Therapy of hepatitis C has been revolutionized by Direct Antiviral Agents. These drugs are safe and efficacious in all infected patients, including those with advanced, or decompensated cirrhosis, ...and are currently largely used in such cases in clinical practice worldwide. It was therefore cause of great concern the publication of two reports suggesting that treatment with DAAs could increase the risk of hepatocellular carcinoma in cirrhotic patients, particularly in those receiving antiviral therapy after having been cured for an HCC. These reports have generated a great and controversial debate and have been followed by a series of other publications not confirming such increased risk. This article summarizes published studies assessing the relation between DAA therapy and HCC in two different clinical setting: HCC recurrence in patients with an history of cured HCC and “de novo” HCC occurrence in patients without previous HCC. Rates of HCC recurrence after DAAs were extremely variable in different studies, reflecting great heterogeneity of this clinical setting. Data on “de novo” HCC incidence were more homogeneous and suggest that treatment with DAAs is not modifying the risk of developing HCC in the first 6‐12 months. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is suggested by some observations but remains unproven. There is clearly a need for prospective studies designed to better define these issues.
Chronic liver diseases are very common worldwide, particularly those linked to viral hepatitis and to alcoholic and non-alcoholic fatty liver. Their natural history is variable and long-term ...evolution differs in individual patients. Optimised clinical management of compensated chronic liver diseases requires precise definition of the stage of liver fibrosis, the main determinant of prognosis and of most therapeutic decisions. Liver biopsy is the gold standard for assessment of hepatic fibrosis. However, it is invasive with possible complications, costly and prone to sampling errors. Many non-invasive markers of liver fibrosis have been recently proposed and assessed in the clinical setting as surrogates of liver biopsy. Direct markers are based on biochemical parameters directly linked to fibrogenesis while indirect markers use simple or more sophisticated parameters that correlate with liver fibrosis stages. Non-invasive markers of liver fibrosis have been tested in different forms of chronic liver disease and showed variable diagnostic performance, but accuracy rarely was above 75%-80%. Better results were obtained when markers were combined. On this line, we have recently proposed a set of algorithms that combine sequentially indirect non-invasive markers of liver fibrosis, reaching 90%-95% diagnostic accuracy with significant reduction in the need for liver biopsy. Based on available evidence, it can be anticipated that non-invasive markers of liver fibrosis and their combined use will soon become a most useful tool in the clinical management of many forms of chronic liver disease. However, their implementation is expected to reduce, but not to completely eliminate, the need for liver biopsy.
Background & Aims Non-invasive assessment of liver fibrosis is a challenging area. Several methods have been proposed in patients with chronic hepatitis C (CHC) but their performance may be improved ...when they are combined as suggested by recently proposed algorithms using either transient elastography (TE) and Fibrotest (FT) (Castera) or AST-to-Platelet Ratio Index (APRI) and FT (SAFE biopsy). The aim of this prospective study was to compare the performance of these two algorithms for diagnosing significant fibrosis and cirrhosis in 302 CHC patients. Methods All patients underwent TE, FT and APRI the same day as liver biopsy, taken as reference standard. Results Significant fibrosis (Metavir F ⩾ 2) was present in 76% of patients and cirrhosis (F4) in 25%. TE failure was observed in eight cases (2.6%). For significant fibrosis, Castera algorithm saved 23% more liver biopsies (71.9% vs. 48.3%, respectively; p < 0.0001) than SAFE biopsy but its accuracy was significantly lower (87.7% vs. 97.0%, respectively; p < 0.0001). Regarding cirrhosis, accuracy of Castera algorithm was significantly higher than that of SAFE biopsy (95.7% vs. 88.7%, respectively; p < 0.0001). The number of saved liver biopsies did not differ between the two algorithms (78.8% vs. 74.8%; p = NS). Conclusions Both algorithms are effective for non-invasive staging of liver fibrosis in chronic hepatitis C. Although the number of liver biopsies avoided does not differ between algorithms for diagnosing cirrhosis, it is significantly higher with Castera algorithm than SAFE biopsy for significant fibrosis.
AIM： To assess the performance of several noninvasive markers and of our recently proposed stepwise combination algorithms to diagnose significant fibrosis （F ≥ 2 by METAVIR） and cirrhosis （F4 by ...METAVIR） in chronic hepatitis B （CHB）.
METHODS： One hundred and ten consecutive patients （80 males, 30 females, mean age： 42.6 ± 11.3） with CHB undergoing diagnostic liver biopsy were included. AST-to-Platelet ratio （APRI）, Forns＇ index, AST-to-ALT Ratio, Goteborg University Cirrhosis Index （GUCD, Hui＇s model and Fibrotest were measured on the day of liver biopsy. The performance of these methods and of sequential algorithms combining Fibrotest, APRI and biopsy was defined by positive （PPV） and negative （NPV） predictive values, accuracy and area under the curve （AUC）.
RESULTS： PPV for significant fibrosis was excellent （100%） with Forns and high （〉 92%） with APR1, GUCI, Fibrotest and Hui. However, significant fibrosis could not be excluded by any marker （NPV 〈 65%）. Fibretest had the best PPV and NPV for cirrhosis （87% and 90%, respectively）. Fibrotest showed the best AUC for both significant fibrosis and cirrhosis （0.85 and 0.76, respectively）. Stepwise combination algorithms of APR1, Fibrotest and biopsy showed excellent performance （0.96 AUC, 100% NPV） for significant fibrosis and 0.95 AUC, 98% NPV for cirrhosis, with 50%-80% reduced need for liver biopsy.
CONCLUSION： In CHB sequential combination of APRI, Fibrotest and liver biopsy greatly improves the diagnostic performance of the single non-invasive markers. Need for liver biopsy is reduced by 50%-80% but cannot be completely avoided. Non-invasive markers and biopsy should be considered as agonists and not antagonists towards the common goal of estimating liver fibrosis.
Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk ...factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.
Methodology: Data references were identified through indexed journals and non‐indexed sources. In this work, 13 000 articles were reviewed and 860 were selected based on their relevance.
Results: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤0.5%) estimates were from northern European countries and the highest (≥3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well‐established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel.
Conclusion: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood‐borne infections in the region.
•Italy has had the highest HCV prevalence in Western Europe over the past 20 years, while current HCV estimates are unknown.•Using a probabilistic approach and a Markov liver disease progression ...modelling to estimate the number of annual historical HCV incident cases, we were able to estimate the number of infected asymptomatic individuals.•High estimated burden of 410,775 individuals with chronic HCV infection of whom 281,809 potentially undiagnosed, yet unlinked to care highlight the need to undertake an active country-based screening strategy to attain HCV elimination goals.
The universal treatment of diagnosed patients with chronic HCV infection has been widely conducted in Italy since 2017. However, the pool of individuals diagnosed but yet to be treated in Italy has been estimated to end around 2025, leaving a significant proportion of infected individuals undiagnosed/without care. Estimates of this population are currently unknown.
A probabilistic modelling approach was applied to estimate annual historical HCV incident cases by their age-group (0–100 years) distribution from available literature and Italian National database (1952 to October 2019). Viraemic infection rates were modelled on the main infection routes in Italy: people who inject drugs (PWID), tattoos, sexual transmission, glass syringe use, blood transfusion and vertical transmission. Annual liver fibrosis stage transition probabilities were modelled using a Markov model. The number of HCV viraemic asymptomatic (fibrosis stage F0-F3:potentially undiagnosed/unlinked to care) and symptomatic (fibrosis stage F4: potentially linked to care) individuals was estimated.
By October 2019, total viraemic HCV individuals in Italy (excluding treated patients since 1992) were estimated to be 410,775 (0.68 % of current population of Italy; 95 % CI: 0.64−0.71%, based on the current Italian population), of which 281,809 (0.47 %; 95 % CI:0.35−0.60%) were fibrosis stage F0-F3. Among different high risk groups in stage F0-F3, the following distribution was estimated: PWID; 52.0 % (95 % CI:37.9–66.6 %), tattoo; 28.8 % (95 % CI:23–32.3 %), sexual transmission; 12.0 % (95 % CI:9.6–13.7 %), glass syringe and transfusion; 6.4 % (95 % CI:2.4–17.8 %), and vertical transmission; 0.7 % (95 % CI:0.4–1.2 %).
Under the assumption that most untreated HCV-infected individuals with stage F0-F3 are undiagnosed, more than 280,000 individuals are undiagnosed and/or unlinked to care in Italy. Marked heterogeneity across the major routes of HCV transmission was estimated. This modelling approach may be a useful tool to characterise the HCV epidemic profile also in other countries, based on country specific epidemiology and HCV main transmission routes.
Although an increase in hepatitis C virus (HCV) prevalence from Northern to Southern Italy has been reported, the burden of asymptomatic individuals in different Italian regions is currently unknown.
...A probabilistic approach, including a Markov chain for liver disease progression, was applied to estimate current HCV viraemic burden. The model defined prevalence by geographic area using an estimated annual historical HCV incidence by age, treatment rate, and migration rate from the Italian National database. Viraemic infection by age group was estimated for each region by main HCV transmission routes of individuals for stage F0-F3 (i.e. patients without liver cirrhosis and thus potentially asymptomatic) and F4 (patients with liver cirrhosis, thus potentially symptomatic).
By January 2020, it was estimated that there were 409,184 Italian individuals with HCV (prevalence of 0.68%; 95% CI: 0.54-0.82%), of which 300,171 (0.50%; 95% CI: 0.4-0.6%) were stage F0-F3. Considering all individuals with HCV in stage F0-F3, the geographical distributions (expressed as the proportion of HCV infected individuals by macroarea within the overall estimated number of F0-F3 individuals and prevalence values, expressed as the percentage of individuals with HCV versus the overall number of individuals for each macroarea) were as follows: North 42.1% (0.45%; 95% CI: 0.36-0.55%), Central 24.1% (0.61%; 95% CI: 0.48-0.74%), South 23.2% (0.50%; 95% CI: 0.4-0.61%), and the Isles 10.6% (0.49%; 95% CI: 0.39-0.59%). The population of people who inject drugs accounted for 50.4% of all individuals infected (F0-F3). Undiagnosed individuals (F0-F3) were ~ 15 years younger (⁓ 50 years) compared with patients with stage F4 (⁓ 65 years), with similar age distributions across macroareas. In contrast to what has been reported on HCV epidemiology in Italy, an increasing trend in the proportion of potentially undiagnosed individuals with HCV (absolute number within the F0-F3) from South (23.2%) to North (42.1%) emerged, independent of similar regional prevalence values.
This targeted approach, which addresses the specific profile of undiagnosed individuals, is helpful in planning effective elimination strategies by region in Italy and could be a useful methodology for other countries in implementing their elimination plans.
In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Non-invasive markers have been proposed but their use is limited by diagnostic accuracy. Our aim was to increase ...the diagnostic performance of non-invasive markers of liver fibrosis by combining them in sequential algorithms.
One hundred and ninety patients with chronic hepatitis C were evaluated for AST to platelets ratio (APRI), Forns' index and Fibrotest at the time of liver biopsy and stepwise combination algorithms were developed and validated prospectively in 100 additional patients.
Three algorithms were developed: (1) significant fibrosis (
F≥2 by METAVIR) was identified with high diagnostic performance (>94% accuracy) using APRI as screening test, followed by Fibrotest in APRI non-classified cases and restricting liver biopsy to patients classified F0–F1 by non-invasive tests. (2) A slightly modified algorithm had similar performance when applied to hepatitis C carriers with normal ALT. (3) Identification of cirrhosis (95% accuracy) was achieved using a dedicated algorithm with different cut-off, reducing by 60–70% the liver biopsies needed.
Stepwise combination of non-invasive markers of liver fibrosis improves the diagnostic performance in chronic hepatitis C. Need for liver biopsy is reduced by 50–70% but cannot be completely avoided.
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