ABSTRACT
BACKGROUND & AIMS: JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection. METHODS: We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period. RESULTS: Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed. CONCLUSIONS: In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712.
Subject(s)
Antiviral Agents/adverse effects , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/drug therapy , Organic Chemicals/adverse effects , Administration, Oral , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Capsid/drug effects , DNA, Viral/blood , DNA, Viral/isolation & purification , Dose-Response Relationship, Drug , Double-Blind Method , Female , Hepatitis B virus/drug effects , Hepatitis B virus/genetics , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Humans , Male , Middle Aged , Organic Chemicals/administration & dosage , Organic Chemicals/pharmacokinetics , Treatment Outcome , Virus Assembly/drug effects , Young AdultABSTRACT
In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.