Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir

NCT00214890 | Completed Phase 2 Results

• 1 other identifier: CCTG584
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 5

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.

Conditions

HIV Infections

Keywords

HIV; nucleoside pharmacology; drug-drug interaction; Treatment Naive; Drug resistance; Drug pharmacokinetics

Outcome Measures

Primary Outcomes (3)

• Change in Short-term Virologic Response

  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. (Change in HIV RNA copies/mL at baseline and day 7 for monotherapy, baseline and day 49 for dual therapy.)

  49 days

• Compare the Plasma Data of the Two Monotherapy Regimens to the Dual NRTI Regimen

  At day 49 of Sequence 2 a 24-hour post dose plasma sample should be collected and processed. All 7 samples from the sparse PK (time 0, 30-min, 1-hr, 2-hr, 3-hr, 6-hr and 24-hr post dose) should be sent overnight to appropriate off-site lab for analysis. Since the patient is on dual therapy and the each drug is measured in separate labs each PBMC samples should be split at each time-point with half of the samples shipped to Gilead and half shipped to USC (two separate shipments). ALL plasma samples should be sent to USC. Since samples have to be split we will need to collect double the blood for the intracellular (PBMC) PK: Blood volume (PBMC-plasma): 40 mL - each draw Blood volume (plasma only): 3 mL - each draw Blood volume: 169 mL- over 2 days Plasma NRTI and intracellular ddNTP concentrations were measured 7 days after treatment with ABC or TDF alone and were compared to levels obtained after 7 days of treatment with both drugs

  49 days

• Compare the Intracellular Pharmacokinetic (PK) Data of the Two Monotherapy Regimens to the Dual NRTI Regimen

  At day 49 of Sequence 2 a 24-hour post dose intracellular (PBMC) should be collected and processed. All 7 samples from the sparse PK (time 0, 30-min, 1-hr, 2-hr, 3-hr, 6-hr and 24-hr post dose) should be sent overnight to appropriate off-site lab for analysis. Since the patient is on dual therapy and the each drug is measured in separate labs each PBMC samples should be split at each time-point with half of the samples shipped to Gilead and half shipped to USC (two separate shipments). ALL intracellular (PBMC) samples should be sent to USC. Since samples have to be split we will need to collect double the blood for the intracellular (PBMC) PK: Blood volume (PBMC-plasma): 40 mL - each draw Blood volume (plasma only): 3 mL - each draw Blood volume: 169 mL- over 2 days Intracellular ddNTP concentrations were measured after 7 days on monotherapy and after 7 days on dual therapy

  49 days

Secondary Outcomes (3)

• Evaluate Change in Cellular Regulatory Enzymes Involved With Nucleoside Analogue Transport Across Cell Membranes as Assessed by RT-PCR of Specific mRNA Transcripts

  Day 1 and Day 63

• 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

  7 days

• Compare the Relative Viral Potency of TDF Monotherapy Versus ABC Monotherapy

  Baseline and day 7

Study Arms (2)

Tenofovir

ACTIVE COMPARATOR

As part of this study visit, you participants will be assigned by chance to receive either TDF alone or ABC alone

Drug: Tenofovir

Abacavir

ACTIVE COMPARATOR

As part of this study visit, you participants will be assigned by chance to receive either TDF alone or ABC alone

Drug: Abacavir

Interventions

Tenofovir DRUG

300 mg once daily

Also known as: (TDF)

Tenofovir

Abacavir DRUG

600 mg once daily

Also known as: (ABC, Ziagen)

Abacavir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Antiretroviral naïve defined as no prior therapy.
• CD4+ cell count \> than 200 cells/ mm3 determined by site clinical laboratory within 90 days of screening.
• HIV-1 RNA level \> 5000 copies/mL obtained by site clinical laboratory within 90 days of screening.
• 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.
• Negative serum or urine pregnancy test within 30 days of study entry.
• Karnofsky performance score ≥ 70.
• Men and women age ≥ 18 years.
• Ability and willingness of subject to give written informed consent.

You may not qualify if:

• Any NRTI or NNRTI-associated resistance mutations as defined by the updated International AIDS Society-USA (IAS-USA) mutation list.
• Pregnancy and breast-feeding.
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Urgent need to initiate antiretroviral therapy, as determined by the patient's primary provider.
• 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.
• Use of any immunomodulator, HIV vaccine, or investigational therapy within 30 days of study entry.
• Use of human growth hormone within 30 days prior to study entry.
• 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)

Sponsors & Collaborators

• University of California, San Diego: lead
• Universitywide AIDS Research Program: collaborator
• GlaxoSmithKline: collaborator
• University of California, Irvine: collaborator
• University of California, Los Angeles: collaborator
• University of Southern California: collaborator
• Santa Clara Valley Medical Center: collaborator

Study Sites (5)

UCI

Irvine, California, 92668, United States

Location

USC

Los Angeles, California, 90033, United States

Location

University of California San Diego

San Diego, California, 92103, United States

Location

Santa Clara Valley Medical Center

San Jose, California, 95128, United States

Location

Harbor-UCLA Medical Center

Torrance, California, 90502, United States

Location

Related Publications (1)

• 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.

  PMID: 20087154 RESULT

Related Links

• CCTG homepage

MeSH Terms

Conditions

HIV Infections

Interventions

Tenofovir; abacavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Sheldon Morris
• Organization: UCSD

shmorris@ucsd.edu

6195438080

Study Officials

• Richard H Haubrich, MD

  University California San Diego

  STUDY CHAIR

• Miguel A Goicoechea, MD

  University California San Diego

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 20, 2005
• First Posted: September 22, 2005
• Study Start: December 7, 2004
• Primary Completion: June 26, 2008
• Study Completion: April 27, 2010
• Last Updated: September 24, 2021
• Results First Posted: March 9, 2021

Record last verified: 2021-09

Locations

US (5)