Evaluation of 3TC or FTC Mono-therapy Compared to Continuing HAART as a Bridging Strategy (P1094)

Evaluation of 3TC or FTC Mono-therapy Compared to Continuing HAART as a Bridging Antiretroviral Strategy in Persistently Non-adherent Children, Adolescents, and Young Adults Who Are Failing HAART and Have the M184V Resistance Mutation.

The purpose of this study was to compare the use of lamivudine (3TC) or emtricitabine (FTC) alone vs. continuing a failing highly active antiretroviral therapy (HAART) regimen in HIV infected children, adolescents and young adults. The study was to see if there were changes in the HIV virus and if there were differences in immune function, viral load and medication side effects between the two groups over 28 weeks. Participants were assigned to either take 3TC or FTC alone or continue on his/her current failing HAART regimen. During the first 28 weeks of this study, if the participant was randomized to the continue HAART arm, he/she was not switched to a different or new, potentially suppressive HAART regimen, but continued on the current failing HAART regimen. However, if continuing HAART, the participant might be switched to a new regimen if their provider felt that it was clinically needed or the participant met certain study endpoints (e.g., drop in CD4, increase in viral load).

At the end of 28 weeks, the participant had the choice of remaining on the assigned study group medication(s) or starting a new HAART regimen prescribed by his/her doctor. Then, they would be followed for another 24 weeks to compare the difference in immune function, viral load and medication side effects between the different groups.

Study Overview

• Status: Terminated
• Conditions: HIV Disease
• Intervention / Treatment: Drug: HAART regimen; Drug: 3TC or FTC monotherapy

Detailed Description

Currently, there is no clear consensus for managing virologic failure. Generally, failure of non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy due to non-adherence is associated with high rates of NNRTI resistance, while failure of protease inhibitor (PI)-based therapy due to non-adherence carries a much lower risk of PI resistance. In the setting of incomplete adherence and virologic failure despite adherence education, an optimal strategy would be one that effectively bridges the period between the cessation of the failing regimen of highly active antiretroviral (ARV) therapy and initiation of a new HAART regimen. This would provide time for interventions to improve adherence to be effective while minimizing accumulation of additional drug resistance mutations. Given the compelling need for an effective bridging strategy, the limited evidence for the safety and efficacy of this bridging regimen, and the high level of acceptability of studying 3TC or FTC monotherapy as an effective alternative, P1094 proposed to conduct a randomized clinical trial (RCT) comparing use of 3TC or FTC monotherapy as a short-term bridging regimen vs. continuation of non-suppressive HAART in non-adherent subjects.

This study closed early due to lack of accrual, with only 33 of the target 344 participants enrolled. Therefore analyses, including the analysis of the primary outcome, are descriptive. Only analyses for Step 1 could be done (Step 2 was observational). The following secondary analyses could not be performed:

Changes in Genotypic HIV Drug Resistance From Baseline Changes HIV Replication Capacity [Time Frame: 28 and 52 weeks] Changes in CD4 Percent and CD4+ T Cell Count [Time Frame: 52 weeks] Changes in HIV-1 RNA Levels [Time Frame: 52 Weeks] Changes in Immune Activation [Time Frame: 28 and 52 Weeks] Number and Percent of Subjects With Adverse Clinical Outcomes [Time Frame: 52 Weeks] Adherence as Measured by 3-day Recall [Time Frame: 52 Weeks]

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1221ADC
    • Hospital General de Agudos Buenos Aires Argentina NICHD CRS (5082)
• Brazil
  • Rio de Janeiro, Brazil, 26030
    • Hospital Geral De Nova Igaucu Brazil NICHD CRS (5097)
  • Sao Paulo, Brazil, 01246-900
    • Insituto de Infectologia Emilio Ribas NICHD CRS (5075)
  • Sao Paulo, Brazil, 14049-900
    • Univ of Sao Paulo Brazil NICHD CRS (5074)
• Puerto Rico
  • San Juan, Puerto Rico, 00936-5067
    • University of Puerto Rico Pediatric HIV/AIDS Research (6601)
• Thailand
  • Chiang Mai, Thailand, 50200
    • Chiang Mai University Pediatrics-Obstetrics CRS (20101)
  • Ratchathewi,
    • Bangkok, Ratchathewi,, Thailand, 10700
      • Siriraj Hospital Mahidol University CRS (8251)
• United States
  • California
    • San Francisco,, California, United States, 94117
      • Univ. of California San Francisco NICHD CRS (5091)
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Med. Ctr. Washington DC NICHD CRS (5015)
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida (5051)
    • Miami, Florida, United States, 33136
      • Univ of Miami Pediatric/Perinatal HIV/AIDS (4201)
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Chicago Children's CRS (4001)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University NICHD CRS (5092)
  • New York
    • Bronx, New York, United States, 10457
      • Bronx-Lebanon Hospital (6901)
    • New York, New York, United States, 10029
      • Metropolitan Hospital (5003)
    • Stony Brook, New York, United States, 11794
      • SUNY Stony Brook NICHD CRS (5040)
  • North Carolina
    • Durham, North Carolina, United States, 27710-3499
      • DUMC Ped. CRS (4701)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 24 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Step 1 Inclusion Criteria:

• Age greater than or equal to 8 to less than 25 years of age, at study entry
• Documentation of HIV-1 infection defined as positive results from two samples collected at different time points
• Treatment experienced patients must have demonstrated failure on the current HAART regimen for 2 months or longer. These patients must have been on ARVs for at least a total of 6 months prior to entry. Thus, if the failing regimen was the first ARV regimen, then the patient must have been on that initial regimen for a minimum of 6 months total.
• CD4+ T cell count greater than or equal to 100 cells/mm3 (confirmed on at least two occasions within 6 months of study entry, including the screening value)
• Documentation of the M184V mutation on genotypic testing at any time prior to study entry
• In the best judgment of the clinical site team, concerns about the subject's ability to adhere made it unsuitable to initiate a new optimal HAART regimen for at least 6 months.
• Subject had not become adherent despite site's adherence interventions
• Female subjects of reproductive potential engaging in sexual activity that could lead to pregnancy had to agree to avoid pregnancy during the entire 52 week trial and to consistently and appropriately use at least two of the following contraception methods: condoms, diaphragm or cervical cap with spermicide, IUD, hormonal-based contraception. A list of acceptable methods can be found at the FDA Birth Control Guide (http://www.fda.gov/womens).
• Parent/legal guardian or subject able and willing to provide signed informed consent when applicable

Step 1 Exclusion Criteria:

• Positive hepatitis B surface antigen or known active hepatitis B infection.
• Pregnant or breastfeeding.
• Active malignancy within the past 2 years.
• Current immunosuppressive therapy, including the equivalent of greater than 1 mg/kg/per day or greater than 20 mg total daily dose of prednisone in the 2 weeks preceding screening. Subjects for whom long-term systemic corticosteroid therapy (greater than 2 weeks) was anticipated were excluded. [Note: non-steroidal anti-inflammatory agents and inhaled, nasal, and topical corticosteroids were not excluded as immunosuppressive therapy.]
• Prior immunization with an HIV-specific vaccine
• Greater than or equal to 1 CDC class C event within the past 12 months.
• Renal disease (as defined by estimated creatinine clearance less than 50 mL/min/1.73m2 confirmed on two occasions within 3 months of screening).
• Active opportunistic infections, including active tuberculosis (TB).
• Current treatment for active systemic TB. If recent, infection must have completed treatment course. INH treatment for latent TB is allowed.
• Viral load greater than 250,000 copies/mL at screening.
• Known greater than or equal than Grade 3 of any of the following laboratory toxicities within 30 days prior to study entry: neutrophil count, hemoglobin, platelets, AST, ALT, lipase, serum creatinine. Note: Subjects could be re-screened and enrolled if repeat value was less than Grade 3 without signs or symptoms of related organ dysfunction.
• Known greater than or equal to Grade 4 laboratory toxicities within 30 days prior to study entry, except with approval of the study team.
• For subjects who were not taking 3TC or FTC at the time of screening: Documented prior intolerance or adverse effect reasonably attributed to 3TC or FTC that resulted in permanent discontinuation.
• Problems with non-adherence attributed to modifiable structural barriers, such as lack of resources (e.g., insurance, transportation).

Step 2 - Inclusion Criteria

• Met requirements for completion of Step 1
• Subject/guardian agree to continue participation in Step 2
• ViroSeq assay results had been received by site and reviewed by investigator

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A, non-suppressive HAART regimen; In Step 1, subjects were randomized to continue their non-suppressive HAART regimen. In Step 2, subjects either began a new HAART regimen, continued randomized treatment, or discontinued therapy while remaining on follow-up, as decided by their provider.	Drug: HAART regimen; The study participant continued their non-suppressive HAART regimen as prescribed by their primary provider.; Other Names: Highly active antiretrovial therapy (HAART)
Active Comparator: Arm B, 3TC or FTC monotherapy; In step 1, subjects were randomized to receive 3TC or FTC (the choice of 3TC or FTC was left to the provider). In Step 2, subjects either began a new HAART regimen, continued randomized treatment, or discontinued therapy while remaining on follow-up, as decided by their provider.	Drug: 3TC or FTC monotherapy; The study participant was assigned to either 3TC or FTC monotherapy (the choice of 3TC or FTC was left to the provider.; Other Names: Lamivudine (3TC); emtricitabine (FTC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Immunologic Deterioration	Immunologic deterioration was declared for a participant if any one of the following conditions is observed within the first 28 weeks: greater than or equal to 30% decline in absolute CD4+ T cell count from entry, or; development of CDC class C events. Results report number of participants with immunologic deterioration at week 28 calculated.	From entry to week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CD4+ T Cell Count	Change in CD4+ T cell count from entry to Week 28 (CD4+ at entry - CD4+ at Week 28).	Entry to week 28
Change in HIV-1 RNA Levels	Change in HIV-1 RNA levels from Entry to Week 28	28 Weeks
Number of Participants Non-adherent as Measured by 3-day Recall	Number of participants reporting a missed medication dose in the past 3 days.	28 Weeks

Collaborators and Investigators

• Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Chair: Allison L. Agwu, MD, Sc.M., Johns Hopkins University

Publications and helpful links

General Publications

• Agwu AL, Warshaw MG, McFarland EJ, Siberry GK, Melvin AJ, Wiznia AA, Fairlie L, Boyd S, Harding P, Spiegel HML, Abrams EJ, Carey VJ; P1094 Study Team. Decline in CD4 T lymphocytes with monotherapy bridging strategy for non-adherent adolescents living with HIV infection: Results of the IMPAACT P1094 randomized trial. PLoS One. 2017 Jun 12;12(6):e0178075. doi: 10.1371/journal.pone.0178075. eCollection 2017.

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: April 16, 2011
• First Submitted That Met QC Criteria: April 18, 2011
• First Posted (Estimate): April 19, 2011

Study Record Updates

• Last Update Posted (Estimate): November 13, 2015
• Last Update Submitted That Met QC Criteria: October 14, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: HIV; Strategy; Bridging
• 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; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; 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; Emtricitabine; Lamivudine
• Other Study ID Numbers: IMPAACT P1094; U01AI068632 (U.S. NIH Grant/Contract)