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

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]

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