Italy
  • Bergamo, Italy
    • 1100.1470.39001 Boehringer Ingelheim Investigational Site
  • Bologna, Italy
    • 1100.1470.39003 Boehringer Ingelheim Investigational Site
  • Como, Italy
    • 1100.1470.39012 Ospedale Sant'Anna
  • Ferrara, Italy
    • 1100.1470.39006 Boehringer Ingelheim Investigational Site
  • Lecco, Italy
    • 1100.1470.39010 Boehringer Ingelheim Investigational Site
  • Torino, Italy
    • 1100.1470.39004 Boehringer Ingelheim Investigational Site
  • Torrette Di Ancona, Italy
    • 1100.1470.39009 Boehringer Ingelheim Investigational Site
  • Varese, Italy
    • 1100.1470.39007 Boehringer Ingelheim Investigational Site
• Mexico
  • Aguascalientes, Mexico
    • 1100.1470.55006 Boehringer Ingelheim Investigational Site
  • Col Obregón, Mexico
    • 1100.1470.55004 Boehringer Ingelheim Investigational Site
  • Col. Los Filtros, San Luis Potosí, Mexico
    • 1100.1470.55008 Boehringer Ingelheim Investigational Site
  • Col. Toriello Guerra, Mexico
    • 1100.1470.55001 Boehringer Ingelheim Investigational Site
  • Guadalajara Jal., Mexico
    • 1100.1470.55007 Boehringer Ingelheim Investigational Site
  • Tlalpan-México D,F, Mexico
    • 1100.1470.55003 Boehringer Ingelheim Investigational Site
• Poland
  • Bydgoszcz, Poland
    • 1100.1470.48003 Boehringer Ingelheim Investigational Site
  • Chorzow, Poland
    • 1100.1470.48001 Boehringer Ingelheim Investigational Site
  • Szczecin, Poland
    • 1100.1470.48002 Boehringer Ingelheim Investigational Site
  • Warsaw, Poland
    • 1100.1470.48004 Boehringer Ingelheim Investigational Site
• Portugal
  • Cascais, Portugal
    • 1100.1470.35102 Boehringer Ingelheim Investigational Site
  • Lisboa, Portugal
    • 1100.1470.35101 Boehringer Ingelheim Investigational Site
  • Porto, Portugal
    • 1100.1470.35103 Boehringer Ingelheim Investigational Site
• Romania
  • Bucharest, Romania
    • 1100.1470.40001 Boehringer Ingelheim Investigational Site
  • Bucharest, Romania
    • 1100.1470.40002 Boehringer Ingelheim Investigational Site
• Spain
  • Alcalá de Henares (Madrid), Spain
    • 1100.1470.34013 Boehringer Ingelheim Investigational Site
  • Badalona, Spain
    • 1100.1470.34008 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1100.1470.34002 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1100.1470.34003 Boehringer Ingelheim Investigational Site
  • L'Hospitalet de Llobregat, Spain
    • 1100.1470.34009 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1100.1470.34010 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1100.1470.34012 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1100.1470.34014 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1100.1470.34015 Boehringer Ingelheim Investigational Site
  • Malaga, Spain
    • 1100.1470.34019 Boehringer Ingelheim Investigational Site
  • Sabadell (Barcelona), Spain
    • 1100.1470.34007 Boehringer Ingelheim Investigational Site
  • San Sebastian, Spain
    • 1100.1470.34004 Boehringer Ingelheim Investigational Site
  • Santa Cruz de Tenerife, Spain
    • 1100.1470.34006 Boehringer Ingelheim Investigational Site
  • Vigo, Spain
    • 1100.1470.34011 Boehringer Ingelheim Investigational Site
• Switzerland
  • Bern, Switzerland
    • 1100.1470.41004 Boehringer Ingelheim Investigational Site
  • Lugano, Switzerland
    • 1100.1470.41001 Boehringer Ingelheim Investigational Site
  • St. Gallen, Switzerland
    • 1100.1470.41003 Boehringer Ingelheim Investigational Site
  • Zürich, Switzerland
    • 1100.1470.41002 Boehringer Ingelheim Investigational Site
• United Kingdom
  • Birmingham, United Kingdom
    • 1100.1470.44004 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1100.1470.44001 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1100.1470.44002 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1100.1470.44005 Boehringer Ingelheim Investigational Site
  • London, United Kingdom
    • 1100.1470.44006 Boehringer Ingelheim Investigational Site
  • Manchester, United Kingdom
    • 1100.1470.44003 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

Inclusion Criteria:

1. Signed informed consent in accordance with Good Clinical Practice (GCP) and local regulatory requirements prior to trial participation
2. HIV-1-infected males or females >= 18 years of age with positive serology confirmed by Western blot
3. No previous antiretroviral treatment (of more than 7 days)
4. Males with CD4+ counts of < 400 cells/mm3 and females with CD4+ counts of < 250 cells/mm3
5. NVP- and ATZ/r susceptibility based on HIV-1 genotypic resistance report
6. Adequate renal function defined as a calculated creatinine clearance (CLCr) >= 50 ml/min according to the Cockcroft-Gault formula
7. Karnofsky score >= 70
8. Acceptable medical history, as assessed by the investigator

Exclusion criteria:

Exclusion Criteria:

1. Active drug abuse or chronic alcoholism at the investigator's discretion
2. Hepatic cirrhosis stage Child-Pugh B or C

3. Female patients of child-bearing potential who:

   • have a positive serum pregnancy test at screening or during the study,
   • are breast feeding,
   • are planning to become pregnant,
   • are not willing to use a barrier method of contraception, or are not willing to use methods of contraception other than ethinyl estradiol containing oral contraceptives
4. Laboratory parameters Division of Acquired Immunodeficiency Syndrome (DAIDS) > grade 2 (triglycerides > DAIDS grade 3; total cholesterol no restrictions)
5. Active hepatitis B or C disease, defined as HBsAg-positive or Hepatitis C-Virus-Ribo Nucleic Acid (HCV-RNA)- positive with Aspartate Transaminase/Alanine Transaminase (AST/ALT) > 2.5x Upper Limit of Normal (ULN) (DAIDS grade 1)
6. Hypersensitivity to any ingredients of the test products
7. Have therapy with nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamidine, tacrolimus, cyclosporine) or potential competitors of renal excretion (e.g., cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, probenecid, high-dose non-steroidal anti-inflammatory drugs (i.e., ibuprofen)) within 3 months prior to study screening or are expected to receive these during the study
8. Patients who are receiving other concomitant treatments which are not permitted
9. Use of other investigational medications within 30 days before study entry or during the trial
10. Use of immunomodulatory drugs within 30 days before study entry or during the trial (e.g., interferon, cyclosporin, hydroxyurea, interleukin 2, chronic treatment with prednisone)
11. Patients with Progressive Multifocal Leukoencephalopathy (PML), Visceral Kaposi's Sarcoma (KS), and/or any lymphoma
12. Any AIDS defining illness that is unresolved, symptomatic or not stable on treatment for at least 12 weeks at screening visit
13. Patients who are receiving systemic treatment for malignant disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: NVP bid; nevirapine (NVP) 200 mg BID in combination with emtricitabine (FTC) and tenofovir DF (TDF)	Drug: nevirapine bid; nevirapine twice daily
Experimental: NVP qd; nevirapine (NVP) 400 mg QD in combination with emtricitabine (FTC) and tenofovir DF (TDF)	Drug: nevirapine qd; nevirapine once daily
Active Comparator: ATZ/r; ritonavir-boosted atazanavir in combination with emtricitabine (FTC) and tenofovir DF (TDF)	Drug: atazanavir; atazanavir once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response at Week 48	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 48 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 48.	From baseline to Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment Response at Week 48 (TLOVR Algorithm)	Treatment response is defined as a VL <50 copies/mL measured at two consecutive visits up to Week 48 and without subsequent rebound or change of ARV therapy up to Week 48, based on time to loss of virologic response (TLOVR) algorithm, as a sensitivity analysis for the primary analysis.	From baseline to Week 48
Proportion of Patients With VL < 50 Copies/ml	VL <50 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT) for the patient	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
Proportion of Patients With VL < 400 Copies/ml	VL <400 copies/mL among observed patients on treatment at each visit, with the final visit at Week 144 or end of trial (EOT)	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
Change in CD4+ Count From Baseline	Change in CD4+ cell count from baseline among patients on treatment at each visit, with the final visit at Week 144 or EOT	From baseline to Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 and 144/EOT
Change in Framingham Score From Baseline	Change in the estimated risk of cardiovascular disease using the Framingham algorithm from baseline to after 48, 96 and 144 weeks, last observation carried forward (LOCF). The score is based on age, gender, systolic blood pressure, total cholesterol, high density lipoprotein cholesterol and smoking status. Scores range from 0 to 21 with higher scores indicating a greater risk.	From baseline to Weeks 48, 96 and 144/EOT
Change in Mental Health Summary (MHS) Score From Baseline	Quality of life (QoL) assessment by change in MHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the Medical Outcomes Study HIV Health Survey (MOS-HIV), a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The MHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL.	From baseline to Weeks 48, 96 and 144/EOT
Change in Physical Health Summary (PHS) Score From Baseline	QoL assessment by change in PHS score from baseline to after 48, 96 and 144 weeks (observed cases), from the MOS-HIV, a 35-item self-administered questionnaire including 10 scales covering: health perceptions, pain, physical functioning, role functioning, social and cognitive functioning, mental health, energy/fatigue, health distress, and QoL. The PHS is a weighted average of the 10 scales and ranges from 0 to 100 with higher scores indicating better QoL.	From baseline to Weeks 48, 96 and 144/EOT
Number of Patients Hospitalized	Cost effectiveness assessment by number of patients hospitalized	From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT
Non-scheduled Physician Visits	Cost effectiveness assessment by number of patients with non-scheduled physician visits	From baseline to Week 24, Week 24 to 48, Week 48 to 96, and Week 96 to 144/EOT
Genotypic Resistance Associated With Virologic Failure	Number of treatment-emergent drug-associated substitutions in patients with virological failure up to Week 48. The total number of genotypic mutations in those patients who were virologic failures is given, not the number of patients with mutations.	From baseline to Week 48
Treatment-emergent AIDS-defining Illness	Treatment-emergent AIDS-defining illness (tr.-emerg. AIDS-def.illness) including worsening during treatment	From baseline to Week 144
Treatment-emergent AIDS-defining Illness Leading to Death	Patients with an AIDS-defining illness leading to death broken out by treatment. Statistical analysis shows time to death from AIDS-defining illness.	From baseline to Week 144
Lipodystrophy	Number of patients with AE lipodystrophy	From baseline to Week 144
Serum Lipid Abnormalities	Number of patients with AE elevated serum lipids (i.e. hypercholesterolaemia)	From baseline to Week 144
Glycaemic Abnormalities	Number of patients with AE elevated serum glucose	From baseline to Week 144
Treatment Response at Week 96	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 96 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 96.	From baseline to Week 96
Treatment Response at Week 144	Treatment response is defined as a viral load (VL) <50 copies/mL measured at two consecutive visits prior to Week 144 and without subsequent rebound or change of antiretroviral (ARV) therapy prior to Week 144.	From baseline to Week 144
Proportion of Patients With Virological Rebound With VL >=50 Copies/mL After CVR (Confirmed Virological Response) at Week 24, 48, 96, 144	The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL)	at Week 24, 48, 96, 144
Proportion of Patients With Virological Rebound With VL >=400 Copies/mL After CVR at Week 24, 48, 96, 144	The analyses of virologic rebound were performed on the original values at each visit(ORGV) rather than calculated results within time windows (CAL)	at Week 24, 48, 96, 144
Proportion of Patients With Virologic Failure at Week 48, 96, 144		at Week 48, 96, 144
Time to Treatment Response (First Confirmed VL<50 Copies/mL)	Time to treatment response was defined as the time from start of treatment until the first measurement of the first confirmed virological response	baseline to week 144
Time to Loss of Virologic Response (Rebound)	Time to loss of virologic response (TLOVR) was defined as the time from start of treatment to the first measurement showing VL ≥ 50 copies/mL in the first virologic rebound, after having a confirmed virological response.	Baseline to week 144
Time to Treatment Failure	Treatment failure is defined as the occurrence of the first of at least one of the following events: early discontinuation of trial drug, change in ARV therapy, failure to achieve an HIV RNA count < 50 copies/mL up to Visit 10 (week 48) or loss of virologic response	baseline to week 144
Change in the Calculated Glomerular Filtration Rate (GFR) at Week 48, 96 and 144	Calculations based on the MDRD algorithm.	From baseline to Week 48, 96, 144
Proportion of Patients With >= DAIDS Grade 2 Laboratory Abnormalities		week 148
Proportion of Patients Reporting Rash of Any Severity	Proportion of Patients reporting rash of any severity	week 148
Proportion of Patients Reporting Hepatic Events of Any Severity	Proportion of Patients reporting hepatic events of any severity	week 148
Proportion of Patients Reporting CNS (Central Nervous System) Side Effects of Any Severity	Proportion of Patients reporting CNS (central nervous system) side effects of any severity	week 148
Change of Cholesterol Values From Baseline to Week 48, 96, 144	Changes frombaseline in total cholesterol, LDL-cholesterol(LDL-c) and HDL	baseline to week 48, 96, 144
Changes of Apolipoprotein Values From Baseline to Week 48, 96, 144	Changes frombaseline apolipoprotein A1 & B	baseline to week 48, 96, 144
Change of hsCRP From Baseline to Week 48, 96, 144	Change of hsCRP from baseline to week 48, 96, 144	baseline to week 48, 96, 144
Change of Total Triglycerides From Baseline to Week 48, 96, 144	Change of total triglycerides from baseline to week 48, 96, 144	baseline to week 48, 96, 144
Change of Total Cholesterol to HDL-cholesterol Ratio From Baseline to Week 48, 96, 144	Change of Total cholesterol to HDL-cholesterol ratio from baseline to week 48, 96, 144	baseline to week 48, 96, 144

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Seclen E, Soriano V, Gonzalez MM, Martin-Carbonero L, Gellermann H, Distel M, Kadus W, Poveda E. Impact of baseline HIV-1 tropism on viral response and CD4 cell count gains in HIV-infected patients receiving first-line antiretroviral therapy. J Infect Dis. 2011 Jul 1;204(1):139-44. doi: 10.1093/infdis/jir218.
• Soriano V, Arasteh K, Migrone H, Lutz T, Opravil M, Andrade-Villanueva J, Antunes F, Di Perri G, Podzamczer D, Taylor S, Domingo P, Gellermann H, de Rossi L; ARTEN investigators. Nevirapine versus atazanavir/ritonavir, each combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1 patients: the ARTEN Trial. Antivir Ther. 2011;16(3):339-48. doi: 10.3851/IMP1745.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: October 17, 2006
• First Submitted That Met QC Criteria: October 17, 2006
• First Posted (Estimate): October 18, 2006

Study Record Updates

• Last Update Posted (Estimate): January 27, 2014
• Last Update Submitted That Met QC Criteria: December 9, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Nevirapine; Atazanavir Sulfate
• Other Study ID Numbers: 1100.1470; 2005-004330-40 (EudraCT Number: EudraCT)