[Current drug treatment of hepatitis C : Useful therapy algorithms taking into consideration economical aspects]. / Aktuelle Arzneimitteltherapie der Hepatitis C : Sinnvolle Therapiealgorithmen unter Berücksichtigung ökonomischer Aspekte.

Treatment of chronic hepatitis C (HCV) has changed dramatically since the approval of the direct-acting antivirals (DAA). Depending on the HCV genotype and the stage of liver disease, sustained HCV clearance can be achieved in more than 95% of patients with a treatment duration of 8-12 weeks in most of the cases. The selection and combination of the drugs depends on previous antivirals therapies, the stage of liver fibrosis, HCV genotype and subtype, viral load at baseline, and renal function. Nowadays, potent antiviral therapy with minimal side effects can be offered to almost every patient. In the real-world setting, a high quality of HCV therapy considering economic aspects has been documented in the German Hepatitis C Registry. A reduction of clinical complications of chronic liver disease by clearance of HCV has already been documented.

Real-world experience with the all-oral, interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus infection in the German Hepatitis C Registry.

Real-world studies are relevant to complement clinical trials on novel antiviral therapies against chronic hepatitis C; however, clinical practice data are currently limited. This study investigated effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r)±dasabuvir (DSV)±ribavirin (RBV) for treatment of HCV genotype (GT) 1 and GT4 infection in a large real-world cohort. The German Hepatitis C Registry is an observational cohort study prospectively collecting clinical practice data on direct-acting antiviral therapies. Patients with GT1/4 infection treated with OBV/PTV/r±DSV±RBV were analysed. Effectiveness was assessed by sustained virologic response in 558 patients who reached post-treatment week 12 (SVR12). Safety is reported in 1017 patients who initiated treatment. Of the patients, 892 (88%) had GT1 and 125 (12%) had GT4 infection. Prior treatment experience and cirrhosis were reported in 598 (59%) and 228 (22%) patients, respectively. Overall, SVR12 (mITT) was 96% (486/505) in GT1- and 100% (53/53) in GT4 patients. SVR12 rates were high across subgroups including patients with cirrhosis (95%, 123/129), patients with moderate to severe renal impairment (100%, 34/34), and subgroups excluded from registrational trials like patients ≥70 years (96%, 64/67) and failures to prior protease inhibitor treatment (96%, 46/48). Adverse events (AEs) and serious AEs were reported in 52% (525/1017) and 2% (21/1017) of patients, respectively, and led to treatment discontinuation in 1.5% (15/1017) of patients. OBV/PTV/r±DSV±RBV was effective and generally well tolerated for treatment of HCV infection in clinical practice.

Response to treatment following recently acquired hepatitis C virus infection in a multicentre collaborative cohort.

Pegylated interferon therapy is highly effective in recently acquired HCV. The optimal timing of treatment, regimen and influence of host factors remains unclear. We aimed to measure sustained virological response (SVR) during recent HCV infection and identify predictors of response. Data were from five prospective cohorts of high-risk individuals in Australia, Canada, Germany and the United States. Individuals with acute or early chronic HCV who commenced pegylated interferon therapy were included. The main outcome was SVR, and predictors were assessed using logistic regression. Among 516 with documented recent HCV infection, 237 were treated (pegylated interferon n = 161; pegylated interferon/ribavirin n = 76) (30% female, median age 35 years, 56% ever injected drugs, median duration of infection 6.2 months). Sixteen per cent (n = 38) were HIV/HCV co-infected. SVR among those with HCV mono-infection was 64% by intention to treat; SVR was 68% among HCV/HIV co-infection. Independent predictors of SVR in HCV mono-infection were duration of HCV infection (the odds of SVR declined by 8% per month of infection, aOR 0.92, 95% CI 0.85-0.99, P = 0.033), IFNL4 genotype (adjusted OR 2.27, 95% CI 1.13-4.56, P = 0.021), baseline HCV RNA <400 000 IU/mL (aOR 2.06, 95% CI 1.03-4.12, P = 0.041) and age ≥40 years (vs <30: aOR 2.92, 95% CI 1.31-6.49, P = 0.009), with no difference by drug regimen, HCV genotype, symptomatic infection or gender. The effect of infection duration on odds of SVR was greater among genotype-1 infection. Interferon-based HCV treatment is highly effective in recent HCV infection. Duration of infection, IFNL4 genotype and baseline HCV RNA levels can predict virological response and may inform clinical decision-making.

Development and evaluation of a baseline-event-anticipation score for hepatitis delta.

Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liver-related morbidity or mortality. We followed 75 HBsAg-anti-HDV-positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline-event-anticipation score (BEA score) was developed based on variables associated with the development of liver-related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA-A mild risk, BEA-B moderate risk and BEA-C high risk. Hazard ratios of BEA-B and BEA-C patients for liver-related clinical endpoints were 9.01 and 25.27 vs BEA-A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and Düsseldorf (n = 62). Delta hepatitis is associated with a very severe long-term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver-related complications in patients with hepatitis delta.

[Costs of guideline-based treatment of hepatitis B patients in Germany]. / Kosten einer leitliniengerechten Versorgung von Hepatitis-B-Patienten in Deutschland.

The costs of guideline-based treatment are unknown for most diseases. This also applies for economically significant infectious diseases like viral hepatitis and HIV. On the basis of the "German Guidelines for the Management of HBV Infection" from 2011 patients were grouped into HBsAg-positive, immuntolerant and chronic hepatitis patients with and without cirrhosis. Costs were divided in baseline diagnostics, monitoring and medical treatment according to the guideline. The calculation was modelled for a period of five years. Costs for virological diagnostics and imaging account for a large proportion of diagnostic costs. The main cost factors are expenses for pharmaceutical treatment with interferon or HBV polymerase inhibitors. On the assumption that only 25 % of the infected patients are diagnosed, 5-year total costs in Germany account for more than 2.5 billion Euros. Therefore, chronic hepatitis B is a disease with a very high economic burden. The aim of a guideline treatment is to prevent the development of cirrhosis with all its complications as well as the development of liver-cell carcinoma. Prophylactic vaccination against hepatitis B should be advised also considering the potential economic impact.

Adefovir serum levels do not differ between responders and nonresponders.

Primary or secondary failure of adefovir dipivoxil (ADV) therapy of chronic hepatitis B is not infrequent. The reasons for suboptimal responses are not well defined. In HIV and hepatitis C virus infection, failure of antiviral drug therapy has been linked with low blood drug levels. We have studied 20 well-defined patients with chronic hepatitis B who were treated with ADV for drug and virus kinetics. Importantly, neither Cmax levels (mean 26 ng/mL, range 14-59 ng/mL) nor the time to maximal drug levels (mean 4 h, range 2-8 h) differed between patients showing a complete virological response to adefovir (n = 10), patients with secondary treatment failure (n = 7) and patients with suboptimal primary response (hepatitis B virus-DNA >10,000 IU/mL after 6 months of treatment; n = 3). Thus, adefovir treatment failure is unlikely to be due to an inability to mount sufficient drug levels in the blood.

Virological and clinical characteristics of delta hepatitis in Central Europe.

Hepatitis D virus (HDV) or delta hepatitis has mainly been studied in Asian and Mediterranean cohorts, but data on virological and clinical characteristics of HDV-infected Central and Northern European patients are limited. We investigated virological patterns, as well as biochemical and clinical features of liver disease in 258 HDV infected patients recruited over a period of 15 years at Hannover Medical School. Virological parameters were compared to 2083 anti-HDV negative hepatitis B surface antigen (HBsAg) positive individuals. In this cohort, (i) HDV infection was associated with both suppressed hepatitis B virus (HBV) and hepatitis C virus (HCV) replication, (ii) the suppression of HBV-DNA and HCV-RNA was not related to HDV-RNA replication, (iii) mean HBsAg levels did not significantly differ between HBV-monoinfected patients and individuals with delta hepatitis, (iv) HCV coinfection was rather frequent as about one third of our delta hepatitis patients tested anti-HCV positive, however, without being associated with more advanced liver disease, (v) delta hepatitis patients presented in a high frequency with an advanced stage of liver disease, and (vi) the course of delta hepatitis did not differ between Turkish-born, Eastern European (EE)-born and German-born patients. In summary, in this cohort of patients which is the largest so far Central European single centre group of delta hepatitis patients, we confirm the presence of frequently severe disease and describe novel virological profiles which require consideration in the management of this difficult to treat group of patients.

Clearance of chronic HCV infection during acute delta hepatitis.

The course of chronic hepatitis C in acute HDV/HBV superinfection is unknown. Here, we report a patient with chronic hepatitis C who cleared HCV during acute self-limited hepatitis B/D superinfection. Recovery from HCV was associated with the appearance of a strong and multispecific HDV-specific memory CD4+ and CD8+ T cell response - but only weak HCV-specific CD4+ T cell responses. These data suggest that HCV can be cleared by bystander mechanisms during acute infections with other pathogens which may be considered in the development of immunotherapies for hepatitis C.

Successful treatment of fulminant hepatitis B during pregnancy.

We here report the use of lamivudine 100 mg daily in a young pregnant woman (24th week of gestation) with fulminant hepatic failure due to acute HBV infection. After initiation of oral lamivudine (100 mg/d), ALT levels rapidly decreased from 5046 U/L to normal values within five weeks. HBe seroconversion occured three weeks after treatment start, followed by HBs seroconversion within less than six months. A preterm female baby was delivered at gestational week 29 (weight 1000 gr) (five weeks after start of lamivudine). The infant received simultaneous active and passive HBV immunisation within 12 hours after delivery. The neonatal check-up revealed meconium ileus which was successfully treated by surgery. At last presentation 241 days after initiation of treatment, both mother and infant showed stable HBs-seroconversion (anti-HBs 169 IU/mL and > 1000 IU/L, respectively). Therefore, lamivudine therapy was withdrawn. This case suggests that oral nucleos(t)ides may be safely used in pregnant patients with fulminant hepatitis B potentially preventing liver transplantation and interruption of pregnancy.

The German Hep-Net acute hepatitis C cohort: impact of viral and host factors on the initial presentation of acute hepatitis C virus infection.

INTRODUCTION: The impacts of viral load, genotype, age, sex and BMI on the clinical course of acute hepatitis C are poorly defined. Here we studied 259 patients with acute HCV infection recruited in the German Hep-Net data base between 1998 and 2008. Antiviral treatment with interferon alpha was initiated in 171 patients (66 %) within 4 months after the diagnosis of acute hepatitis C. RESULTS: In this cohort (i) the mode of infection was associated with age as iv-drug users were significantly younger than non-iv-drug users while the proportion of patients who acquired HCV by medical procedures increased with age; (ii) patients younger than 30 years were more often infected with genotype 3 (26 % versus 8 % for patients older than 50 years; p = 0.03); (iii) 51 % of patients were icteric and 28 % presented with a 30-fold elevation of liver enzymes, however, no fulminant hepatic failure occurred; (iv) HCV genotype was not associated with disease severity and time to onset of symptoms; (v) low HCV viremia was associated with lower serum AST levels and a longer time from exposure to onset of symptoms; (vi) disease severity was independent from the mode of infection, age, sex and body mass index (BMI). CONCLUSIONS: In this large cohort of patients admitted for antiviral therapy, acute hepatitis C took a rather mild course of disease in the majority of patients. Disease severity was not associated with HCV genotype, viral load, age, sex and BMI.

Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis.

BACKGROUND: Hepatitis C virus (HCV) clearance with IFN-based therapies reduces the incidence of hepatocellular carcinoma (HCC). There has been some debate if IFN-free therapy with direct-acting antivirals alters the risk for HCC. AIM: To investigate the HCC incidence in cirrhotic HCV patients who cleared HCV with direct-acting antivirals vs untreated controls. METHODS: We prospectively monitored 373 patients with chronic hepatitis C who received IFN-free therapies with direct-acting antiviral after January 2014. A retrospective control cohort of untreated cirrhotic patients was recruited out of 3715 HCV patients who were followed at our centre between 2007 and 2013, with similar HCC screening protocols. RESULTS: 158 direct-acting antiviral-treated and 184 control patients with liver cirrhosis were included in this analysis. The groups did not differ in gender and genotype distribution, severity of liver disease and prevalence of diabetes mellitus. Patients were followed up for a median of 440 (range 91-908) and 592 (range 90-1000) days. HCCs developed in 6 and 14 patients during follow-up, resulting in an incidence of 2.90 vs 4.48 HCCs per 100 person-years. In the direct-acting antiviral-treated group, there was no new case of HCC later than 450 days after treatment initiation. In multivariate analysis, higher MELD-Scores and AFP-levels were independently associated with HCC development. Transplant-free patient survival was similar in both groups. CONCLUSIONS: IFN-free direct-acting antiviral therapy of chronic hepatitis C does not alter the short-term risk for HCC in patients with liver cirrhosis. A reduced HCC incidence may become evident after more than 1.5 years of follow-up.

Dominance of hepatitis C virus (HCV) is associated with lower quantitative hepatitis B surface antigen and higher serum interferon-γ-induced protein 10 levels in HBV/HCV-coinfected patients.

Different viral dominance patterns have been documented in coinfection with hepatitis B virus (HBV) and hepatitis C virus (HCV) based on HBV DNA and HCV RNA quantification. In most cases, HCV is dominant and suppresses HBV replication. In vitro studies revealed that there is most probably no direct interference between HBV and HCV replication. We hypothesized that indirect mechanisms mediated by host immune responses might be responsible for the different dominance patterns. In this study we analysed quantitative hepatitis B surface antigen (HBsAg) as a marker for immune control of HBV and interferon γ-induced protein 10 (IP-10) as host marker for the endogenous interferon in 85 patients with HBV/HCV coinfection. Levels of HBsAg were closely associated with viral dominance patterns in 85 HBV/HCV-coinfected patients. HBsAg levels were lowest in patients with HCV dominance, even lower compared with HBV-monoinfected patients undergoing treatment with nucleos(t)ide analogues (NA) but comparable to low replicative HBsAg carriers. An increase in HCV RNA during follow up was associated with HBsAg decline. Patients with HCV dominance had significantly higher serum IP-10 levels compared with HBV-dominant patients or HBV-monoinfected patients treated with NA. Lower HBsAg and higher IP-10 levels in HCV-dominant HBV/HCV-coinfected patients suggest that HCV suppresses HBV DNA replication and also HBsAg production by immune mechanisms.

Hepatitis B core-related antigen (HBcrAg) levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D.

Hepatitis B core-related antigen (HBcrAg) has been suggested as an additional marker of hepatitis B virus (HBV) infection. HBcrAg combines the antigenic reactivity resulting from denatured hepatitis B e antigen (HBeAg), HBV core antigen and an artificial core-related protein (p22cr). In Asian patients, high levels of HBcrAg have been suggested to be an independent risk factor for hepatocellular carcinoma, while low levels could guide safe cessation of treatment with nucleos(t)ide analogues. We here studied HBcrAg levels in different phases of HBV infection in a large European cohort predominantly infected with genotypes A and D: HBeAg-positive immune tolerance (n = 30), HBeAg-positive immune clearance (IC) (n = 60), HBeAg-negative hepatitis (ENH) (n = 50), HBeAg-negative inactive/quiescent carrier phase (c) (n = 109) and acute hepatitis B (n = 8). Median HBcrAg levels were high in the immune tolerance and immune clearance phases (8.41 and 8.11 log U/mL, respectively), lower in ENH subjects (4.82 log U/mL) but only 2.00 log U/mL in ENQ subjects. Correlation between HBcrAg and HBV DNA varied among the different phases of HBV infection, while HBcrAg moderately correlated with hepatitis B surface antigen in all phases. ENQ patients had HBcrAg levels <3 log U/mL in 79%, in contrast to only 12% in the ENH group. HBcrAg levels vary significantly during the different phases of HBV infection. HBcrAg may serve as valuable marker for virus replication and reflect the transcriptional activity of intrahepatic cccDNA. In HBeAg-negative patients, HBcrAg may help to distinguish between inactive carriers (ENQ) and those with active disease (ENH).

Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies.

BACKGROUND: Successful antiviral treatment of decompensated hepatitis B with HBV polymerase inhibitors is associated with improvement of liver function. To what extent liver function also improves in cirrhotic patients with chronic hepatitis C receiving novel interferon-free (IFN-free) therapies is unknown. AIM: To study liver function in cirrhotic HCV patients receiving IFN-free therapies. METHODS: We here studied 80 consecutive patients with advanced HCV associated liver cirrhosis including 34 patients (43%) with Child B/C cirrhosis and 42 patients (53%) with platelet counts of <90.000/µL receiving different combinations of direct acting antivirals without interferon [sofosbuvir/ribavirin (n = 56), sofosbuvir/simeprevir ± ribavirin (n = 15) and sofosbuvir/daclatasvir ± ribavirin (n = 9)]. The majority of patients was infected with HCV genotype 1 (n = 50); HCV genotypes 2, 3 and 4 were present in 4, 24 and 2 patients, respectively. RESULTS: Liver function parameters including albumin, bilirubin, cholinesterase and prothrombin time all improved in the majority of patients during antiviral therapy irrespectively of the underlying HCV genotype, however, with different kinetics. MELD scores improved until post-treatment week 12 in 44% of the patients but worsened in 15%. A sustained virological response was achieved in 63% of the patients. HCV RNA relapse led to moderate ALT increases in 15/23 patients but was not associated with hepatic decompensations. CONCLUSION: This real-world single centre study showed that interferon-free treatment of hepatitis C patients with advanced liver cirrhosis restores liver function, and may thereby reduce the need for liver transplantations.

[Knowledge and management of hepatitis B virus infected patients in Germany]. / Kenntnisse und Versorgung von Hepatitis-B-Infizierten in Deutschland.

BACKGROUND AND AIM: Hepatitis B is a significant health burden in Germany. The aim of this study was (I) to gain more information on knowledge of hepatitis B patients and patient management considering epidemiologic and socio-economic factors, (II) to investigate the knowledge of relatives of patients with hepatitis B about liver disease, modes of infection and possibilities of prevention. PATIENTS AND METHODS: Structured questionnaires were sent to 1000 patients with hepatitis B as a project of the Model Region North of the German network of excellence for viral hepatitis. The patients were asked to forward additional questionnaires to their relatives and household members. RESULTS: 312 (31 %) questionnaires were sent back and evaluated. The majority of responding patients had an immigration background (75 %). The knowledge of hepatitis B patients about their disease status was very heterogeneous. While most of them were aware of their ALT-values, only some patients knew their HBV viral loads. Patients with a low socio-economic status consulted physicians more often but did not receive medical examinations more frequently. The knowledge of relatives (384 relatives from families of 216 patients) about the mode of transmission and the possibilities of prevention were also heterogeneous. Only 84 % of the partners and children were vaccinated against hepatitis B and only 75 % of relatives knew that condoms protect against HBV infection. CONCLUSION: Not only patients with hepatitis B but also relatives and household members should be informed about consequences of liver disease and HBV infection. The poor vaccination coverage even of sexual partners of HBV-infected individuals requires attention and should lead to a better education.

Steroid treatment for severe acute cryptogenic hepatitis.

OBJECTIVE: Acute cryptogenic hepatitis may represent both a self-limited disease as well as the onset of chronic hepatitis. The aim of this analysis was to evaluate the effect of steroid treatment in patients with acute cryptogenic hepatitis. METHODS: We retrospectively analyzed four patients with acute cryptogenic hepatitis. Histories were negative for alcohol and hepatotoxic drug intake. Markers of metabolic liver disease, liver-related autoantibodies, and viral markers were negative in all patients. Gamma globulins were in the normal range. ALT rose above 1000 U/L in all patients and bilirubin levels were elevated to more than 400 micromol/L. Histopathological assessment revealed minimal infiltration with plasma cells, eosinophils and bile duct lesions. Using the international scoring system for the diagnosis of autoimmune hepatitis, all patients were classified as 'probable disease' in the absence of specific markers. RESULTS: We started immunosuppressive treatment with prednisolone because of persisting high aminotransferases and impaired liver function. All patients responded to steroids with normalization of liver function and a rapid decrease of aminotransferases. In one patient, additional treatment with azathioprine was necessary due to rebounding aminotransferases during steroid tapering. CONCLUSION: Steroids have to be taken into account in the therapy for severe acute cryptogenic hepatitis. The response to steroid treatment could be indicative for an autoimmune genesis of the disease.

Improved outcome of chronic hepatitis B after heart transplantation by long-term antiviral therapy.

Chronic hepatitis B progresses to cirrhosis in the majority of immunosuppressed patients. The outcome of long-term antiviral therapy in HBV-infected organ transplant recipients is unknown. In 1996, we included 20 heart transplant (HT) recipients in a pilot trial to treat chronic hepatitis B with famciclovir. At that time, bridging fibrosis or cirrhosis was evident in 15 individuals (75%). From 1998 onwards, patients were switched to lamivudine in case of primary or secondary virological nonresponse to famciclovir. Adefovir or tenofovir became available at our centre for HT recipients in 2002. After 103 months, one patient was still on famciclovir showing a complete virological response. Sixteen patients were switched to lamivudine after 0.5-4 years of famciclovir therapy. Six of those showed a long-term response to lamivudine therapy lasting for up to 7 years. Lamivudine resistance developed in the remaining 10 patients (63%), in 4 of them successful rescue therapy (adefovir n = 3, tenofovir n = 1) could be initiated. Only one hepatocellular carcinoma developed, which was successfully treated by locoregional ablative therapy. Nine patients died (45%), with lamivudine-resistance-related liver failure as the cause of death in five cases. Significant improvement of Ishak fibrosis scores could be demonstrated in six of the seven patients with more than two sequential liver biopsies available. Long-term antiviral therapy of chronic hepatitis B can lead to regression of liver cirrhosis in patients after organ transplantation, unless viral resistance occurs. This study demonstrates the urgent need for further antivirals to overcome antiviral resistance.