Effect of Addition of Raltegravir (MK-0518) to PI- or NNRTI-Based ART Regimens in HIV Infected Subjects With Undetectable Viral Load

A Double-Blind, Randomized, Pilot Study to Measure the Effect of Treatment Intensification With a Potent Integrase Inhibitor, Raltegravir (MK-0518), on the Level of Persistent Plasma Viremia Below 50 Copies/ml in Subjects on Protease Inhibitor- or Non-Nucleoside Reverse Transcriptase Inhibitor-Containing Regimens

Raltegravir (MK-0518) is an HIV-1 integrase inhibitor with potent in vitro activity against HIV-1 strains including those resistant to currently available antiretroviral drugs. The purpose of this study is to assess the effectiveness of raltegravir in further reducing viral load in HIV infected patients that have already achieved viral suppression below the level of detection of standard viral load assays when added to antiretroviral therapy (ART).

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Raltegravir (MK-0518); Drug: Placebo

Detailed Description

Although ART has reduced the morbidity and mortality from HIV-1 infection, most individuals who stop ART experience rapid viral rebound. Effective ART can suppress viral load to less than 50 copies/ml; however, current treatment regimens cannot completely eliminate the infection. The primary purpose of this study was to assess the ability of the HIV-1 integrase inhibitor, raltegravir, to reduce viral load when added to ART regimens of HIV-1 infected patients who have achieved viral suppression to less than 50 copies/ml.

The study lasted 24 weeks. Participants were randomly assigned to one of two arms. Participants in Arm A were administered raltegravir in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted raltegravir use and received a placebo until Week 24. Participants in Arm B were administered the placebo in addition to their usual ART regimen from study entry until Week 12. At Week 12, subjects halted the placebo and received raltegravir until Week 24. A real-time polymerase chain reaction (PCR) single copy assay (SCA) capable of detecting 1 copy of HIV RNA was used to assay viral load. The cross-over design allowed assessment of the effect of intensification with raltegravir between the two arms at Weeks 10/12 and every participant enrolled in the study receiving raltegravir for 12 weeks. Primary analysis focused on weeks 10/12 measurement and with no washout period, typical analysis of cross-over design was not intended.

All participants had scheduled visits at Weeks 0, 2, 4, 10, 12, 14, 16, 22, and 24. A targeted physical exam occurred at all visits. Blood and urine collection occurred at selected visits. A medical/medication assessment occurred at trial entry. Drug dispensing and an adherence questionnaire occurred at some visits. A pregnancy test occurred at select visits. Participants' background ART medications were not provided by the study.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-2050
      • Alabama Therapeutics CRS
  • California
    • Palo Alto, California, United States, 94304-5350
      • Stanford CRS
    • San Francisco, California, United States, 94110
      • Ucsf Aids Crs
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital CRS
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington U CRS
  • New York
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS
    • New York, New York, United States, 10032-3732
      • Columbia P&S CRS
    • New York, New York, United States, 10011
      • Cornell CRS
    • New York, New York, United States, 10037
      • Harlem ACTG CRS
    • Rochester, New York, United States, 14642
      • Univ. of Rochester ACTG CRS
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Unc Aids Crs
    • Durham, North Carolina, United States, 27710
      • Duke Univ. Med. Ctr. Adult CRS
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • MetroHealth CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp. of the Univ. of Pennsylvania CRS
    • Pittsburgh, Pennsylvania, United States, 15213-2582
      • Pitt CRS
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS

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:

• HIV-1 Infection
• ART for at least 12 months prior to study entry that includes at least two NRTIs and either an NNRTI or a ritonavir-boosted PI
• No change in ART regimen for at least 3 months prior to study entry
• CD4 count of 200 or more at screening
• Viral load below the limit of quantification of an ultrasensitive assay for at least 6 months prior to study entry
• Viral load less than 50 copies/ml using Roche Amplicor HIV-1 RNA Ultrasensitive assay within 60 days of study entry
• All viral load assays obtained within 6 months prior to study entry lower than limits of quantification on all tests
• Pre-ART viral load level greater than 100,000 copies/ml
• Detectable viral load of 1 copy or more on the screening SCA
• Available pre-study entry plasma sample for SCA viral load determination
• Absolute neutrophil count of 750/mm3 or more
• Hemoglobin of 9 g/dL or more for female subjects and 10 g/dL or more for male subjects
• Platelet count of 50,000/mm3 or more
• Calculated creatinine clearance of 30 ml/min or more
• AST, ALT, and alkaline phosphate less than or equal to 5 x ULN
• Total bilirubin less than or equal to 2.5 x ULN. If subject is taking indinavir or atazanavir at screening, total bilirubin must be less than or equal to 5 x ULN.
• Negative serum or urine pregnancy test within 48 hours prior to study entry for females with reproductive potential
• Willing to use acceptable means of contraception

Exclusion Criteria:

• Previous documented virologic failure on an antiretroviral regimen
• Unstable clinical condition that would preclude the subject from undergoing study procedures
• Use of immunosuppressive medications within 60 days prior to study entry. Participants using inhaled or nasal steroids are not excluded.
• Opportunistic infection within 60 days prior to study entry
• Allergy or sensitivity to components of study drug
• Active drug or alcohol abuse
• Serious illness requiring systemic treatment within 60 days prior to study entry
• Receipt of non-HIV vaccination within 30 days prior to study entry
• Receipt of any HIV vaccines
• Plan to change background ART within 24 weeks after study entry
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Raltegravir then Placebo (Arm A); 400 mg raltegravir (MK-0518) administered twice daily in addition to optimized background regimen (OBR) from entry to Week 12; halt raltegravir at Week 12 and add placebo twice daily for 12 weeks	Drug: Raltegravir (MK-0518); 400 mg tablet taken orally twice daily; Drug: Placebo; 400 mg placebo tablet taken orally twice daily
Experimental: Placebo then Raltegravir (Arm B); Placebo administered twice daily in addition to OBR from entry until Week 12; halt placebo at Week 12 and add 400 mg raltegravir tablet twice daily for 12 weeks	Drug: Raltegravir (MK-0518); 400 mg tablet taken orally twice daily; Drug: Placebo; 400 mg placebo tablet taken orally twice daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HIV-1 RNA Level	HIV-1 RNA level, as measured by single copy assay (units are copies/ml), averaged at weeks 10 and 12. The quantification limit of single copy assay was determined by the volume of plasma tested. When averaging the week 10 and 12 measurements, if one of both measurements were below the single copy assay lower limits, the lower limit of quantification was used to compute the average and the result was treated as below the averaged value.	At Weeks 10 and 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HIV-1 RNA Level	Change in HIV-1 RNA level, as measured by single copy assay (units are copies/ml), from baseline to weeks 10/12 . When averaging the measurements at pre-entry and entry, and at weeks 10 and 12, measurements below the lower limit of quantification (LLQ) were imputed a value of the LLQ divided by 2.	At pre-entry, entry, weeks 10 and 12
Change in Total CD4 Cell Count	CD4 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12	At pre-entry, entry, and week 12
Change in Total CD8 Cell Count	CD8 cell counts were assessed by flow cytometry at pre-entry and entry (the baseline value was the average of the two measurements) and at week 12	At pre-entry, entry, and week 12
Change in CD4+/CD38+/HLA-DR+ Percent	Level of CD4+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD4+/CD38+/HLA-DR+% at week 12 minus CD4+/CD38+/HLA-DR+% at baseline.	At pre-entry, entry, and week 12
Change in CD8+/CD38+/HLA-DR+ Percent	Level of CD8+ T-cell activation was determined by measuring the percentage of cells that expressed both the activation marker CD38 and Human leukocyte antigen (HLA)-DR. Levels measured at pre-entry and entry were averaged. Change from baseline to week 12 was defined as CD8+/CD38+/HLA-DR+% at week 12 minus CD8+/CD38+/HLA-DR+% at baseline.	At pre-entry, entry, and week 12
Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From First Day of Treatment to Week 12	Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are "possibly", "probably" or "definitely" related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.	From first day of treatment to week 12
Number of Participants Who Experienced Study Related Grade 2 or Higher Signs/Symptoms, Grade 3 or Higher Laboratory Abnormalities and Clinical Events From Week 12 to Week 24	Participant who experienced at least one study related grade 2 or higher signs/symptoms, grade 3 or higher laboratory abnormalities and clinical events that are 'possibly', probably', or definitely' related to study treatment. DAIDS Toxicity Grading Table (2004) was used for grading.	From week 12 to week 24
Number of Participants Who Discontinued Study Drug	Participants who discontinued randomized study treatment for any reason	From first day of treatment to week 12

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Rajesh T Gandhi, MD, Massachusetts General Hospital; Study Chair: Joseph J Eron Jr., MD, University of North Carolina, Chapel Hill; Study Chair: John W Mellors, MD, University of Pittsburgh Medical Center

Publications and helpful links

General Publications

• Grinsztejn B, Nguyen BY, Katlama C, Gatell JM, Lazzarin A, Vittecoq D, Gonzalez CJ, Chen J, Harvey CM, Isaacs RD; Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007 Apr 14;369(9569):1261-1269. doi: 10.1016/S0140-6736(07)60597-2.
• Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.
• Markowitz M, Morales-Ramirez JO, Nguyen BY, Kovacs CM, Steigbigel RT, Cooper DA, Liporace R, Schwartz R, Isaacs R, Gilde LR, Wenning L, Zhao J, Teppler H. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2006 Dec 15;43(5):509-15. doi: 10.1097/QAI.0b013e31802b4956. Erratum In: J Acquir Immune Defic Syndr. 2007 Apr 1;44(4):492.
• Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, Alatrakchi N, Jacobson JM, Wiegand A, Kearney M, Coffin JM, Mellors JW, Eron JJ; AIDS Clinical Trials Group A5244 team. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010 Aug 10;7(8):e1000321. doi: 10.1371/journal.pmed.1000321.
• Gandhi RT, Coombs RW, Chan ES, Bosch RJ, Zheng L, Margolis DM, Read S, Kallungal B, Chang M, Goecker EA, Wiegand A, Kearney M, Jacobson JM, D'Aquila R, Lederman MM, Mellors JW, Eron JJ; AIDS Clinical Trials Group (ACTG) A5244 Team. No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr. 2012 Mar 1;59(3):229-35. doi: 10.1097/QAI.0b013e31823fd1f2.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): November 1, 2008

Study Registration Dates

• First Submitted: August 10, 2007
• First Submitted That Met QC Criteria: August 10, 2007
• First Posted (Estimate): August 14, 2007

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: November 2, 2021
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Treatment Experienced
• 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; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Raltegravir Potassium
• Other Study ID Numbers: A5244; 10440 (Other Identifier: CTEP); ACTG A5244