Benjamin Maasoumy

Natural history of acute and chronic hepatitis C

Hepatitis C virus (HCV) infection remains a major global health burden. Hepatitis C causes significant liver-related morbidity and mortality due to hepatic decompensation and development of hepatocellular carcinoma. In addition, extra-hepatic manifestations of hepatitis C are frequent. There is a very large interindividual variability in the natural history of both acute and chronic hepatitis C which can be explained in part by a combination of various host, viral and environmental factors. Successful antiviral treatment can prevent short- and long-term complications of HCV infection in many patients. Still, the relative contribution of distinct risk factors for disease progression in different phases of HCV infection needs to be better defined. Personalized treatment approaches for HCV infection should consider individual risk profiles to avoid both under- and over-treatment - which will remain important also in upcoming era of interferon-free treatment of hepatitis C.

Eligibility and Safety of Triple Therapy for Hepatitis C: Lessons Learned from the First Experience in a Real World Setting

Background HCV protease inhibitors (PIs) boceprevir and telaprevir in combination with PEG-Interferon alfa and Ribavirin (P/R) is the new standard of care in the treatment of chronic HCV genotype 1 (GT1) infection. However, not every HCV GT1 infected patient is eligible for P/R/PI therapy. Furthermore phase III studies did not necessarily reflect real world as patients with advanced liver disease or comorbidities were underrepresented. The aim of our study was to analyze the eligibility and safety of P/R/PI treatment in a real world setting of a tertiary referral center. Methods All consecutive HCV GT1 infected patients who were referred to our hepatitis treatment unit between June and November 2011 were included. Patients were evaluated for P/R/PI according to their individual risk/benefit ratio based on 4 factors: Treatment-associated safety concerns, chance for SVR, treatment urgency and nonmedical patient related reasons. On treatment data were analyzed until week 12. Results 208 patients were included (F3/F4 64%, mean platelet count 169/nl, 40% treatment-naïve). Treatment was not initiated in 103 patients most frequently due to safety concerns. 19 patients were treated in phase II/III trials or by local centers and a triple therapy concept was initiated at our unit in 86 patients. Hospitalization was required in 16 patients; one patient died due to a gastrointestinal infection possibly related to treatment. A platelet count of <110/nl was associated with hospitalization as well as treatment failure. Overall, 128 patients were either not eligible for therapy or experienced a treatment failure at week 12. Conclusions P/R/PI therapies are complex, time-consuming and sometimes dangerous in a real world setting, especially in patients with advanced liver disease. A careful patient selection plays a crucial role to improve safety of PI based therapies. A significant number of patients are not eligible for P/R/PI, emphasizing the need for alternative therapeutic options.

Drug-Drug Interactions With Novel All Oral Interferon-Free Antiviral Agents in a Large Real-World Cohort.

BACKGROUND With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. METHODS Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-druginteractions.org and the relevant prescribing information. RESULTS The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir ± dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. CONCLUSIONS A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure.

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).

Clinical value of on-treatment HCV RNA levels during different sofosbuvir-based antiviral regimens.

BACKGROUND & AIMS The European Association for the Study of the Liver (EASL) guidelines recommend HCV RNA measurements at specific time points during sofosbuvir(SOF)-therapy. However, it remains unclear, how these results should be interpreted. We aimed to analyze whether on-treatment HCV RNA levels predict relapse comparing the CobasAmpliPrep/CobasTaqMan v2.0 (CAP/CTM) and Abbott RealTime HCV (ART) assays. METHODS Samples were collected from 298 patients (HCV genotypes; GT1-5) at weeks (w) 0, 1, 2, 4, 8, 12, 16, 20 and 24 during SOF-based therapy at two university clinics and tested for HCV RNA level by CAP/CTM and ART. Patients were treated with SOF/ribavirin (RBV) 12/24 w (n=99), pegylated-interferon-alfa (PegIFN)/SOF/RBV 12 w (n=51), SOF/simeprevir (SMV)±RBV 12 w (n=69) or SOF/daclatasvir±RBV 12/24 w (n=79). RESULTS HCV RNA levels during the first 4weeks of SOF/RBV therapy were significantly lower in GT3 patients who achieved SVR compared with those who relapsed. All GT3 patients with a week 2 result <45IU/ml by CAP/CTM achieved SVR but only 33% of those with ⩾45IU/ml (p=0.0003). Similar results were documented with ART and 60IU/ml as cut-off (SVR: 100% vs. 29%; p=0.0002). In contrast, HCV RNA levels during early treatment phases were not significantly related to relapse in patients treated with other SOF-based regimens. Residual HCV RNA was frequently detected by ART at later stages of therapy. However, SVR rates remained high in these patients. At the end of SOF/SMV±RBV therapy HCV RNA was detectable with ART in 20% of patients, of whom 92% achieved SVR. CONCLUSIONS HCV RNA levels assessed at week 2 of SOF/RBV therapy can predict relapse in GT3-patients. Detectable HCV RNA results at later stages during SOF-based therapy may occur frequently with the more sensitive ART. However, this should not lead to treatment extension. LAY SUMMARY We analyzed the predictive value of hepatitis C virus (HCV) RNA levels measured at different time points for treatment efficacy. We found that the level of HCV RNA measured at week 2 of antiviral therapy can be used to predict treatment success in patients with HCV genotype 3 infection treated with sofosbuvir and ribavirin but not in patients treated with other sofosbuvir-based regimens. Low level HCV RNA is frequently detected by the RealTime HCV assay during later stages of antiviral therapy. However, this is not associated with reoccurrence of HCV RNA after the end of treatment.

Detection of low HCV viraemia by repeated HCV RNA testing predicts treatment failure to triple therapy with telaprevir

Early on‐treatment virological response is one of the most important predictors for sustained virological response (SVR) to treatment of chronic hepatitis C virus (HCV) genotype 1 infection with triple therapy including HCV protease inhibitors (PI). Treatment duration (24 vs. 48 weeks) is based on HCV RNA results at weeks 4 and 12 of PI therapy when HCV RNA must be ‘undetectable’ to allow shorter therapy.

Limited effectiveness and safety profile of protease inhibitor-based triple therapy against chronic hepatitis C in a real-world cohort with a high proportion of advanced liver disease

Background/objective Triple therapy with pegylated-interferon-&agr;, ribavirin, and a protease inhibitor (PI), boceprevir or telaprevir, is the standard of care for the treatment of chronic hepatitis C genotype 1 in several countries. Pivotal studies showed reasonable results for safety and efficacy. However, it remains uncertain to what extent this can be transferred to the real world. Here, we aimed to analyze the effectiveness and safety of pegylated-interferon-&agr;/ribavirin/PI triple therapy in a real-world cohort of a tertiary referral center. Patients and methods Between June 2011 and November 2011, a total of 208 consecutive patients with chronic hepatitis C genotype 1 were evaluated for the initiation of a triple-therapy regimen and included in this study. Eighty-six patients (86% F3/F4) started a triple-therapy regimen and were followed until 12 weeks after the end of treatment. Results Overall, 36 out of the 86 treated patients (42%) achieved a sustained virological response. However, only 17% of the initially screened 208 patients were cured with triple therapy at our center. A high rate of serious adverse events (28%) was documented during treatment. The risk/benefit ratio was poor for patients with signs of advanced liver cirrhosis (n=33, 38%), indicated by increased bilirubin, low albumin, and/or low platelet count at baseline. Conclusion The effectiveness and safety of PI-based triple therapy can be limited in real-world cohorts including large numbers of patients with advanced liver disease. Future therapies can only overcome these limitations if interferon-free regimens are established.

Eligibility and safety of the first interferon-free therapy against hepatitis C in a real-world setting

Several real world data demonstrated that eligibility for and tolerability of triple therapy against hepatitis C virus (HCV) infection with a first‐wave protease inhibitor is limited. With the approval of sofosbuvir (SOF) effective treatment with and without pegylated interferon (PEG‐IFN) has become available for most genotypes. However, no data are available regarding the added benefit of an interferon‐free treatment concerning eligibility and tolerability in a real‐world scenario. We aimed to assess the eligibility and safety of SOF based therapies in patients with primarily advanced cirrhosis, including decompensated cirrhosis, in a real‐world setting.

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.

The clinical significance of drug-drug interactions in the era of direct-acting anti-viral agents against chronic hepatitis C.

Drug–drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct‐acting anti‐virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P‐glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs.