Active intravenous drug use during chronic hepatitis C therapy does not reduce sustained virological response rates in adherent patients.

SUMMARY: Reluctance has been expressed about treating chronic hepatitis C in active intravenous (IV) drug users (IDUs), and this is found in both international guidelines and routine clinical practice. However, the medical literature provides no evidence for an unequivocal treatment deferral of this risk group. We retrospectively analyzed the direct effect of IV drug use on treatment outcome in 500 chronic hepatitis C patients enrolled in the Swiss Hepatitis C Cohort Study. Patients were eligible for the study if they had their serum hepatitis C virus (HCV) RNA tested 6 months after the end of treatment and at least one visit during the antiviral therapy, documenting the drug use status. Five hundred patients fulfilled the inclusion criteria (199 were IDU and 301 controls). A minimum exposure to 80% of the scheduled cumulative dose of antivirals was reached in 66.0% of IDU and 60.5% of controls (P = NS). The overall sustained virological response (SVR) rate was 63.6%. Active IDU reached a SVR of 69.3%, statistically not significantly different from controls (59.8%). A multivariate analysis for treatment success showed no significant negative influence of active IV drug use. In conclusion, our study shows no relevant direct influence of IV drugs on the efficacy of anti-HCV therapy among adherent patients.

Recurrent Hepatitis C After Liver Transplantation Experience of the First 21 Patients Treated in Lausanne

BACKGROUND AND AIM: Recurrent hepatitis C is a major cause of morbidity and mortality after liver transplantation (LT), and optimal treatment algorithms have yet to be defined. Here, we present our experience of the first 21 patients with recurrent hepatitis C treated in Lausanne. PATIENTS AND METHODS: Twenty-one patients with histologyproven recurrent hepatitis C after LT were treated since 2003. Treatment was initiated with pegylated interferon-α2a 135 μg per week and ribavirin 400 mg per day in the majority of patients, and subsequent doses were adapted individually based on on-treatment virological responses and clinical and/or biochemical side effects. RESULTS: On an intention-to-treat basis, sustained virological response (SVR) was achieved in 12/21 (57%) patients (5/11 [45%], 2/3 [67%], 4/5 [80%] and 1/2 [50%] of patients infected with genotypes 1, 2, 3 and 4, respectively). Two patients experienced relapse and 6 did not respond to treatment (NR). Treatment duration ranged from 24 to 90 weeks. It was stopped prematurely due to adverse events in 5/21 (24%) patients (with SVR achieved in 2 patients, NR in 2 patients, and death of one patient awaiting re-transplantation). Of note, SVR was achieved in a patient with combined liver and kidney transplantation. Importantly, SVR was achieved in some patients despite the lack of an early virological response or HCV RNA negativity at week 24. Darbepoetin α and filgrastim were used in 33% and 14%, respectively. CONCLUSION: Individually adapted treatment of recurrent hepatitis C can achieve SVR in a substantial proportion of LT patients. Conventional stopping rules do not apply in this setting so that prolonged therapy may be useful in selected patients.

Response Prediction in Chronic Hepatitis C by Assessment of IP-10 and IL28B-Related Single Nucleotide Polymorphisms.

BACKGROUND: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. METHODS AND FINDINGS: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. CONCLUSIONS: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

Identification of naturally processed hepatitis C virus-derived major histocompatibility complex class I ligands.

Fine mapping of human cytotoxic T lymphocyte (CTL) responses against hepatitis C virus (HCV) is based on external loading of target cells with synthetic peptides which are either derived from prediction algorithms or from overlapping peptide libraries. These strategies do not address putative host and viral mechanisms which may alter processing as well as presentation of CTL epitopes. Therefore, the aim of this proof-of-concept study was to identify naturally processed HCV-derived major histocompatibility complex (MHC) class I ligands. To this end, continuous human cell lines were engineered to inducibly express HCV proteins and to constitutively express high levels of functional HLA-A2. These cell lines were recognized in an HLA-A2-restricted manner by HCV-specific CTLs. Ligands eluted from HLA-A2 molecules isolated from large-scale cultures of these cell lines were separated by high performance liquid chromatography and further analyzed by electrospray ionization quadrupole time of flight mass spectrometry (MS)/tandem MS. These analyses allowed the identification of two HLA-A2-restricted epitopes derived from HCV nonstructural proteins (NS) 3 and 5B (NS3₁₄₀₆₋₁₄₁₅ and NS5B₂₅₉₄₋₂₆₀₂). In conclusion, we describe a general strategy that may be useful to investigate HCV pathogenesis and may contribute to the development of preventive and therapeutic vaccines in the future.

Mise à jour sur l'hépatite E [An update on hepatitis E].

The hepatitis E virus (HEV) is an RNA virus transmitted via the fecal-oral route or through uncooked animal meat products. Of the 4 known genotypes, genotype 3 is responsible for autochthonous infections in industrialized countries, with a seroprevalence in Switzerland estimated as high as 22%. The majority of infections is asymptomatic but a minority of patients, notably men over 50 or with underlying liver disease, can present with severe acute hepatitis. Chronic hepatitis E with HEV of genotype 3 has been observed in immunosuppressed patients, mostly transplant recipients. Serology is not sufficiently sensitive, especially in immunosuppressed patients, making PCR identification the preferred test for diagnosing active infection. Ribavirin or interferon-alpha can be used to treat chronic hepatitis E if reduction of immunosuppressive treatment does not result in viral elimination.

Prise en charge de l'hépatite B chronique: un défi en évolution constante [Management of chronic hepatitis B].

Chronic hepatitis B predisposes to the development of cirrhosis and hepatocellular carcinoma. Treatment of chronic hepatitis B is aimed at halting viral replication and, thereby, hepatic inflammation. Treatment indication should be established carefully and with full knowledge of the advantages and limitations of currently available antiviral drugs. Patients on long-term nudcleos(t)ide analogue treatment should be followed regularly in order to avoid the appearance of antiviral resistance. The purpose of this review is to provide a concise overview of the diagnosis and management of chronic hepatitis B.

Hepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic.

BACKGROUND: Hepatitis C virus (HCV) infection has a growing impact on morbidity and mortality in patients infected with human immunodeficiency virus (HIV). We assessed trends in HCV incidence in the different HIV transmission groups in the Swiss HIV Cohort Study (SHCS). METHODS: HCV infection incidence was assessed from 1998, when routine serial HCV screening was introduced in the SHCS, until 2011. All HCV-seronegative patients with at least 1 follow-up serology were included. Incidence rates (IRs) of HCV infections were compared between men who have sex with men (MSM), injection drug users (IDU), and heterosexuals (HET). RESULTS: HCV incidence was assessed in 3333 MSM, 123 IDU, and 3078 HET with a negative HCV serology at baseline. Over 23 707 person-years (py) for MSM, 733 py for IDU, and 20 752 py for HET, 101 (3%), 41 (33%), and 25 (1%) of patients seroconverted, respectively. The IR of HCV infections in MSM increased from 0.23 (95% credible interval [CrI], .08-.54) per 100 py in 1998 to 4.09 (95% CrI, 2.57-6.18) in 2011. The IR decreased in IDU and remained <1 per 100 py in HET. In MSM, history of inconsistent condom use (adjusted hazard ratio [HR], 2.09; 95% CI, 1.33-3.29) and past syphilis (adjusted HR, 2.11; 95% confidence interval [CI], 1.39-3.20) predicted HCV seroconversion. CONCLUSIONS: In the SHCS, HCV infection incidence decreased in IDU, remained stable in HET, and increased 18-fold in MSM in the last 13 years. These observations underscore the need for improved HCV surveillance and prevention among HIV-infected MSM.

Analyse der Hepatitis-C-Situation bei den drogenkonsumierenden Personen in der Schweiz

Die Analyse der Hepatitis-C-Situation bei den drogenkonsumierenden Personen in der Schweiz beruht auf verschiedenen Methoden: Analyse der publizierten und grauen Literatur zu diesem Thema, Sekundäranalyse verfügbarer Daten, Befragung nationaler Fachpersonen, Befragung drogenkonsumierender Personen (DU), Fallstudien in vier Kantonen (Zürich, Waadt, Aargau, Wallis), Internetumfrage bei den Einrichtungen, die DU stationär oder ambulant behandeln, sowie bei den niederschwelligen Einrichtungen zur Risikominderung. In den vergangenen zwei Jahrzehnten erreichte die Zahl der neu gemeldeten Infektionen mit dem Hepatitis-C-Virus (HCV) Ende der 90er-Jahre eine Spitze mit mehr als 2500 Fällen pro Jahr, wobei mehr als 30 % dieser Fälle Personen betrafen, die intravenös Drogen konsumieren (IDU). Die Zahl neu gemeldeter Fälle sank anschliessend bis auf 1500 Fälle im Jahr 2011 und stieg dann wieder auf mehr als 1700 Fälle im Jahr 2013 an. Der Anteil der IDU belief sich auf etwas mehr 20 % (436 Fälle, kein Wiederanstieg der Anzahl neuer Fälle in dieser Bevölkerungsgruppe). Die für die Gesamtbevölkerung der Schweiz geschätzte Prävalenz der HCV-Infektionen bewegt sich je nach Autor zwischen 0,7 % und 1,75 %. Bei Männern, die Sex mit Männern haben (MSM), ist dieser Wert etwas höher (2 %). Bei Staatsangehörigen aus Ländern mit einer höheren Prävalenz (Afrika südlich der Sahara, bestimmte Länder des Nahen Ostens und Südostasiens) ist die Prävalenzrate vermutlich erhöht; es sind jedoch keine Werte bekannt. Auch in Gefängnissen ist die HCV-Prävalenz höher als in der Gesamtbevölkerung, da DU und Staatsangehörige aus Ländern mit höherer Prävalenz stärker vertreten sind (zwischen 5 und 10 %). Es wird davon ausgegangen, dass es bei etwa zwei Drittel der Fälle zu einem chronischen Krankheitsverlauf kommt.

Nonstructural protein 3-4A: the Swiss army knife of hepatitis C virus.

Summary.  Hepatitis C virus (HCV) nonstructural protein 3-4A (NS3-4A) is a complex composed of NS3 and its cofactor NS4A. It harbours serine protease as well as NTPase/RNA helicase activities and is essential for viral polyprotein processing, RNA replication and virion formation. Specific inhibitors of the NS3-4A protease significantly improve sustained virological response rates in patients with chronic hepatitis C when combined with pegylated interferon-α and ribavirin. The NS3-4A protease can also target selected cellular proteins, thereby blocking innate immune pathways and modulating growth factor signalling. Hence, NS3-4A is not only an essential component of the viral replication complex and prime target for antiviral intervention but also a key player in the persistence and pathogenesis of HCV. This review provides a concise update on the biochemical and structural aspects of NS3-4A, its role in the pathogenesis of chronic hepatitis C and the clinical development of NS3-4A protease inhibitors.