Clinical trial NCT00357552: Safety and Effectiveness of Lopinavir/Ritonavir in Individuals Who Have Failed Prior HIV Therapy
Official title: A Pilot Study of Lopinavir/Ritonavir in Participants Experiencing Virologic Relapse on NNRTI-Containing Regimens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2006-07-27
Enrollment: 123
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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)

Primary outcomes:
measure: Percentage of Enrolled Participants With Virologic Success at Week 24 on LPV/r Monotherapy
timeFrame: From study entry to week 24
measure: Probability of Grade 3 or 4 Sign or Symptom, or Laboratory Toxicity Over 24 Weeks on Study.
timeFrame: From study entry to week 24
Secondary outcomes:
measure: Number of Screened Subjects With at Least One NNRTI, or NRTI-associated Resistance Mutation at A5230 Screening.
timeFrame: Screening
measure: Time to Treatment Failure, Defined as the First Occurrence of Death, Disease Progression, or Virologic Failure.
timeFrame: Study entry to Week 104
measure: Number of Participants With Study-targeted Diagnoses and Clinical Events
timeFrame: Study entry to week 104
measure: Number of Subjects With at Least One New PI-associated Resistance Mutation at Time of Virologic Failure.
timeFrame: At time of virologic failure
measure: Percentage of Subjects Reporting Not Skipping Medications in the Last Month.
timeFrame: Study entry and weeks 2, 4, 8, 12, 16, 20, and 24
measure: Time to First New Grade 3 or 4 Sign or Symptom or Laboratory Toxicity Following LPV/r Intensification
timeFrame: From LPV/r intensification to week 104
measure: Level of HIV-1 RNA as Ascertained From Paired DBS and Plasma
timeFrame: At study entry and weeks 24 and 48
measure: HIV-1 Viral Sequence as Ascertained From Paired DBS and Plasma
timeFrame: At study entry and virologic failure
measure: Proportion of Participants With Plasma HIV-1 RNA Levels < 400 Copies/mL From Baseline to Week 104
timeFrame: At Weeks 0, 12, 16, 20, 24, 32, 40, 48, 56, 68, 80, 92, 104
measure: Change in CD4+ Cell Counts From Study Entry to Week 104
timeFrame: Study entry and week 104
Other outcomes:
Locations:
city: Chennai
country: India
facility: Y.R.G Ctr, for AIDS Research and Education (11701)
city: Lilongwe
country: Malawi
facility: University of North Carolina Lilongwe CRS (12001)
city: Johannesburg
country: South Africa
facility: Wits HIV CRS (11101)
state: Gauteng
city: Moshi
country: Tanzania
facility: Kilimanjaro Christian Medical CRS
city: Chiang Mai
country: Thailand
facility: Chiang Mai University ACTG CRS (11501)
Study officials:
affiliation: Y. R. Gaitonde Centre for AIDS Research and Education
name: Nagalingeswaran Kumarasamy, MBBS, PhD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Duke University Medical Center
name: John Bartlett, MD
role: STUDY_CHAIR
References:
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citation: Campo RE, Lalanne R, Tanner TJ, Jayaweera DT, Rodriguez AE, Fontaine L, Kolber MA. Lopinavir/ritonavir maintenance monotherapy after successful viral suppression with standard highly active antiretroviral therapy in HIV-1-infected patients. AIDS. 2005 Mar 4;19(4):447-9. doi: 10.1097/01.aids.0000161777.38438.ed. No abstract available.
citation: Joly V, Descamps D, Peytavin G, Touati F, Mentre F, Duval X, Delarue S, Yeni P, Brun-Vezinet F. Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs. Antimicrob Agents Chemother. 2004 Jan;48(1):172-5. doi: 10.1128/AAC.48.1.172-175.2004.
citation: Bartlett JA, Ribaudo HJ, Wallis CL, Aga E, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Kallungal BA, Kumarasamy N. Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS. 2012 Jul 17;26(11):1345-54. doi: 10.1097/QAD.0b013e328353b066.
citation: Kumarasamy N, Aga E, Ribaudo HJ, Wallis CL, Katzenstein DA, Stevens WS, Norton MR, Klingman KL, Hosseinipour MC, Crump JA, Supparatpinyo K, Badal-Faesen S, Bartlett JA. Lopinavir/Ritonavir Monotherapy as Second-line Antiretroviral Treatment in Resource-Limited Settings: Week 104 Analysis of AIDS Clinical Trials Group (ACTG) A5230. Clin Infect Dis. 2015 May 15;60(10):1552-8. doi: 10.1093/cid/civ109. Epub 2015 Feb 18.