4-Day-A-Week Treatment Plan for HIV Infected Adolescents

• Assess CD4+ T-cell count over time for subjects on SCT from baseline to week 48 [ Time Frame: 48 Weeks ] [ Designated as safety issue: Yes ]
  To assess CD4+ T-cell count over time for subjects on SCT from baseline to week 48. These values will be compared at (1) the period of time from study entry to viral load rebound (> 400 copies/ml), (2) the period of time from study entry to subject dropout, or (3) the period of time from study entry to administrative end of study at 48 weeks, depending on each subject's disposition.
• Compare differences in various values from study entry to Weeks 24 and 48 [ Time Frame: 48 Weeks ] [ Designated as safety issue: Yes ]
  To compare differences in fasting cholesterol, triglycerides, LDL, HDL, and VLDL levels from study entry to weeks 24 and 48
• Assess the adherence level over time [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
  To assess the adherence level over time using the PACTG Pediatric Adherence Questionnaire Module I, every two weeks up to week 24 and every four weeks until week 48
• Assess genotypic resistance as necessary [ Time Frame: 48 Weeks ] [ Designated as safety issue: Yes ]
  To assess subject-specific plasma genotypic resistance for subjects with viral load >1000 copies/ml at time of viral load rebound.

• CD4+ T-cell count monthly to week 24 and then every other month to week 48
• Difference between levels of fasting cholesterol, triglycerides, LDL, HDL, and VLDL from study entry to week 24, and from study entry to administrative end of study at 48 weeks
• Adherence levels over time (Using the PACTG Pediatric Adherence Questionnaire Module I) will be measured as another secondary outcome

This study will determine if taking anti-HIV drugs 4 days a week will control HIV-1 viral replication in patients who have already had at least 6 months of documented viral suppression with full-time treatment. If this strategy is shown to be safe in this study, a larger study will be undertaken to determine if the strategy can decrease overall drug exposure and help young people adjust more easily to a chronic medication schedule.

HIV infected adolescents who require therapy face a lifetime of antiretroviral treatment. Highly active antiretroviral therapy (HAART) is associated with short- and long-term complications, and concerns are mounting about the cumulative effect of these complications as adolescents enter the third and fourth decade of life. A management strategy that can suppress the virus and decrease overall drug exposure is needed. In addition, the scheduling requirements for antiretroviral therapies interfere with the socialization and independence that an adolescent must accomplish to gain skills for a successful adult life. Not surprisingly, nonadherence to prescribed medications is common in teens. This multicenter, prospective, proof of concept trial will evaluate Short Cycle Therapy (SCT) in adolescents with sustained viral suppression of at least 6 months. While maintenance of viral load suppression can be viewed as either a safety or efficacy endpoint, the trial is constructed as an assessment of safety.

Eligible participants who have been on standard HAART therapy consisting of a Protease Inhibitor will switch to SCT therapy(4 days on treatment, 3 days off treatment each week) at entry. Participants will be seen in the clinic every other Monday during the first month, then monthly up to 24-weeks and then once every two months until the end of the 48-week study period. Plasma HIV RNA levels and CD4 cell counts will be performed at every visit. Medication adherence by self-report will be conducted every 2 weeks until week 24 and every 4-weeks thereafter until week 48. Fasting serum triglycerides and cholesterol will be measured at baseline, at week 24 and at the end of the study.

Inclusion Criteria:

• Twelve to 24 years of age, regardless of the mode of transmission.
• Subjects must have been on a stable HAART regimen containing at least one PI and two NRTIs and no NNRTI for at least 3 months and be willing to continue the PI-containing regimen throughout the study period.
• Acceptable viral load defined as at least three plasma HIV-1 RNA levels ≤ 400 copies/ml within 12 months of study entry and no plasma HIV-1 RNA levels > 400 copies/ml within 6 months of entry date employing any clinically available viral load assay.
• Pre entry plasma HIV-1 RNA level <200 copies/ml by ultra-sensitive assay (Roche 1.5) within 30 days of study entry, performed in an assigned PACTG core virology laboratory.
• CD4+ T cell count >350 cells/microL within 30 days of study entry.
• Ability of subject and parent or legal guardian (when appropriate) to give written informed assent/consent and permission respectively.

• Subjects currently enrolled in ATN 015 Version 2.0 are eligible as follows:

  • Subjects randomized to standard continuous therapy (control arm). These subjects are eligible to be enrolled in ATN 015 Version 3.0 as new subjects if they meet the entry criteria for ATN Version 3.0. If eligible, they will be followed for the full 48 weeks.
  • Subjects randomized to short cycle therapy (experimental arm). These subjects are eligible to rollover to ATN 015 Version 3.0 and continue on SCT if they have not met a study endpoint. These subjects may not have a viral load value that meets a study endpoint (viz. a confirmed viral load of >400 copies/ml) and will continue on the intensive monitoring until they have completed 24 weeks when they will enter the less intensive 24 week phase of the study.
• Female subjects must be non-pregnant and willing to remain on effective contraception for the duration of the study. (Examples of acceptable forms of birth control include but are not limited to any form of hormonal contraception along with a barrier method, double barrier method, tubal ligation, or abstinence if it is the choice of the subject.)

Exclusion Criteria:

• On a HAART regimen containing an NNRTI or a HAART regimen with Abacavir (including Trizivir®).
• On any prohibited medication at the time of screening. Subjects with underlying reactive airway disease who are on either inhaled or brief, intermittent systemic steroids can be considered but their status must be reviewed with the protocol chair or vice chair through the standard ATN protocol query process.
• Active HIV-related opportunistic infection or any malignancy at the time of screening. (Female subjects who have been treated adequately for cervical dysplasia or CIN are eligible for study unless they are on systemic immunosuppressive therapy).
• Current treatment for known or suspected active serious bacterial infection.
• Pregnancy.
• Any laboratory abnormalities Grade 3 or greater as defined in Appendix III at the time of screening.
• Subjects receiving pharmacological treatment for elevated cholesterol and triglyceride levels.

If a candidate fails the eligibility criteria (inclusion or exclusion), she or he may be screened again for eligibility after a period of 30 days.

• National Institute on Drug Abuse (NIDA)
• National Institute of Mental Health (NIMH)
• National Institute on Alcohol Abuse and Alcoholism (NIAAA)