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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Pilot Study of Lopinavir/Ritonavir in Participants Experiencing Virologic Relapse on NNRTI-Containing Regimens

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Emtricitabine/Tenofovir disoproxil fumarate
* Drug: Lopinavir/Ritonavir


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LPV/r monotherapy<br>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<br>* Once daily<br>* Other names: Truvada;Drug: Lopinavir/Ritonavir<br>* Twice daily<br>* Other names: Kaletra, Aluvia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy | 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. | From study entry to week 24 | 
| Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study. | 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. | From study entry to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening. | Number of screened subjects with at least one NNRTI, or NRTI-associated resistance mutation. Resistance interpretations used the November 30, 2011 Stanford algorithm. | Screening | 
| Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure. | 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. | Study entry to Week 104 | 
| Number of Participants With Study-targeted Diagnoses and Clinical Events | 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. | Study entry to week 104 | 
| Number of Subjects With at Least One New PI-associated Resistance Mutation 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. | At time of virologic failure | 
| Percentage of Subjects Reporting Not Skipping Medications in the Last Month. | The percentage of subjects reporting never missing medications in the last month. | Study entry and weeks 2, 4, 8, 12, 16, 20, and 24 | 
| Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification | 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. | From LPV/r intensification to week 104 | 
| Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma | 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). | At study entry and weeks 24 and 48 | 
| HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma | HIV-1 viral sequencing as ascertained from paired DBS and plasma | At study entry and virologic failure | 
| Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104 |  | At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104 | 
| Change in CD4+ Cell Counts From Study Entry to Week 104 |  | Study entry and week 104 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced