Clinical trial NCT00214890: Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir
Official title: CCTG584: Viral Dynamics and Pharmacokinetics of Tenofovir and Abacavir Monotherapy Versus the Combination Therapy of TDF-ABC in HIV-Infected Treatment Naive Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: HIV
nucleoside pharmacology
drug-drug interaction
Treatment Naive
Drug resistance
Drug pharmacokinetics
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Universitywide AIDS Research Program
name: GlaxoSmithKline
name: University of California, Irvine
name: University of California, Los Angeles
name: University of Southern California
name: Santa Clara Valley Medical Center
First posted: 2005-09-22
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a comparative, open-labeled study of a dual NRTI regimen, TDF + ABC, compared to ABC and TDF monotherapy administered for 7 days. Each patient will be randomized to a 7-day sequence of either ABC or TDF once-daily followed by a 35-day washout period. After completion of the monotherapy sequence all patients will then receive dual NRTI therapy of TDF + ABC for an additional 7 days. After completion of the dual NRTI sequence patients will enter the HAART treatment stage with the addition of EFV and continue on a once-daily regimen of EFV + ABC + TDF for an additional 14 days. At day 63, TDF will be stopped and 3TC will be substituted. Patients will then continue on a once-daily regimen of EFV + ABC + 3TC for an additional 46 weeks.
Primary purpose: TREATMENT

Brief summary: Once-daily nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combinations form the backbone of many regimens. Although efficacy data exists between tenofovir and the pyrimidine analogues (i.e. lamivudine and emtricitabine), recent clinical data suggests a potential interaction between tenofovir and purine analogs (i.e. abacavir and didanosine).

Specific Aim 1: To evaluate the impact of an acyclic nucleoside phosphonate, tenofovir (TDF), on the intracellular metabolism of a purine nucleoside analog, abacavir (ABC), as a determinant of the antiviral potency of this nucleotide/nucleoside reverse transcriptase inhibitor (NtRTI/NRTI) combination.

* Hypothesis #1: ABC and TDF dosed together will have reduced antiviral activity, as measured by early plasma HIV RNA decay kinetics, than the drugs given alone.
* Hypothesis #2: ABC dosed with TDF will have reduced intracellular concentrations, as measured by the ratio of carbovir triphosphate (active metabolite of ABC) to deoxyguanosine triphosphate (endogenous nucleotide), compared to ABC given alone.

Detailed description: The primary objectives of this study are to compare the virologic potency and pharmacology of TDF and ABC alone and in combination. Since it is not feasible or ethical to give mono or dual-therapy with these agents for prolonged intervals, this project was designed to take advantage of a short term drug exposure. The study performs intensive lab monitoring with a cross-over design to compare short courses of monotherapy and dual-therapy. This is an open-labeled study of a dual NRTI/NtRTI combination, ABC + TDF, compared to ABC and TDF monotherapy administered for 7 days. A screening genotype will be done to confirm that there are no resistance-associated mutations at baseline. Each subject will then be randomized to a 7-day sequence of monotherapy (ABC or TDF), and four measurements for plasma HIV RNA will be done to calculate the slope of the phase one viral decay. Prior to initiation of nucleoside analogues, PBMCs will be collected to measure baseline expression of nucleoside transport enzymes via RT-PCR and Western blot analysis. On days 7 and 8, serial blood specimens will be collected for plasma and intracellular levels of TDF and ABC. The monotherapy sequence will be followed by a 35-day washout period.

After the washout (day 42), subjects will initiate the dual NRTI/NtRTI therapy sequence for an additional 7 days. During dual NRTI/NtRTI therapy, again, four measurements for HIV RNA will be done to calculate the slope of the phase one viral decay. On day 48 and 49, serial plasma and intracellular levels of ABC + TDF will be evaluated. On Day 49 a second HIV genotype will be performed in real time. On day 49, after the second 7-day sequence, all subjects will receive EFV in addition to the ABC + TDF combination for 14 days. Afterwards, a second sample of PBMCs will be collected to evaluate for a potential induction or suppression of nucleoside transport enzymes. Since the long-term efficacy of the TDF + ABC nucleoside backbone is not yet known, TDF will be discontinued (day 63) and 3TC will be substituted. Subjects will then continue on the HAART portion of the study for an additional 46 weeks of EFV + ABC + 3TC.

Eligibility criteria: Inclusion Criteria:

1. HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
2. Antiretroviral naïve defined as no prior therapy.
3. CD4+ cell count \> than 200 cells/ mm3 determined by site clinical laboratory within 90 days of screening.
4. HIV-1 RNA level \> 5000 copies/mL obtained by site clinical laboratory within 90 days of screening.
5. Laboratory values obtained by screening laboratories within 30 days of entry:

   * Absolute neutrophil count (ANC) ≥ 750/mm3.
   * Hemoglobin ≥ 8.0 g/dL.
   * Platelet count ≥ 50,000/mm3.
   * Calculated creatinine clearance (CrCl) \> 50 mL/min as estimated by the
   * AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 5 x ULN.
   * Total bilirubin ≤ 2.5 x ULN.
6. Negative serum or urine pregnancy test within 30 days of study entry.
7. Karnofsky performance score ≥ 70.
8. Men and women age ≥ 18 years.
9. Ability and willingness of subject to give written informed consent.

Exclusion Criteria:

1. Any NRTI or NNRTI-associated resistance mutations as defined by the updated International AIDS Society-USA (IAS-USA) mutation list.
2. Pregnancy and breast-feeding.
3. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
4. Urgent need to initiate antiretroviral therapy, as determined by the patient's primary provider.
5. Serious illness (requiring systemic treatment and/or hospitalization) until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 14 days prior to study entry.
6. Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry.
7. Use of human growth hormone within 30 days prior to study entry.
8. Initiation of testosterone or anabolic steroids within 30 days prior to study entry. (Exception: Chronic replacement dosages in patient's with diagnosed hypogonadism is allowed)

Primary outcomes:
measure: Change in Short-term Virologic Response
timeFrame: 49 days
measure: Compare the Plasma Data of the Two Monotherapy Regimens to the Dual NRTI Regimen
timeFrame: 49 days
measure: Compare the Intracellular Pharmacokinetic (PK) Data of the Two Monotherapy Regimens to the Dual NRTI Regimen
timeFrame: 49 days
Secondary outcomes:
measure: Evaluate Change in Cellular Regulatory Enzymes Involved With Nucleoside Analogue Transport Across Cell Membranes as Assessed by RT-PCR of Specific mRNA Transcripts
timeFrame: Day 1 and Day 63
measure: Determine Total Number of NRTI-associated Mutations After 7 Days of ABC or TDF Monotherapy or After 7 Days of Dual NRTI Therapy With ABC + TDF
timeFrame: 7 days
measure: Compare the Relative Viral Potency of TDF Monotherapy Versus ABC Monotherapy
timeFrame: Baseline and day 7
Other outcomes:
Locations:
city: Irvine
country: United States
facility: UCI
state: California
city: Los Angeles
country: United States
facility: USC
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Medical Center
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
Study officials:
affiliation: University California San Diego
name: Richard H Haubrich, MD
role: STUDY_CHAIR
affiliation: University California San Diego
name: Miguel A Goicoechea, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goicoechea M, Jain S, Bi L, Kemper C, Daar ES, Diamond C, Ha B, Flaherty J, Sun S, Richman D, Louie S, Haubrich R; California Collaborative Treatment Group. Abacavir and tenofovir disoproxil fumarate co-administration results in a nonadditive antiviral effect in HIV-1-infected patients. AIDS. 2010 Mar 13;24(5):707-16. doi: 10.1097/QAD.0b013e32833676eb.