H.W. Reesink

Miravirsen dosing in chronic hepatitis C patients results in decreased microRNA-122 levels without affecting other microRNAs in plasma

MicroRNA‐122 (miR‐122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti‐miR‐122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients.

Viral hepatitis C therapy: pharmacokinetic and pharmacodynamic considerations.

Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.

Risk Factors for Sexual Transmission of Hepatitis C Virus Among Human Immunodeficiency Virus-Infected Men Who Have Sex With Men: A Case-Control Study

Background. Since 2000, incidence of sexually acquired hepatitis C virus (HCV)-infection has increased among human immunodeficiency virus (HIV)-infected men who have sex with men (MSM). To date, few case-control and cohort studies evaluating HCV transmission risk factors were conducted in this population, and most of these studies were initially designed to study HIV-related risk behavior and characteristics. Methods. From 2009 onwards, HIV-infected MSM with acute HCV infection and controls (HIV-monoinfected MSM) were prospectively included in the MOSAIC (MSM Observational Study of Acute Infection with hepatitis C) study at 5 large HIV outpatient clinics in the Netherlands. Written questionnaires were administered, covering sociodemographics, bloodborne risk factors for HCV infection, sexual behavior, and drug use. Clinical data were acquired through linkage with databases from the Dutch HIV Monitoring Foundation. For this study, determinants of HCV acquisition collected at the inclusion visit were analyzed using logistic regression. Results. Two hundred thirteen HIV-infected MSM (82 MSM with acute HCV infection and 131 MSM without) were included with a median age of 45.7 years (interquartile range [IQR], 41.0–52.2). Receptive unprotected anal intercourse (adjusted odds ratio [aOR], 5.01; 95% confidence interval [CI], 1.63–15.4), sharing sex toys (aOR, 3.62; 95% CI, 1.04–12.5), unprotected fisting (aOR, 2.57; 95% CI, 1.02–6.44), injecting drugs (aOR, 15.62; 95% CI, 1.27–192.6), sharing straws when snorting drugs (aOR, 3.40; 95% CI, 1.39–8.32), lower CD4 cell count (aOR, 1.75 per cubic root; 95% CI, 1.19–2.58), and recent diagnosis of ulcerative sexually transmitted infection (aOR, 4.82; 95% CI, 1.60–14.53) had significant effects on HCV acquisition. Conclusions. In this study, both sexual behavior and biological factors appear to independently increase the risk of HCV acquisition among HIV-infected MSM.

LO7 : A single subcutaneous dose of 2mg/kg or 4mg/kg of RG-101, a GalNAc-conjugated oligonucleotide with antagonist activity against MIR-122, results in significant viral load reductions in chronic hepatitis C patients

GWAS hits were validated in independent cohorts from Germany (529 cases vs. 761 controls) and Belgium (619 cases vs. 161 controls) and the results of the joint analyses combined. Genotyping was undertaken using Illumina BeadChips (Illumina Inc., San Diego, CA, USA); SNP replication was undertaken using Taqman chemistry (Applied Biosystems, Foster City, Ca, USA) on an automated platform. Results: The strongest association signal in the initial metaanalysis was observed between the rs738409 variant in PNPLA3 (Pmeta =1.17×10−28, OR=2.38 [2.08–2.69]); 102 separate variants at the PNPLA3 locus associated with genome-wide significance (Pthreshold <5×10−8). In addition, nine other independent loci provided borderline association signals (Pthreshold ≤1.1×10−5). Validation genotyping for rs738409 in PNPLA3 and lead markers for the top 10 associated regions confirmed disease association for rs738409 in PNPLA3, and for (MBOAT7: rs641738 Preplication = 1.35×10−4; Pcombined = 9.25×10−10; OR=1.63 [1.46–1.80] and TM6SF2: rs10401969 Preplication = 3.29×10−5; Pcombined = 1.73×10−8; OR=1.35 [1.25–1.44]).

First-in-human study of the pharmacokinetics and antiviral activity of IDX375, a novel nonnucleoside hepatitis C virus polymerase inhibitor.

ABSTRACT IDX375 is a potent and selective palm-binding nonnucleoside inhibitor of the hepatitis C virus (HCV) genotype 1 polymerase. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics of IDX375 in healthy volunteers, as well as its antiviral activity in HCV-infected patients. IDX375, as a choline salt, was administered for 1 day to 40 healthy male volunteers (25- to 200-mg IDX375-equivalent single ascending doses and a 200-mg twice-daily [BID] dose) and three patients chronically infected with HCV genotype 1 (200 mg BID only). IDX375 was well absorbed and well tolerated by all of the study participants. A single-day 200-mg BID dose resulted in exposure-related anti-HCV activity with maximal 0.5 to 1.1 log10 reductions in plasma HCV RNA. These observations support further clinical investigations of IDX375.

HLA-C and KIR combined genotype as new response marker for HBeAg-positive chronic hepatitis B patients treated with interferon-based combination therapy

Current treatment for chronic hepatitis B infection (CHB) consists of interferon‐based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA‐C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA‐C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa‐2a + adefovir. Genotyping of killer immunoglobin‐like receptors (KIRs) was performed by SSP‐PCR. One SNP in HLA‐C (rs2308557) was significantly associated with combined response in HBeAg‐positive CHB patients (P = 0.003). This SNP is linked to the HLA‐C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA‐C2 was observed significantly more often in HBeAg‐positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1‐C2 predicted response independent of HBV genotype and ALT at baseline. HLA‐C and KIR genotype is strongly associated with response in HBeAg‐positive CHB patients treated with interferon‐based therapy. In combination with other known response markers, HLA‐C/KIR genotype could enable the selection of patients more likely to respond to interferon‐based therapy.

Daclatasvir/peginterferon lambda-1a/ribavirin in patients with chronic HCV infection and haemophilia who are treatment naïve or prior relapsers to peginterferon alfa-2a/ribavirin

This study explores the potential role of a novel interferon‐containing regimen for treatment of patients with chronic hepatitis C (CHC) and underlying haemophilia.

HBsAg loss after peginterferon‐nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow‐up

Combining peginterferon‐alfa‐2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow‐up. In the initial study, 92 CHB patients (44 HBeAg‐positive, 48 HBeAg‐negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 μg/week and 10 mg adefovir dipivoxil daily. For the long‐term follow‐up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg‐positive, 38 HBeAg‐negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg‐positive patients and 16% (6/38) of HBeAg‐negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5‐year cumulative Kaplan‐Meier estimate for HBsAg loss was 17.2% for HBeAg‐positive patients and 19.3% for HBeAg‐negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow‐up developed anti‐HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg‐positive and 71% (27/38) of HBeAg‐negative patients were retreated with nucleos(t)ide analogues during follow‐up. The cumulative Kaplan‐Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow‐up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti‐HBs antibodies.

Evolutionary dynamics of hepatitis C virus NS3 protease domain during and following treatment with narlaprevir, a potent NS3 protease inhibitor

Narlaprevir, a hepatitis C virus (HCV) NS3/4A serine protease inhibitor, has demonstrated robust antiviral activity in a placebo‐controlled phase 1 study. To study evolutionary dynamics of resistant variants, the NS3 protease sequence was clonally analysed in thirty‐two HCV genotype 1–infected patients following treatment with narlaprevir. Narlaprevir monotherapy was administered for one week (period 1) followed by narlaprevir/pegylated interferon‐alpha‐2b combination therapy with or without ritonavir (period 2) during two weeks, interrupted by a washout period of one month. Thereafter, all patients initiated pegylated interferon‐alpha‐2b/ribavirin combination therapy. Longitudinal clonal analysis was performed in those patients with NS3 mutations. After narlaprevir re‐exposure, resistance‐associated mutations at position V36, T54, R155 and A156 were detected in five patients in >95% of the clones. Narlaprevir retreatment resulted in a 2.58 and 5.06 log10 IU/mL viral load decline in patients with and without mutations, respectively (P = <0.01). After treatment, resistant variants were replaced with wild‐type virus within 2–24 weeks in three patients. However, the R155K mutation was still observed 3.1 years after narlaprevir dosing in two patients in 5% and 45% of the viral population. Resistant variants could be detected early during treatment with narlaprevir. A slower viral load decline was observed in those patients with resistance‐associated mutations detectable by direct population sequencing. These mutations disappeared within six months following treatment with the exception of R155K mutation, which persisted in two patients.

509 SERUM IP10 LEVELS AT BASELINE AND DURING THERAPY DO NOT PREDICT SVR IN CHRONIC HEPATITIS C PATIENTS TREATED WITH HIGH INDUCTION DOSE INTERFERON

508 IDENTIFICATION OF HBV AND HCV INFECTIONS IN THE PRIMARY CARE SETTING: PRE-DEFINED RISK SCENARIOS ARE A BETTER SCREENING STRATEGY THAN ELEVATED ALT VALUES J. Wiegand, O. Batz, I. Wolffram, J. Kramer, K. Jedrysiak, H. Tenckhoff, T. Berg, German “Check-Up 35” Study Group. Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University of Leipzig, Leipzig, LADR GmbH Medizinisches Versorgungszentrum Dr. Kramer und Kollegen, Geesthacht, Sudstadtpraxis Paderborn, Paderborn, Germany E-mail: johannes.wiegand@medizin.uni-leipzig.de