HIV Disease
Conditions
Keywords
HIV, Bridging, Strategy
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 \[Time Frame: 52 Weeks\]
Interventions
DRUGHAART regimen
The study participant continued their non-suppressive HAART regimen as prescribed by their primary provider.
DRUG3TC 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.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
International Maternal Pediatric Adolescent AIDS Clinical Trials Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 24 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Argentina, Brazil, Puerto Rico, Thailand, United States
Participant flow
Recruitment details
Participants were recruited from 17 sites in the United States, Argentina, Brazil and Thailand. Enrollment occurred from May 10, 2011 to January 16, 2013.
Pre-assignment details
Eligible participants were HIV-infected, ≥8 to \<25 years of age with documentation of the M184V HIV resistance mutation, were failing their current antiretroviral regimen and were persistently non-adherent. Participants were randomized equally to the two study arms.
Participants by arm
| Arm | Count |
|---|---|
| Arm A, Non-suppressive HAART Regimen In Step 1, subjects will be randomized to continue their non-suppressive HAART regimen as prescribed by their primary provider.
In Step 2, subjects will either begin a new HAART regimen, continue randomized treatment, or discontinue therapy while remaining on follow-up, as decided by their provider. | 15 |
| Arm B, 3TC or FTC Monotherapy In step 1, subjects will be randomized to receive 3TC or FTC (the choice of 3TC or FTC will be left to the provider).
In Step 2, subjects will either begin a new HAART regimen, continue randomized treatment, or discontinue therapy while remaining on follow-up, as decided by their provider. | 17 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Found ineligible after starting | 1 | 0 |
| Overall Study | Unexpected closure of study | 10 | 9 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Arm B, 3TC or FTC Monotherapy | Total | Arm A, Non-suppressive HAART Regimen |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 18 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 14 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 14 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 17 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| HIV-1 RNA viral load | 3.8 log10 copies/mL STANDARD_DEVIATION 0.7 | 3.9 log10 copies/mL STANDARD_DEVIATION 0.9 | 4.0 log10 copies/mL STANDARD_DEVIATION 1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 17 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 10 Participants | 4 Participants |
| Region of Enrollment Argentina | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Brazil | 4 participants | 5 participants | 1 participants |
| Region of Enrollment Thailand | 3 participants | 6 participants | 3 participants |
| Region of Enrollment United States | 9 participants | 18 participants | 9 participants |
| Screening CD4 count | 511 cells/mm3 STANDARD_DEVIATION 277 | 510 cells/mm3 STANDARD_DEVIATION 232 | 509 cells/mm3 STANDARD_DEVIATION 176 |
| Sex: Female, Male Female | 10 Participants | 21 Participants | 11 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 16 | 15 / 17 |
| serious Total, serious adverse events | 0 / 16 | 0 / 17 |
Outcome results
Primary
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.
Time frame: From entry to week 28
Population: All eligible participants who entered the study were included in analyses. One participant on Arm A did not meet entry eligibility criteria; was taken off study after the entry visit, and is therefore excluded from all analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A, Non-suppressive HAART Regimen | Number of Participants With Immunologic Deterioration | 0 participants |
| Arm B, 3TC or FTC Monotherapy | Number of Participants With Immunologic Deterioration | 5 participants |
p-value: 0.03Log Rank
Secondary
Change in CD4+ T Cell Count
Change in CD4+ T cell count from entry to Week 28 (CD4+ at entry - CD4+ at Week 28).
Time frame: Entry to week 28
Population: All eligible participants with CD4+ cell count results available at entry and at week 28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A, Non-suppressive HAART Regimen | Change in CD4+ T Cell Count | 27.5 CD4+ T cell count/mL |
| Arm B, 3TC or FTC Monotherapy | Change in CD4+ T Cell Count | 76 CD4+ T cell count/mL |
Secondary
Change in HIV-1 RNA Levels
Change in HIV-1 RNA levels from Entry to Week 28
Time frame: 28 Weeks
Population: All eligible participants with HIV-1 RNA results available at entry and at week 28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A, Non-suppressive HAART Regimen | Change in HIV-1 RNA Levels | 3087 copies/mL |
| Arm B, 3TC or FTC Monotherapy | Change in HIV-1 RNA Levels | -2241 copies/mL |
Secondary
Number of Participants Non-adherent as Measured by 3-day Recall
Number of participants reporting a missed medication dose in the past 3 days.
Time frame: 28 Weeks
Population: All eligible participants with adherence data available at week 28.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A, Non-suppressive HAART Regimen | Number of Participants Non-adherent as Measured by 3-day Recall | 3 participants |
| Arm B, 3TC or FTC Monotherapy | Number of Participants Non-adherent as Measured by 3-day Recall | 1 participants |