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  17th International Workshop
on Clinical Pharmacology of
HIV and Hepatitis Therapy
June 8-10, 2016, Washington DC
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Tenofovir Levels in Red Blood Cells Jump 4-Fold With Sofosbuvir/Ribavirin
  17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC
Mark Mascolini
Tenofovir-diphosphate (TFV-DP) levels in dried blood spots quadrupled through 12 weeks of sofosbuvir/ribavirin therapy for acute HCV infection, according to analysis of 15 men taking a tenofovir disoproxil fumarate (TDF) regimen in the SWIFT-C trial [1]. But tenofovir concentrations in plasma did not change during sofosbuvir/ribavirin therapy.
ACTG 5327, the SWIFT-C trial, is an ongoing study of sofosbuvir-containing regimens for acute HCV infection in people chronically infected with HIV [2]. Cohort 1 of SWIFT-C combined sofosbuvir with weight-based (1000- or 1200-mg) ribavirin for 12 weeks. The sustained virologic response (SVR) rate reached only 59% because 41% of participants had a relapse. ACTG investigators determined that relapsers had significantly lower ribavirin plasma concentrations (P = 0.01), which may indicate poor adherence to this agent.
In a new analysis, the ACTG team aimed to assess adherence to antiretrovirals during the trial. This analysis focused on gauging tenofovir levels in two ways--in dried blood spots (a measure of cumulative dosing and long-term adherence) and in plasma (a measure of recent dosing and short-term adherence). The investigators collected plasma and dried blood spots from participants at study entry, after 12 weeks of sofosbuvir/ribavirin, and 12 weeks after the end of treatment with sofosbuvir/ribavirin (EOT+12). They measured TFV-DP in 3-mm blood spot punches and TFV concentrations in plasma.
The analysis included 15 men taking a TDF-containing regimen, all of whom completed 12 weeks of sofosbuvir/ribavirin. Eleven men were Hispanic and 4 Caucasian. Age averaged 44.3 years (+/-9.5 standard deviation) and weight 76.5 kg (+/-10.3). The men had normal renal function (average baseline creatinine clearance 123.88 mL/min +/-24.34).
At study entry TFV-DP in blood spots averaged 1685 fmol/punch, a level consistent with concentrations in HIV-positive people with good adherence. After 12 weeks of sofosbuvir/ribavirin, TFV-DP in blood spots more than quadrupled (geometric mean ratio [GMR] 4.3, range 1.4 to 15.8, P = 0.0005), averaging 6608 fmol/punch. At EOT+12 TFV-DP in blood spots had declined to 2101 fmol/punch, a level numerically similar to the entry concentration. Dried blood spot TFV-DP levels at week 12 did not differ significantly between people who achieved sustained virologic response and those who relapsed.
TFV-DP levels in peripheral blood mononuclear cells reflected the overall changes measured in dried blood spots: 79 fmol/million cells at study entry, 149 fmol/million cells after 12 weeks of sofosbuvir/ribavirin (GMR 2.3, range 0.5 to 17.4, P = 0.06), and 81 fmol/million cells at EOT+12.
TFV levels in plasma proved similar to historical data and did not change substantially over the study period, averaging 97 ng/mL at entry, 95 ng/mL at treatment week 12, and 93 ng/mL at EOT+12. Renal function as assessed by creatinine clearance did not change significantly between entry (123.88 +/-24.34 mL/min) and week 12 (118.05 +/-20.54 mL/min).
The ACTG investigators believe their findings "suggest a new type of drug interaction at the cellular level." They suspect that sofosbuvir, not ribavirin, caused the jump in TFV-DP levels during therapy because of preliminary data from another ongoing study of sofosbuvir/ledipasvir. The researchers suggested their finding may not have clinical significance for HCV therapy, which lasts only a few months. But the finding could become meaningful in other contexts.
Pharm: Increased Tenofovir Diphosphate in Cells, but Not Tenofovir in Plasma, with Sofosbuvir and Ribavirin - (06/10/15)
1. MacBrayne CE, Marks KM, Fierer DS, et al. Increased tenofovir diphosphate in red blood cells, but not tenofovir in plasma, with sofosbuvir and ribavirin. 17th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, June 8-10, 2016, Washington DC. Abstract O19.
2. ClinicalTrials.gov. Sofosbuvir-containing regimens without interferon for treatment of acute hepatitis C virus (HCV) infection (SWIFT-C).https://clinicaltrials.gov/ct2/show/NCT02128217