Telaprevir‐based treatment effects on hepatitis C virus in liver and blood

Abstract

Background Understanding hepatitis C virus (HCV) replication has been limited by access to serial samples of liver, the primary site of viral replication. Our understanding of how HCV replicates and develops drug resistant variants in the liver is limited. Methods We studied 15 patients chronically infected with genotype 1 HCV treated with telaprevir (TVR)/pegylated-interferon alfa/ribavirin. Hepatic fine needle aspiration was performed pretreatment and at hour 10, days 4 and 15, and week 8 after initiation of antiviral therapy. We measured viral kinetics, resistance patterns, TVR concentrations, and host transcription profiles. Results All patients completed all protocol defined procedures that were generally well tolerated. First phase HCV decline (baseline-treatment day 4) was significantly slower in liver than in plasma (slope plasma, −0.29; liver, −0.009 [p<0.001]) while second phase decline (post-treatment day 4 to 15) did not differ between the two body compartments (−0.11 and −0.15, respectively, p=0.1). TVR-resistant variants were first detected in the plasma, but not in the liver (where only wild-type virus was detected). Based upon NS3 sequence analysis, no compartmentalization of viral populations was observed between plasma and liver compartments. Gene expression profiling revealed strong tissue-specific expression signatures. Human intrahepatic TVR concentration, measured for the first time, was lower compared to plasma on a gram per milliliter basis. We found moderate heterogeneity between HCV RNA levels from different intrahepatic sites, indicating differences in hepatic microenvironments. Conclusion These data support an integrated model for HCV replication wherein the host hepatic milieu and innate immunity control the level of viral replication, and the early antiviral response observed in the plasma is predominantly driven by inhibition of hepatic high-level HCV replication sites.

Interferon-Free Treatment of Hepatitis C Virus in HIV/Hepatitis C Virus-Coinfected Subjects Results in Increased Serum Low-Density Lipoprotein Concentration

“…Interestingly, a recent study examining viral kinetics in serum and liver during treatment with telaprevir/IFN/RBV revealed a slower HCV RNA decline in the liver compared to plasma. 39 Given the estimated 7-day half-life of infected hepatocytes, 40 a persistent burden of intrahepatic HCV is likely still present at day 3 of treatment in this trial, but has likely declined significantly by week 2. Thus, changes in serum LDL-C may be a reflection of intrahepatic HCV burden and direct intracellular viral modulation of cholesterol metabolism.…”

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques

“…DAAs, drugs which target the hepatocyte and whose liver concentration has been shown to vary considerably, can be used to examine factors that affect liver drug accumulation and the resultant pharmacodynamic effect, as assessed by sampling HCV RNA levels (10,11,18). Few studies, however, have measured DAA concentrations within the liver, largely because of the need for invasive sampling techniques, i.e., biopsy or surgical resection, and the difficulty in interpretation of liver drug concentration measurements compared to measurements made with traditional matrices (i.e., plasma, blood, and urine) (19).…”

“…It also permitted development of a normalization procedure to determine the percentage of liver contained within the sample through the identification of liver-enriched genes (21). As a follow-up to the initial study, we conducted two studies investigating liver-to-plasma drug concentration ratios (10,11). In the first, we performed CNB on three patients treated with vaniprevir and demonstrated higher human liver concentrations than the concentrations in plasma (11).…”

“…In the second study, we performed serial FNA procedures on 15 patients treated with telaprevir, pegylated interferon, and ribavirin. In the first study of its type, we assessed the intrahepatic HCV RNA decline as well as the pharmacokinetics and pharmacodynamics of a regimen that contained a DAA (10). Based upon these data, we proposed an integrated model to explain the potential mechanism of control of viral replication by these agents.…”

“…Our group recently pioneered techniques for serial liver drug concentration assessments in vivo by using different methods of liver sample collection (10)(11)(12). While core needle biopsy (CNB) and fine-needle aspiration (FNA) are techniques that have been used for the past half century to obtain liver specimens during the clinical evaluation of patients with liver disease, a comparison of different sampling techniques for measurement of liver drug concentrations has not been performed previously (13)(14)(15)(16)(17).…”