C. Sarrazin

Expert opinion on the treatment of patients with chronic hepatitis C

Summary.  The current preferred treatment for patients with hepatitis C virus (HCV) is combination therapy consisting of pegylated interferon alfa and ribavirin (RBV) for 24–48 weeks. Although this approach appears to be highly effective for patients with HCV genotypes 2 or 3, who have a sustained virological response (SVR) of approximately 80%, the treatment algorithm is less effective for patients with HCV genotype 1, as these patients have SVR rates of just 40–50%. In order to improve treatment outcomes, this article explores potential approaches for the optimization of treatment for patients with HCV genotype 1: considering shorter treatment periods for patients with a rapid virological response (RVR), increasing treatment periods for slow responders, and increasing RBV dose are all suggestions. Results from clinical trials suggest that approximately 20% of the HCV genotype 1‐infected population are slow responders, and around 15% of all HCV genotype‐1 infected patients could benefit from a shorter treatment duration without compromising the SVR rate. Interest has also focused on whether treatment duration could be individualized in some patients with genotype 2 and 3 infection. Here all the findings from recent studies are translated into practical advice, to help practitioners make evidence‐based treatment decisions in everyday clinical practice. Although there are areas where currently available data do not provide conclusive evidence to suggest amending treatment approaches, there is clearly potential for individualized treatment in all aspects of hepatitis treatment in the future.

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Mutations selected in the hepatitis C virus NS3 protease domain during sequential treatment with boceprevir with and without pegylated interferon alfa-2b.

Summary.  Treatment with hepatitis C virus (HCV)‐NS3‐protease inhibitors lead to the selection of resistant variants. Viral kinetics and resistance profiles in patients who are re‐treated with the same protease inhibitor are unknown. Viral kinetics and NS3‐resistance mutations obtained by clonal sequencing of the NS3‐protease were analyzed in nine HCV‐genotype‐1‐infected nonresponder patients who were sequentially treated with boceprevir (400 mg t.i.d.) for 1 week, peginterferon‐alfa‐2b for 2 weeks and combination of the two for 2 weeks in varying order. In addition to predominant wild‐type isolates, previously described boceprevir‐resistant mutations (V36, T54, R155, A156, V170) were observed. Furthermore, two resistant mutations (Q41, F43) were detected for the first time in vivo. In three patients, mutations selected after initial treatment with boceprevir were re‐selected during subsequent boceprevir exposure. However, mutational patterns after the first and second exposure to boceprevir were different in five patients. In one patient, a viral variant (V55A) known to reduce susceptibility to boceprevir was the predominant variant observed at baseline and throughout treatment and was associated with a shallow viral decline. Different resistance mutations were selected during treatment with boceprevir ± peginterferon. Sequential short‐term dosing of boceprevir was not associated with accumulation of resistant variants but pre‐existing variants may impair virologic response.

Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C

Summary.  In patients with chronic hepatitis C, alanine aminotransferase (ALT) levels do not accurately reflect the extent of liver inflammation. The discrepancy between ALT level and liver damage could be related to the mode of cell death. In the present study, we quantified serum levels of apoptotic cytokeratin 18 (CK‐18) neoepitopes that are generated by activated caspases during apoptosis. Apoptotic CK‐18 neoepitopes were quantified by enzyme linked immunosorbent assay in sera from patients with chronic hepatitis C and elevated ALT levels (n = 72), patients with chronic hepatitis C and persistently normal ALT levels (n = 27) and healthy controls (n = 19). Serum CK‐18 neoepitope levels were strongly correlated with ALT (r = 0.659, P < 0.0001) and the histology activity index (r = 0.374, P < 0.001). Patients with chronic hepatitis C and persistently normal ALT levels had higher apoptotic CK‐18 neoepitope levels than healthy controls (P = 0.03) but lower levels than patients with chronic hepatitis C and elevated ALT levels (P < 0.001). Highest serum CK‐18 neoepitope levels were observed in patients with cirrhosis (P = 0.002). Hence apoptotic CK‐18 neoepitopes in serum of patients with chronic hepatitis C are associated with ALT level and histological liver damage. Serum apoptotic CK‐18 neoepitope levels are elevated both in patients with chronic hepatitis C and elevated ALT levels as well as in patients with normal ALT levels indicating that also patients with chronic hepatitis C and normal ALT have an increased hepatocyte loss by apoptosis.

Prospective study of bone mineral density and metabolism in patients with chronic hepatitis C during pegylated interferon α and ribavirin therapy

Summary.  The importance of osteoporosis as a complication of end‐stage liver disease is well known. However, significant osteopenia may occur in earlier stages of chronic hepatitis C (CHC). Furthermore, antiviral therapy may influence bone metabolism. Thirty patients with CHC genotype 1 infection and without established cirrhosis were treated with peginterferon‐alfa and ribavirin. Dual‐energy x‐ray absorptiometry was performed at baseline, after 48 weeks of therapy, and by the end of a 24‐week follow‐up period. Bone mineral density (BMD), T‐scores, and Z‐scores were assessed. Serum C‐terminal propeptide of type I collagen (CICP) and osteocalcin levels were measured. Thirteen patients had osteopenia (43%) and osteoporosis was present in four patients (13%). Antiviral therapy led to significant on‐treatment increases of lumbar spine and hip BMD (P ≤ 0.05) as well as T‐scores (P ≤ 0.05) and Z‐scores (P ≤ 0.01) irrespective of subsequent treatment response. Further analyses showed that in patients with sustained virological response (n = 19) most parameters remained highly above baseline values by the end of the 24‐week follow‐up period, while patients with virological relapse (n = 11) had decreases of BMD, T‐scores and Z‐scores thereafter that did not differ from baseline. Serum CICP and osteocalcin levels decreased during therapy. Osteocalcin levels remained below baseline in sustained responder, but showed an increase in relapsers by the end of the 24‐week follow‐up (P ≤ 0.05). Osteopenia is detectable in a substantial proportion of CHC patients without established cirrhosis. Antiviral therapy leads to an on‐treatment increase of BMD, which may last in those patients who achieve a sustained virological response.

Regression of fibrosis and portal hypertension in HCV-associated cirrhosis and sustained virologic response after interferon-free antiviral therapy

It is still controversial, whether and to what amount cirrhosis and portal hypertension are reversible in patients with hepatitis C virus (HCV)‐associated cirrhosis and sustained virologic response (SVR) after interferon‐free antiviral therapy. In this study, we prospectively evaluated dynamics of liver and spleen stiffness in HCV‐infected patients with advanced liver disease and SVR after interferon‐free treatment. A total of 54 patients with HCV‐associated cirrhosis and SVR were included. Liver and spleen stiffness was measured at therapy baseline (BL), end of treatment (EOT) and 24 weeks after EOT (FU24) by transient liver elastography (L‐TE) as well as by acoustic radiation force impulse of the liver (L‐ARFI) and spleen (S‐ARFI), as well as biochemical, virologic and clinical data. Improvement of liver and spleen stiffness was found in 44 of 50 (88%), 31 of 54 (57%) and 25 of 54 (46%) of patients assessed by L‐TE, L‐ARFI and S‐ARFI between baseline and FU24. Liver stiffness assessed by L‐TE improved between BL [median (range), 32.5 (9.1–75) kPa] and EOT [median (range), 21.3 (6.7–73.5) kPa; (P<.0001)], and between BL and FU24 [median (range), 21.2 (5.4–70) kPa; (P<.0001)]. Liver stiffness assessed by L‐ARFI improved between BL [median (range), 2.7 (1.2–4.1) m/s] and FU24 [median (range), 2.4 (1.2–3.9) m/s; P=.002), while spleen stiffness remained unchanged. Our data suggest that improvement of liver stiffness may be rather due to reduced necroinflammation and may be due to a less extent to regression of cirrhosis, as dynamics of liver stiffness improvement was more pronounced between BL and EOT than BL and FU24.

Impaired health‐related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels

Summary.  A significant impact of hepatitis C virus (HCV) infection on health‐related quality of life (HRQOL) has been previously described. However, comprehensive data on the quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels (PNAL) are currently not available. One hundred fifteen patients with chronic hepatitis C (45 with persistently normal aminotransferases and 70 with elevated aminotransferases) and 50 healthy subjects were enrolled. Emotional and psychological states were assessed by Profile of Mood States (POMS) scale and HRQOL was assessed by the ‘Everyday Life’ questionnaire (EDLQ), a validated questionnaire related to the SF‐36 Health Survey. An impairment in HRQOL was observed in patients with chronic hepatitis C showing PNAL compared with healthy subjects with significant differences for the factor scores depression and anger in the POMS scale as well as for the items body, relationship to partner, self‐confidence and zest of life in the EDLQ. No differences in any questionnaire were observed between patients with chronic hepatitis C showing PNAL or elevated aminotransferase levels except of a worse mean level for factor score anger in POMS scale in patients with persistently normal aminotransferases. No association of quality of life with severity of liver disease was found. Impairment of HRQOL by chronic infection with HCV is similar in patients with PNAL and those with elevated aminotransferase levels.

Serum microRNA-122 kinetics in patients with chronic hepatitis C virus infection during antiviral therapy.

The levels of the liver‐specific microRNA‐122 (miR‐122) circulating extracellularly in the blood have been shown to be increased upon liver damage. However, it is unknown if the levels of serum miR‐122 are altered during antiviral therapy and reflect the therapeutic success. Here, we investigated miR‐122 serum levels in patients with chronic hepatitis C virus (HCV) genotype 1 infection during antiviral therapy with pegylated interferon and ribavirin. Therefore, sera from 60 patients with chronic HCV infection genotype 1 showing sustained virological response (SVR), non‐response or relapse to therapy obtained at baseline, 4, 12, 24 weeks, end of treatment and follow‐up were analysed retrospectively for miR‐122 content by quantitative real‐time reverse transcription PCR. The time courses of miR‐122 were correlated with HCV RNA as well as standard liver parameters. We found that while there was no relation between serum miR‐122 and HCV RNA levels at baseline, the decline in HCV RNA upon beginning of the therapy closely correlated with the reduction of serum miR‐122 in the three different patient groups. Moreover, the serum miR‐122 level correlated well with alanine aminotransaminase, a marker of ongoing liver damage. At follow‐up serum miR‐122 levels remained low in SVR, but increased to baseline levels in patients not responding or showing relapse to therapy. In contrast, the serum concentration of the ubiquitously expressed miR‐16 did not change during therapy. We conclude that the serum level of miR‐122 well reflects the success of interferon/ribavirin therapy in patients with chronic HCV infection.

12 DETECTION OF RESISTANT VARIANTS IN THE HEPATITIS C VIRUS NS3 PROTEASE GENE BY CLONAL SEQUENCING AT LONG-TERM FOLLOW-UP IN PATIENTS TREATED WITH BOCEPREVIR

M. Manns1, H. Reesink2, C. Moreno3, T. Berg4, Y. Benhamou5, Y. Horsmans6, G. Dusheiko7, R. Flisiak8, P. Meyvisch9, O. Lenz9, V. Sekar10, G. van ’t Klooster9, K. Simmen9, R. Verloes9. 1Medizinische Hochschule Hannover, Hannover, Germany; 2Amsterdam Medical Center, Amsterdam, The Netherlands; 3Erasme Hospital, Universite Libre de Bruxelles, Brussel, Belgium; 4Charite-Universitatsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany; 5Centre Hospitalier Universitaire Pitie-Salpetriere Paris, Paris, France; 6Saint-Luc Universite Catholique de Louvain, Brussel, Belgium; 7Royal Free Hospital, London, UK; 8Medical University of Bialystok, Bialystok, Poland; 9Tibotec BVBA, Mechelen, Belgium; 10Tibotec Pharmaceuticals, Yardley, PA, USA E-mail: rverloes@tibbe.jnj.com