Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir

HIV Infections Clinical Trial

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

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• HIV Infections

• NCT number: NCT00214890
• Study type: Interventional
• Source: University of California, San Diego
• Status: Completed
• Phase: Phase 2
• Start date: December 7, 2004
• Completion date: April 27, 2010