The purpose of this study is to see if the full daily dose of Combivir (zidovudine [ZDV]/lamivudine [3TC]) taken once a day is as effective as the usual recommended twice-a-day dose. Studies have shown that the antiviral activity of ZDV can continue in the body even after there does not appear to be any ZDV left in the blood. This occurs because the body breaks down the drug into substances that remain active against HIV. The body also breaks down 3TC, a drug that is combined with ZDV in the Combivir product, in a similar way. Since antiviral activity may continue after Combivir is removed from the body, it may not be necessary to take the drug as often as once thought. This study carefully measures levels of the active substances in order to find out whether the same amount of antiviral activity occurs with less-frequent dosing.

Condition	Treatment or Intervention	Phase
HIV Infections	Drug: Lamivudine/Zidovudine	Phase I

Further Study Details: 

Expected Total Enrollment:  20

Initial dosing regimens of ZDV were based on the plasma half-life of the drug. However, recent studies of the intracellular metabolism of ZDV have demonstrated that the active anabolite, ZDV-TP, is present within the cell for an extended period of time relative to the drug in the plasma. This suggests that antiviral activity may be present for a sufficient time frame with less-frequent dosing of the drug. Careful comparison of the rate and extent of intracellular phosphorylated ZDV metabolites as a function of schedule will determine whether less-frequent dosing has a sound pharmacological basis. Also, the intracellular metabolism of 3TC is via different enzymes than that of ZDV and there are quantitative differences in the amount of triphosphate formed from both drugs. This study will provide information about intracellular metabolites when both ZDV and 3TC are concurrently administered.

This is a study of 2 schedules of Combivir therapy. At study entry or Part I, all patients take Combivir twice daily for the 7-day adherence assessment. Patients who have demonstrated 70 percent or greater adherence [AS PER AMENDMENT 7/20/01: 70 percent compliance with the study regimen for Combivir. This corresponds to taking at least 10 of the prescribed 14 Combivir tablets during the 7 days prior to an adherence assessment, including all scheduled doses in the 24-hour period prior to that assessment.], and have taken all scheduled Combivir doses in the previous 24 hours, have pharmacokinetic samples obtained and are randomized to Group A or Group B in Part II. Group A patients take 2 Combivir tablets once daily; Group B patients take 1 Combivir tablet twice daily. After patients have completed the targeted duration of Part II (7 days for Group A and 7-14 days for Group B), they are assessed for adherence. Patients who have demonstrated 70 percent or greater adherence, and have taken all scheduled Combivir doses in the previous 24 hours, have pharmacokinetic samples obtained and then change to the alternate dosing schedule. Group A patients take 1 Combivir tablet twice daily; Group B patients take 2 Combivir tablets once daily. After patients have completed the targeted duration of Part III (7-14 days for Group A and 7 days for Group B), they are assessed for adherence. All patients who meet the adherence criteria have pharmacokinetic samples obtained. After completion of Part III pharmacokinetic studies, patients have completed the study. (Note: Combivir will not be provided in this study.)

Ages Eligible for Study:  12 Years   -   24 Years,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Patients may be eligible for this study if they:

• Are 12 through 24 years of age.
• Are HIV-positive.
• Weigh more than 40 kg.
• Have a CD4 cell count above 250 cells/microL.
• Have taken at least 4 weeks of 3 or more anti-HIV medications, which must include ZDV and 3TC (as individual drugs or Combivir) and either a protease inhibitor or nonnucleoside reverse transcriptase inhibitor, and do not plan to change these medications during the study period.
• Have consent of a parent or guardian if under 18 years of age.
• Have a negative pregnancy test, if female and able to have children.
• Agree to use 2 effective methods of birth control (birth control pills plus a barrier method or 2 barrier methods) while taking study medication, if female and able to have children.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have an opportunistic (AIDS-related) infection that requires treatment at study entry.
• Are receiving anti-cancer medications for cancer.
• Are taking certain anti-HIV medications (nucleoside or nucleotide reverse transcriptase inhibitors, other than ZDV and 3TC), or hydroxyurea.
• Are pregnant or breast-feeding.
• Have diseases (other than HIV infection) or other conditions that, in the investigator's opinion, would interfere with the study.

California
      Los Angeles County - USC Med Ctr, Los Angeles,  California,  90033,  United States
      Univ of California, San Diego, San Diego,  California,  92103,  United States
Florida
      Univ of Florida Health Science Ctr / Pediatrics, Jacksonville,  Florida,  32209,  United States
Georgia
      Emory Univ Hosp / Pediatrics, Atlanta,  Georgia,  30306,  United States
Illinois
      Chicago Children's Memorial Hosp, Chicago,  Illinois,  606143394,  United States
      Cook County Hosp, Chicago,  Illinois,  60612,  United States
      Mt Sinai Hosp Med Ctr / Dept of Pediatrics, Chicago,  Illinois,  60608,  United States
Louisiana
      Tulane Univ / Charity Hosp of New Orleans, New Orleans,  Louisiana,  701122699,  United States
Massachusetts
      Children's Hosp of Boston, Boston,  Massachusetts,  021155724,  United States
Mississippi
      Univ of Mississippi Med Ctr, Jackson,  Mississippi,  39213,  United States
New Jersey
      Univ of Medicine & Dentistry of New Jersey / Univ Hosp, Newark,  New Jersey,  071032714,  United States
      St Joseph's Hosp & Med Center, Paterson,  New Jersey,  07503,  United States
New York
      Metropolitan Hosp Ctr, New York,  New York,  10029,  United States
      SUNY Health Sciences Ctr at Syracuse / Pediatrics, Syracuse,  New York,  13210,  United States
      State Univ of New York at Stony Brook, Stony Brook,  New York,  117948111,  United States
Pennsylvania
      Children's Hosp of Philadelphia, Philadelphia,  Pennsylvania,  191044318,  United States
      Temple University School of Medicine, Philadelphia,  Pennsylvania,  19140,  United States
Tennessee
      Saint Jude Children's Research Hosp of Memphis, Memphis,  Tennessee,  381052794,  United States
Texas
      Texas Children's Hosp / Baylor Univ, Houston,  Texas,  77030,  United States
Puerto Rico
      Univ of Puerto Rico / Univ Children's Hosp AIDS, San Juan,  009365067,  Puerto Rico

Study chairs or principal investigators

Patricia Flynn,  Study Chair

Study ID Numbers:  ACTG P1012; PACTG P1012
Record last reviewed:  August 2004
Last Updated:  April 7, 2005
Record first received:  April 7, 2001
ClinicalTrials.gov Identifier:  NCT00014014
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08