Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir

• To evaluate the relative potencies of two monotherapy regimens (TDF alone vs. ABC alone) compared to the dual NRTI regimen of TDF+ABC as assessed by the short-term virologic response [ Time Frame: 49 days ] [ Designated as safety issue: No ]
• To compare the plasma and intracellular pharmacokinetic data of the two monotherapy regimens to the dual NRTI regimen [ Time Frame: 49 days ] [ Designated as safety issue: No ]

• 1. To evalute the relative potencies of two monotherapy regimens (TDF alone vs. ABC alone) compared to the dual NRTI regimen of TDF+ABC as assessed by the short-term virologic response
• 2. To compare the plasma and intracellular pharmacokinetic data of the two monotherapy regimens to the dual NRTI regimen.

• To evaluate the change in cellular regulatory enzymes involved with nucleoside analogue transport across cell membranes after TDF+ABC exposure [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
• To compare the relative viral potency of TDF monotherapy versus ABC monotherapy [ Time Frame: 7 weeks ] [ Designated as safety issue: No ]
• To evaluate the long-term viral response to efavirenz + ABC + lamivudine after two 7-day sequences of mono/dual therapy [ Time Frame: 46 weeks ] [ Designated as safety issue: No ]

• 1. To evaluate the change in cellular regulatory enzymes involved with nucleoside analogue transport across cell membranes after TDF+ABC exposure.
• 2. To compare the relative viral potency of TDF monotherapy versus ABC monotherapy.
• 3. To evaluate the long-term viral response to efavirenz + ABC + lamivudine after two 7-day sequences of mono/dual therapy.

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.

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 total of 20 ARV-naïve subjects will be enrolled in this study. 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.

• Drug: Tenofovir
  300 mg once daily
• Drug: Abacavir
  600 mg once daily

• Active Comparator: Tenofovir
  Intervention: Drug: Tenofovir
• Active Comparator: Abacavir
  Intervention: Drug: Abacavir

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)

• The University-Wide AIDS Research program
• GlaxoSmithKline
• University of California, Irvine
• University of California, Los Angeles
• University of Southern California
• Santa Clara Valley Health & Hospital System