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

Phase 4

Terminated

Conditions: HIV Disease

Interventions: Drug: HAART regimen
Drug: 3TC or FTC monotherapy

Registration Number: NCT01338025

Lead Sponsor: International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Brief Summary: 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.

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 \[Time Frame: 52 Weeks\]

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 33

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A, non-suppressive HAART regimen	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.
Arm B, 3TC or FTC monotherapy	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Immunologic Deterioration	From entry to week 28	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.

Secondary Outcome Measures

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

Trial Locations

Locations (17): Univ of Sao Paulo Brazil NICHD CRS (5074)
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Sao Paulo, Brazil
Metropolitan Hospital (5003)
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New York, New York, United States
University of Florida (5051)
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Jacksonville, Florida, United States
Bronx-Lebanon Hospital (6901)
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Bronx, New York, United States
Univ of Miami Pediatric/Perinatal HIV/AIDS (4201)
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Miami, Florida, United States
SUNY Stony Brook NICHD CRS (5040)
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Stony Brook, New York, United States
Chicago Children's CRS (4001)
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Chicago, Illinois, United States
DUMC Ped. CRS (4701)
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Durham, North Carolina, United States
Siriraj Hospital Mahidol University CRS (8251)
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Bangkok, Ratchathewi,, Thailand
Chiang Mai University Pediatrics-Obstetrics CRS (20101)
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Chiang Mai, Thailand
Univ. of California San Francisco NICHD CRS (5091)
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San Francisco,, California, United States
Children's National Med. Ctr. Washington DC NICHD CRS (5015)
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Washington, District of Columbia, United States
Johns Hopkins University NICHD CRS (5092)
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Baltimore, Maryland, United States
Hospital General de Agudos Buenos Aires Argentina NICHD CRS (5082)
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Buenos Aires, Argentina
Insituto de Infectologia Emilio Ribas NICHD CRS (5075)
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Sao Paulo, Brazil
Hospital Geral De Nova Igaucu Brazil NICHD CRS (5097)
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Rio de Janeiro, Brazil
University of Puerto Rico Pediatric HIV/AIDS Research (6601)
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San Juan, Puerto Rico