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Safety and Effectiveness of Lopinavir/Ritonavir in Individuals Who Have Failed Prior HIV Therapy

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ClinicalTrials.gov Identifier: NCT00357552
Recruitment Status : Completed
First Posted : July 27, 2006
Results First Posted : September 25, 2012
Last Update Posted : March 20, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
AIDS Clinical Trials Group

Study Description
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Brief Summary:
Most anti-HIV regimens include a non-nucleoside reverse transcriptase inhibitor (NNRTI); however, some individuals fail on these regimens. The purpose of this study is to evaluate the safety and effectiveness of the protease inhibitor (PI) lopinavir/ritonavir (LPV/r) in HIV infected individuals who are failing an anti-HIV regimen that includes an NNRTI.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: Emtricitabine/Tenofovir disoproxil fumarate Drug: Lopinavir/Ritonavir Not Applicable

Detailed Description:

Standard effective antiretroviral therapy for HIV infected individuals includes three-drug combinations of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a PI or an NNRTI. However, three-drug regimens may not be ideal in resource-limited settings, where viral load and resistance testing may not be readily available. The purpose of this study is to evaluate the safety and efficacy of the PI LPV/r alone in treatment-experienced, PI-naive HIV infected individuals who are experiencing virologic failure on three-drug regimens.

This study will last 104 weeks. All participants will receive LPV/r twice daily for up to 104 weeks. Participants who experience virologic failure will receive emtricitabine/tenofovir disoproxil fumarate once daily in addition to LPV/r twice daily for the remainder of the study.

There will be 16 study visits for participants on LPV/r monotherapy and 12 study visits for participants who have intensified LPV/r with emtricitabine/tenofovir disoproxil fumarate. Blood collection and clinical assessment will occur at all visits; urine collection and resistance testing will occur at selected visits.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 123 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study of Lopinavir/Ritonavir in Participants Experiencing Virologic Relapse on NNRTI-Containing Regimens
Study Start Date : January 2008
Actual Primary Completion Date : October 2010
Actual Study Completion Date : May 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
U.S. FDA Resources

Arms and Interventions
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Arm Intervention/treatment
Experimental: LPV/r monotherapy
Participants will receive lopinavir/ritonavir twice daily for up to 104 weeks. Upon confirmation of virologic failure, emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) once a day will be added to their regimen.
 Drug: Emtricitabine/Tenofovir disoproxil fumarate
Once daily
Other Name: Truvada
Drug: Lopinavir/Ritonavir
Twice daily
Other Name: Kaletra, Aluvia


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy [ Time Frame: From study entry to week 24 ]
    Virologic success at week 24 on LPV/r monotherapy was defined as remaining on LPV/r monotherapy at week 24 without prior virologic failure. Virologic failure was met with either of these two conditions: (i) failure to suppress HIV-1 RNA to < 400 copies/mL by week 24 or (ii) confirmed HIV-1 RNA >= 400 copies/mL after confirmed HIV-1 RNA < 400 copies/mL.

  2. Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study. [ Time Frame: From study entry to week 24 ]
    Probability of Grade 3 or 4 sign or symptom, or laboratory toxicity over 24 weeks on study using Kaplan-Meier estimates of the cumulative probability of Grade 3 or 4 sign or symptom, or laboratory toxicity at week 24. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.


Secondary Outcome Measures :
  1. Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening. [ Time Frame: Screening ]
    Number of screened subjects with at least one NNRTI, or NRTI-associated resistance mutation. Resistance interpretations used the November 30, 2011 Stanford algorithm.

  2. Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure. [ Time Frame: Study entry to Week 104 ]
    25th percentile in weeks from study entry to treatment failure, defined as the first occurrence of death, disease progression, or virologic failure. Virologic failure was defined as HIV-1 >= 400 copies/mL after week 24 or 2 consecutive HIV-1 RNA >= 400 copies/mL after week 16 following suppression on LPV/r monotherapy.

  3. Number of Participants With Study-targeted Diagnoses and Clinical Events [ Time Frame: Study entry to week 104 ]
    Cardiac disorders, Infections and infestations, Metabolism and nutrition disorders, Neoplasms benign, malignant and unspecified (including cysts and polyps), Pregnancy, puerperium and perinatal conditions, Vascular disorders, were specified a priori as study-targeted events by the study chair.

  4. Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure. [ Time Frame: At time of virologic failure ]
    Number of subjects with at least one new PI-associated resistance mutation at time of virologic failure. Resistance interpretations used the May 6, 2009 Stanford algorithm.

  5. Percentage of Subjects Reporting Not Skipping Medications in the Last Month. [ Time Frame: Study entry and weeks 2, 4, 8, 12, 16, 20, and 24 ]
    The percentage of subjects reporting never missing medications in the last month.

  6. Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification [ Time Frame: From LPV/r intensification to week 104 ]
    25th percentile in weeks from study entry to first new grade 3 or 4 sign or symptom or laboratory toxicity following LPV/r intensification. Grading of adverse events (signs and symptoms and laboratory toxicities) was according to Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, December 2004.

  7. Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma [ Time Frame: At study entry and weeks 24 and 48 ]
    Proportion of DBS samples with HIV-1 RNA level <= 400 copies/mL, proportion of plasma samples with HIV-1 RNA level <= 400 copies/mL and proportion of paired DBS and plasma samples that are concordant (both <= 400 copies/mL or both > 400 copies/mL). Results are pooled over 4 different storage temperature conditions (-80C, -20C, 4C and room temperature).

  8. HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma [ Time Frame: At study entry and virologic failure ]
    HIV-1 viral sequencing as ascertained from paired DBS and plasma

  9. Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 [ Time Frame: At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104 ]
  10. Change in CD4+ Cell Counts From Study Entry to Week 104 [ Time Frame: Study entry and week 104 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Step 1 Participants:

  • HIV infected
  • Continuous treatment with a three-drug, NNRTI-containing regimen for at least 6 months prior to study entry
  • Viral load of 1,000 copies/ml or greater and less or equal to 200,000 copies/ml obtained within 30 days of study entry
  • Negative pregnancy test within 48 hours of study entry
  • Willing to use acceptable forms of contraception for the duration of the study

  • Laboratory values obtained within 30 days of study entry:

    • Hemoglobin greater or equal to 8.0 g/dL
    • Platelet count greater or equal to 50,000/mm3
    • Estimated Creatinine Clearance greater or equal to 60 mL/min x ULN
    • AST (SGOT), ALT (SGPT) and alkaline phosphatase < 3 x ULN
    • Total bilirubin less or equal to 2.5 x ULN
  • Ability and willingness of participant or legal guardian/representative to give informed consent

Inclusion Criteria for Step 2 Participants:

  • Virologic failure on LPV/r monotherapy defined as viral load of 400 copies/ml or greater after 24 consecutive weeks on LPV/r monotherapy OR virologic failure after initial viral suppression on LPV/r monotherapy
  • Estimated creatinine clearance of 60 ml/min or greater
  • Negative pregnancy test within 48 hours of entry into Step 2
  • Willing to use acceptable forms of contraception for the duration of the study

Exclusion Criteria for All Participants:

  • Breastfeeding
  • Known allergy or sensitivity to study drugs
  • Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with study adherence to study requirements
  • History of chronic hepatitis B infection

Exclusion Criteria for Step I Participants:

  • Prior use of any protease inhibitor treatment
  • Acute therapy for any serious medical condition within 14 days of study entry. For ongoing or chronic therapy, the participant must be on the treatment regimen for at least 14 days, and clinically stable prior to entry. If a potential participant has TB and has received treatment for more than 2 weeks, the TB treatment would have to be modified to include a rifabutin-containing regimen. TB compatible syndromes will also be carefully evaluated prior to entry.

Exclusion Criteria for Step 2 Participants:

- Active opportunistic infection, including tuberculosis (TB)

Contacts and Locations
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00357552


Locations
India
Y.R.G Ctr, for AIDS Research and Education (11701)
Chennai, India
Malawi
University of North Carolina Lilongwe CRS (12001)
Lilongwe, Malawi
South Africa
Wits HIV CRS (11101)
Johannesburg, Gauteng, South Africa
Tanzania
Kilimanjaro Christian Medical CRS
Moshi, Tanzania
Thailand
Chiang Mai University ACTG CRS (11501)
Chiang Mai, Thailand, 50202
Sponsors and Collaborators
AIDS Clinical Trials Group
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Nagalingeswaran Kumarasamy, MBBS, PhD Y. R. Gaitonde Centre for AIDS Research and Education
Study Chair: John Bartlett, MD Division of Infectious Diseases, Duke University Medical Center
More Information
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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Other Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: AIDS Clinical Trials Group
ClinicalTrials.gov Identifier: NCT00357552     History of Changes
Other Study ID Numbers: ACTG A5230
1U01AI068636 ( U.S. NIH Grant/Contract )
First Posted: July 27, 2006    Key Record Dates
Results First Posted: September 25, 2012
Last Update Posted: March 20, 2018
Last Verified: February 2018

Keywords provided by AIDS Clinical Trials Group:
Treatment Experienced

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Lopinavir
Tenofovir
Emtricitabine
 Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors