Trial Outcomes & Findings for Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir (NCT NCT00214890)

Results Overview

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.)

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

49 days

Results posted on

2021-09-24

Participant Flow

Participant milestones

Participant milestones
Measure	Tenofovir Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Abacavir Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy
Overall Study STARTED	10	11
Overall Study COMPLETED	10	11
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Viral Dynamics and Pharmacokinetics of Abacavir and Tenofovir

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Total n=21 Participants Total of all reporting groups
Age, Continuous	NA years n=5 Participants	NA years n=7 Participants	37 years n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Race/Ethnicity, Customized White	6 Participants n=5 Participants	8 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Black	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized American Indian	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Other or unknown	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: 49 days

Population: Median monotherapy decay slopes compared to dual therapy decay slopes after addition of second antiviral agent.

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.)

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
Change in Short-term Virologic Response dual therapy (combined TDF+ABC)	-.16 log(10) copies/mL per day Interval -0.26 to -0.05	-.16 log(10) copies/mL per day Interval -0.2 to -0.07
Change in Short-term Virologic Response monotherapy	-.15 log(10) copies/mL per day Interval -0.25 to -0.04	-.11 log(10) copies/mL per day Interval -0.16 to -0.03

PRIMARY outcome

Timeframe: 49 days

Population: Plasma NRTI concentrations were measured after 7 days on monotherapy and after 7 days on dual therapy

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

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
Compare the Plasma Data of the Two Monotherapy Regimens to the Dual NRTI Regimen monotherapy	12.54 (mcg/mL)*hr Interval 6.35 to 24.67	3.82 (mcg/mL)*hr Interval 1.74 to 7.96
Compare the Plasma Data of the Two Monotherapy Regimens to the Dual NRTI Regimen dual therapy	13.62 (mcg/mL)*hr Interval 7.44 to 58.29	4.09 (mcg/mL)*hr Interval 1.85 to 13.92

PRIMARY outcome

Timeframe: 49 days

Population: Intracellular ddNTP concentrations were measured after 7 days on monotherapy and after 7 days on dual therapy

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

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
Compare the Intracellular Pharmacokinetic (PK) Data of the Two Monotherapy Regimens to the Dual NRTI Regimen monotherapy	72.2 fmol/10^6 cells Interval 19.3 to 503.8	49.3 fmol/10^6 cells Interval 25.2 to 916.8
Compare the Intracellular Pharmacokinetic (PK) Data of the Two Monotherapy Regimens to the Dual NRTI Regimen dual therapy	80.9 fmol/10^6 cells Interval 26.8 to 376.0	108.1 fmol/10^6 cells Interval 42.4 to 508.4

SECONDARY outcome

Timeframe: Day 1 and Day 63

At day 1 and day 63 a PBMC sample for RT-PCR of nucleoside analogue transport enzymes (enzymes for efflux, influx) will be collected. The day 1 specimen should be stored and sent with day 8 PK specimens to USC. Day 63 specimen should be sent to USC after collection and processing. Blood volume: 20 mL Blood volume: 20 mL

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
Evaluate Change in Cellular Regulatory Enzymes Involved With Nucleoside Analogue Transport Across Cell Membranes as Assessed by RT-PCR of Specific mRNA Transcripts dGTP concentrations	2464 fmol/10^6 cells The median value was taken from Goicoechea et al (2010) and the dispersion data was not reported and original data can not be ascertained	4026 fmol/10^6 cells The median value was taken from Goicoechea et al (2010) and the dispersion data was not reported and original data can not be ascertained
Evaluate Change in Cellular Regulatory Enzymes Involved With Nucleoside Analogue Transport Across Cell Membranes as Assessed by RT-PCR of Specific mRNA Transcripts dATP concentrations	3314 fmol/10^6 cells The median value was taken from Goicoechea et al (2010) and the dispersion data was not reported and original data can not be ascertained	3238 fmol/10^6 cells The median value was taken from Goicoechea et al (2010) and the dispersion data was not reported and original data can not be ascertained

SECONDARY outcome

Timeframe: 7 days

Subjects will be randomized to either TDF or ABC PO route for 7 days, which involves a fixed number of subjects. A sample size of 20 subjects (10 ABC and 10 TDF monotherapy and 20 ABC+TDF dual-therapy in HIV-positive patients). We determined the count of NRTI-associated mutations that emerged after 7 days of ABC or TDF monotherapy or after 7 days of dual NRTI therapy with ABC + TDF.

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
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	0 mutations	0 mutations

SECONDARY outcome

Timeframe: Baseline and day 7

Eligible patients will be randomized into two monotherapy arms (TDF and ABC) for a short (one week) viral dynamics and pharmacokinetics evaluation to determine their potency. After a one-month washout period, all patients will start a dual-therapy of ABC+TDF. Viral dynamics and pharmacokinetics of the dual-therapy will be evaluated during the first week of the treatment. EFV will be added to the regimen after one week of the dual-therapy administered. Relative potencies of two monotherapy regimens (TDF alone vs. ABC alone) assessed by the short-term virologic response. (Change in HIV RNA copies/mL at baseline and day 7 for monotherapy)

Outcome measures

Outcome measures
Measure	Abacavir n=11 Participants Monotherapy abacavir (600mg) for 7 days followed by a 35-day washout period then 7 days of ABC + TDF dual therapy	Tenofovir n=10 Participants Monotherapy tenofovir (300mg) for 7 days followed by a 35-day washout period then 7 days of TDF + ABC dual therapy
Compare the Relative Viral Potency of TDF Monotherapy Versus ABC Monotherapy	-0.15 log(10) copies/mL per day Interval -0.25 to -0.04	-0.11 log(10) copies/mL per day Interval -0.16 to -0.03

Adverse Events

Tenofovir

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Abacavir

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Sheldon Morris

UCSD

Phone: 6195438080

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place