Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: Tenofovir; Abacavir
Intervention description: 300 mg once daily; 600 mg once daily
Intervention MeSH terms: Tenofovir; Abacavir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
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.
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; nucleoside pharmacology; drug-drug interaction; Treatment Naive; Drug resistance; Drug pharmacokinetics

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.
    

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)