Wednesday, January 4, 2017

Cost-Effectiveness of Treating Hepatitis C with Sofosbuvir/Ledipasvir in Germany

Cost-Effectiveness of Treating Hepatitis C with Sofosbuvir/Ledipasvir in Germany
Jona T. Stahmeyer , Siegbert Rossol, Sebastian Liersch, Ines Guerra, Christian Krauth
Published: January 3, 2017

Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.

Material and Methods
We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.

Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.

Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.

Discussion Only
View Full Text Article Online @ PLOS ONE or Download PDF
The introduction of direct acting antivirals was the milestone in the treatment of chronic hepatitis C. Newly introduced treatment regimens have substantially increased SVR-rates, shortened treatment duration and show a favorable toxicity profile. Furthermore, these regimens allow curing patients who could not be treated previously (e.g. due to interferon intolerance, advanced cirrhosis, comorbidities).

We analyzed cost-effectiveness of SOF/LDV±RBV for the treatment of HCV genotype 1 patients. Analyses were conducted for treatment-naive and treatment-experienced patients considering presence/absence of liver cirrhosis. This regimen is recommended by the current German guideline as well as the regimen containing PTV/r/OMV/DSV±RBV and was also included our analyses [57].

Results show that treatment with SOF/LDV±RBV is cost-effective compared to prior standard of care considering a willingness-to-pay threshold of €30,000. The regimen of SOF/LDV even is cost saving (showed better outcomes and lower costs) in treatment-naive non-cirrhotic patients as a large part only require treatment for 8 weeks; treatment in cirrhotic patients resulted in 3,383 €/QALY. Incremental cost-effectiveness ratios were 26,426 €/QALY in non-cirrhotic and 1,397 €/QALY in cirrhotic treatment-experienced patients. Results were robust in multiple sensitivity analyses.

Several international studies have analyzed cost-effectiveness of newly introduced direct acting antivirals, especially for the US, but have not been performed for the German setting yet.

Najafzadeh et al (2015) analyzed cost-effectiveness of novel treatment regimens in treatment-naive hepatitis C patients. In genotype 1 patients, different strategies were compared to the previous standard of care (BOC+PegIFN+RBV). Treatment with SOF/LDV for 12 weeks resulted in an incremental cost-effectiveness ratio of 12,825 $/QALY. Other interferon-free regimens showed less favorable results (12 weeks SMV/SOF: 71,445 $/QALY; 12 weeks DCV/SOF: 63,355 $/QALY). The authors conclude that new treatment regimens represent good long-term economic value in genotype 1 patients [9].

Results from another US study by Chhatwal et al. (2015) evaluated cost-effectiveness of SOF/LDV (8 or 12 weeks) compared to the old standard of care (TVR+ PegIFN+RBV and BOC+PegIFN+RBV). The analyses showed incremental cost-effectiveness ratios of 31,452 $/QALY for non-cirrhotic and 9,703 $/QALY for cirrhotic treatment-naive patients. In treatment-experienced patients 35,853 $/QALY and 79,238 $/QALY were estimated for non-cirrhotic and cirrhotic patients, respectively. Assuming a willingness-to-pay threshold of 50,000 €/QALY treatment of genotype 1 patients with SOF/LDV is cost-effective in most patient groups [8].

A study by Younossi et al. (2015) comes to the conclusion that SOF/ treatment LDV (8,12 or 24 weeks depending on patient characteristics) dominates other treatment strategies except for SOF+SMV (12 or 24 weeks), which provides slightly better results but is considerably more expensive. Sensitivity analyses show that costs of alternative treatment strategies have the greatest impact on study results [7].

Zhang et al. (2015) analyzed cost-effectiveness of recently introduced regimens, primarily considering treatment-naive patients [10]. In non-cirrhotic genotype 1 patients both, SOF/LDV (12 weeks) and OMV/PTV/RTV + DSV + RBV (12 weeks), dominate triple-therapy with TVR + PegIFN/RBV the prior standard of care (higher effectiveness and lower lifetime costs). In patients with cirrhosis SOF/LDV (12 weeks) dominates TVR+PegIFN+RBV, whereas treatment with OMV/PTV/RTV+DSV+RBV (12 weeks) shows an incremental cost-effectiveness ratio of 25,227 $/QALY [10].

In comparing different studies, it has to be taken into account that transferability of economic evaluations is limited since healthcare systems, structures of care provision and remuneration schemes differ considerably between countries [58]. The comparability is made even more difficult considering differences in study design like modeling approaches, patient characteristics and treatment strategies. Therefore, there is a high need for the defining of up-to-date national data. Nevertheless, there are comparable results such as the dominant factor of treatment costs on study results. Most studies prove that treatment with SOF/LDV is cost-effective.

There are some limitations that have to be taken into account when interpreting the results of our study. Efficacy data is based on the results from different clinical trials and data for certain treatment regimens are based on a relatively small patient samples. Usually SVR-rates from clinical trials are not easily transferable into clinical practice [59]. Nevertheless, recent data from real-world SVR-rates show comparable SVR-rates in clinical practice. In the TRIO study SVR-rates in treatment-naive non-cirrhotic patients of 95% for an 8-week treatment with SOF/LDV and 96% for a 12-week treatment with SOF/LDV±RBV were observed [60]. Data on treatment-experienced patients show SVR-rates of 84% for 12 weeks of SOF/LDV, 96% for 12 weeks of SOF/LDV+RBV and 92% for 24 weeks of SOF/LDV [61]. German data confirm high SVR-rates for newly introduced interferon-free regimens [62]. A general problem is the reliability and availability of data. Extensive literature analyses were performed to determine the best available data. Furthermore, the impact of special patient types (e.g. with certain comorbidities, alcohol or drug abuse) was insufficiently taken into account as data refers to average patients. To determine cost-effectiveness in special HCV populations separate analyses and modeling approaches are necessary.

Although several studies have shown that HCV treatment with new DAA is cost-effective or even cost-saving in certain patient groups, affordability for healthcare systems and payers is doubtful. In addition to high costs of newly introduced agents, new treatment options allow to treat and cure patients who were not eligible for treatment in the past (e.g. patients with certain comorbidities or advanced liver disease, interferon-intolerant). Therefore, the number of patients available for treatment increased significantly, which stresses healthcare budgets further. Even western countries have limited or delayed access to new treatment options and restricted the use for patients with advanced liver disease [63;64]. Prioritization of severely ill might be a short-term solution for reducing expenditure. However, it should be taken into account that a major goal of treating hepatitis C is to prevent the development of liver cirrhosis and its complications. Even if patients with liver cirrhosis are successfully treated, they are still at risk of decompensation or developing HCC [43].

Treatment with SOF/LDV is recommended by national and international guidelines. Our analyses showed that this treatment is cost-effective compared to the prior standard of care in genotype 1 patients (triple-therapy with TVR). Besides individual treatment costs, impact of new treatments on healthcare budgets should not be forgotten.
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FDA Grants Fast Track Designation to Enanta’s EDP-305, for the treatment of NASH with Liver Fibrosis

Enanta Pharmaceuticals : FDA Grants Fast Track Designation to Enanta’s FXR Agonist Candidate, EDP-305, for the treatment of NASH with Liver Fibrosis

Enanta Pharmaceuticals, Inc. (NASDAQ:ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs for viral infections and liver diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted Enanta’s drug candidate EDP-305, an FXR agonist, Fast Track designation for the treatment of patients with non-alcoholic steatohepatitis (NASH) with liver fibrosis.

Fast track is a process designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. A drug that receives Fast Track designation is also eligible for more frequent meetings and communications with the FDA to discuss the drug's development plan.1

“We are extremely pleased to receive this Fast Track designation from the FDA and look forward to working with the agency to bring this investigational treatment to patients as soon as possible,” stated Jay R. Luly, Ph.D.

EDP-305 is currently in Phase 1 clinical development. Enanta’s double-blind, placebo-controlled Phase 1a/b study is designed to evaluate the safety, tolerability and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses (MAD) of EDP-305 in healthy adults, and in adults with presumptive non-alcoholic fatty liver disease (NAFLD) (obese, with or without pre-diabetes or type 2 diabetes). The study will enroll approximately 90 subjects and is planned to evaluate up to 5 dose cohorts, with EDP-305 administered orally, once daily.

The current study includes subjects with presumptive NAFLD in order to obtain initial safety data and additional data regarding the relationship between EDP-305 plasma concentration levels and certain pharmacological effects in the context of fatty liver disease. This relationship will be explored by using biomarkers that are relevant to the disease and to the activity of EDP-305, such as evaluation of lipids, glucose, insulin resistance and specific markers of FXR activity.

About EDP-305, a Farnesoid X Receptor (FXR) Agonist
EDP-305 is a potent FXR agonist and Enanta’s lead product candidate being developed for the treatment of NASH and PBC. EDP-305 represents a new class of FXR agonists that has been designed to take advantage of increased binding interactions with the receptor. Further, this non-bile acid class contains steroid and non-steroid components, and does not contain the carboxylic acid group normally present in other classes of FXR agonists and natural bile acids that can lead to the formation of taurine and glycine conjugates. EDP-305 is currently in Phase 1 clinical development.

About NAFLD, NASH, and FXR
Non-alcoholic fatty liver disease (NAFLD) is the accumulation of excessive fat in the form of triglycerides in patients’ liver cells (steatosis) that is not caused by alcohol. NAFLD is widely considered to be the liver expression of metabolic disease associated with type 2 diabetes, insulin resistance, obesity, and hyperlipidemia. A subgroup of NAFLD patients also develops liver cell injury and inflammation. This condition is called non-alcoholic steatohepatitis (NASH). Patients with NASH can develop fibrosis (the first stage of scarring of the liver) and ultimately cirrhosis of the liver, potentially leading to hepatocellular carcinoma or requiring a liver transplant. Farnesoid X receptor (FXR) is a nuclear receptor and a main regulator of bile acid levels in the liver and small intestine. It responds to bile acids by regulating gene transcription of key enzymes and transporters, many of which play important roles in lipid metabolism, insulin resistance, inflammation, and fibrosis.

Monday, January 2, 2017

Hepatitis C - Natco Pharma launches generic version of Sofosbuvir 400mg/Velpatasvir 100mg fixed dose combination in Nepal

NRK/Natco Pharma launches Hepatitis C drug in Nepal
Natco Pharma Limited (NSE: NATCOPHARM; BSE: 524816) announced today that it has launched the first generic version of Sofosbuvir 400mg/Velpatasvir 100mg fixed dose combination in Nepal. Sofosbuvir 400mg/Velpatasvir 100mg fixed dose combination is sold by Gilead Sciences, Inc., under brand name Epclusa®.

Epclusa® is the first all-oral, pan-genotypic, single tablet regimen for the treatment of adults with genotype 1-6 chronic hepatitis C virus (HCV) infection. Epclusa is also the first single tablet regimen approved for the treatment of patients with HCV genotype 2 and 3, without the need for Ribavirin.
Natco will market Sofosbuvir 400mg/Velpatasvir 100mg under the brand name VELPANAT®.

Natco priced its generic medicine of VELPANAT at an MRP of INR 25,000/- equivalent for a bottle of 28 tablets in Nepal. Natco has signed a non-exclusive licensing agreement with Gilead Sciences, Inc., to manufacture and sell generic versions of its chronic hepatitis C medicines in 101 developing countries.

2016/2017 - New HCV two and three drug regimens on their way: what do they promise?

Summary for AASLD 2016 for Hepatitis C - New HCV two and three drug regimens on their way: what do they promise? And what do clinicians need to look out for under DAA combination therapy and beyond SVR?
Jurgen K. Rockstroh M.D., Professor of Medicine University of Bonn, Germany

Jules Levin Executive Director of National AIDS Treatment Advocacy Project (NATAP) recently added this complete summary of AASLD 2016 including links to each study cited in the article. Here is a summary of the topics and introduction with a few links of interest, click here to view the full text article.

Topic Summary
Risk of HBV reactivation after starting DAA therapy
Surveillance for hepatocellular carcinoma (HCC) and risk for HCC after achieving SVR following DAA therapy.
Intravenous drug users and patients on opioid substitution therapy
Patients in the prison setting
HIV/HCV coinfected patients
Patients with renal insufficiency or on hemodialysis
Patients older than 70 years
Patients receiving short treatment durations of 8 week
HCV three drug rescue combinations with licensed drugs
New dual DAA combinations
New three drug combinations


At present, besides the Abbvie 3-D regimen, mostly dual hepatitis C (HCV) direct acting antiviral (DAA) combinations which are coformulated as single tablet regimens have become the gold standard for first line treatment of all HCV genotypes. Despite SVR rates on average above 95% there are still attempts in the field to develop three drug combinations (so called triplets) or very potent new dual regimens which may allow shortening of treatment duration and may also add to the antiviral pangenotypic activity of all oral DAA combination therapy. Obviously, even with the currently licensed HCV drugs, three drug combinations may play a role in retreatment of the few patients which experience virological failure under dual DAA-based HCV therapy. Various studies at AASLD this year where devoted to effectiveness and safety of these new three DAA regimens in treatment naïve as well as treatment experienced patients including prior DAA-based treatment failure (1-7). In addition, data on the new and very potent Abbvie dual combination (Glecaprevir (ABT-493)/Pibrentasvir (ABT-530)), again in treatment-naïve, experienced- and prior DAA-failures, was presented (8-10). Another important topic was feedback on safety and effectiveness of various all oral DAA combinations from real-world cohorts including a whole variety of special populations including intravenous drug users, patients on opioid substitution therapy, patients in the prison setting, HIV coinfected, patients with renal insufficiency, patients older than 70 years, patients receiving short treatment durations of 8 week and much more (11-19). As more and more data arises from very diverse patient populations it appears as if no special or hard to treat patient group seems to exist any longer. In the end it really is more about getting access to therapy feasible for some of those more marginalized patient groups. A further important topic was around clinically relevant issues which clinicians who treat HCV need to be aware of, including risk for hepatitis B (HBV) reactivation after starting DAA therapy, as well as the risk for development of hepatocellular cancer (HCC) after achieving SVR (20-24). Although HCV remained to be a widely recognized topic throughout AASLD, it is becoming apparent that other topics in hepatology including NASH, alcoholic hepatitis, hepatitis B, HCC and primary biliary cholangitis are gaining importance and presentation space especially in the late-breaker session. A more intensified discussion on national HCV screening programs, HCV treatment uptake and linkage to care at AASLD would be desirable to politically underline the need to continue the fight to ensure global access of HCV therapies throughout the world.

View full text article with slides over at National AIDS Treatment Advocacy Project (NATAP)

Of Interest
Hepatitis C Hot Topics - Research and News of 2016
Take a look back at the top HCV news stories of 2016. Sit back and review a collection of hepatitis C research articles, guideline updates, conference reports, learning activities, and news from around the web

AbbVie Awaits NDA Approval For Hepatitis C Treatment
Dec. 19, 2016
AbbVie (ABBV), a global biopharmaceutical company, announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the company's investigational, pan-genotypic regimen of glecaprevir/pibrentasvir (G/P), being evaluated for the treatment of chronic hepatitis C virus (HCV).

Gilead Submits NDA to FDA for Sofosbuvir/Velpatasvir/Voxilaprevir HCV Genotype 1-6
December 8, 2016
Gilead Submits New Drug Application to U.S. Food and Drug Administration for the Investigational Single Tablet Regimen Sofosbuvir/Velpatasvir/Voxilaprevir
- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single Tablet Regimen Available as a Salvage Therapy for Patients Infected with HCV Genotype 1-6 Who Have Failed Prior Treatment with DAA Regimens Including NS5A Inhibitors -

Sunday, January 1, 2017

Review Screening for hepatocellular carcinoma: What is missing?

Just In Case You Missed It
Check out a new Open Access journal entitled Hepatology Communications published by American Association for the Study of Liver Diseases. Here is a recent article to get you started, view all articles, here.

Review Screening for hepatocellular carcinoma: What is missing?
Authors Neil J. Mehta, Aygul Dogan Celik, Marion G. Peters
First published: 19 December 2016
Full publication history
DOI: 10.1002/hep4.1014

Potential conflict of interest: Dr. Peters has received honoraria for advisory boards from Merck, Hoffmann La Roche, Johnson and Johnson, Gilead Sciences, Abbott, and honararium from Genentech. Spouse works for Hoffmann La Roche.


While there are guidelines from all major liver societies for the screening and management of hepatocellular carcinoma (HCC), many issues remain surrounding the actual practice of screening. This review discusses how to diagnose and screen HCC and more importantly, how well we diagnose and screen for HCC. Improved survival and outcomes after HCC diagnosis depend upon accurate diagnosis of cirrhosis and the timeliness of screening. With all oral direct-acting antivirals now widely available for hepatitis C, there are increasing numbers of patients who may be cured but are still at risk of HCC. Some uncontrolled studies suggest that direct-acting antiviral therapy may even increase the risk of HCC. Before we discuss expansion of who should be screened, we need physicians to realize how poorly we screen those patients who are already recommended for screening by guidelines. (Hepatology Communications 2016)

Enhanced PDF
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alanine aminotransferase
Barcelona Clinic Liver Cancer
computed tomography
European Association for the Study of the Liver
hepatitis B virus
hepatocellular carcinoma
hepatitis C virus
magnetic resonance imaging
sustained virologic response
Veterans Health Administration

How big is the problem?
The last four decades has seen a rising incidence of hepatocellular carcinoma (HCC) in the United States from 1.5 per 100,000 persons to nearly 14 per 100,000 persons and a 5-year survival under 12%.[1] While most of the increase is associated with aging of the baby-boomer population with hepatitis C, hepatitis B and nonalcoholic fatty liver disease also contribute. In a Markov model of 2.7 million persons infected with the hepatitis C virus (HCV) who are in primary care in the United States, it is estimated that 1.47 million will develop cirrhosis and 350,000 will develop liver cancer over their lifetime. The burden of HCC from HCV is estimated to peak at 12,000 per year by approximately 2030.[2]

Who should be screened
Surveillance is the process of providing a screening test at regular intervals to patients at risk for HCC. Surveillance is deemed cost-effective if the expected HCC risk exceeds 1.5% per year in patients with hepatitis C and 0.2% per year in patients with hepatitis B.[3] All patients with cirrhosis should be screened. While it is possible to perform HCC risk stratification in these patients using clinical risk scores[4, 5] and genomic biomarkers,[6] neither yet appear able to reliably identify those patients with cirrhosis who are at such a low risk of HCC development that screening is not warranted. In addition to screening all patients with cirrhosis, hepatitis B virus (HBV) Asian males ≥ 40 years, Asian females ≥ 50 years, and sub-Saharan Africans ≥ 20 years as well as HBV patients with a family history of HCC should be screened. The European Association for the Study of the Liver (EASL) recommends screening HCV patients with stage 3 fibrosis as well.[7] One of the major problems in deciding who to screen is in identifying those patients who have cirrhosis.[8] If patients are decompensated with ascites, jaundice, encephalopathy, splenomegaly, and muscle wasting, the diagnosis is relatively easy. However, in some patients with Child's A cirrhosis, few signs may be noted, and many such patients have normal liver tests. With decreasing use of liver biopsy, noninvasive markers of fibrosis may miss many patients. Transient elastography can be used to stage fibrosis in a noninvasive manner by measuring shear wave velocity. This technique is not readily available throughout the United States at this time so patients with cirrhosis may not be appropriately diagnosed.

How to screen
Screening is recommended by all liver societies; 6-monthly ultrasounds are recommended by the EASL and American Association for the Study of Liver Diseases[7, 9] and ultrasound and alpha-fetoprotein (AFP) are recommended by the Asian Pacific Association for the Study of the Liver.[10] Screening every 6 months is recommended because the doubling time of HCC is estimated to be 4-6 months.[11] The only randomized controlled trial of screening versus no screening was in 18,816 hepatitis B patients in China.[12] Patients underwent AFP and ultrasound every 6 months; 58.2% were screened and 41.8% were not. There were 86 tumors in the screened patients and 67 tumors in the nonscreened patients. Only the screened patients had subclinical, small, or resectable HCC lesions (Table 1). Survival was markedly better in those who were screened versus those who were not (65.9% versus 31.2% at 1 year; 46.4% versus 0% at 5 years).

AFP is limited as a screening test because of both false positives and false negatives. A third (20%-40%) of patients with HCC have normal AFP, and 20%-30% of patients without HCC have abnormal AFP, especially in those with active inflammation and elevated alanine aminotransferase (ALT) from HCV[5] and HBV.[13] Analyzing nearly 12,000 HCV patients with cirrhosis in the Veterans Health Administration (VHA) system, an AFP-based algorithm was created that also included ALT, platelet count, and age to predict the development of HCC.[5] The authors found that taken alone, a patient with an AFP of 120 ng/mL had an 11% probability of developing HCC within 6 months; however, if that same patient was known to have minimal liver inflammation (ALT 40), platelet count of 100, and be older (age 70), the probability of developing HCC within 6 months rose to 29%. While AFP is not a particularly sensitive screening test and should be considered alongside additional clinical factors, such as ALT, there is no doubt that the higher the AFP, the more likely the diagnosis is HCC. In addition, AFP can be used as a prognostic marker because it predicts overall mortality in HCC,[14] predicts prognosis after resection,[15] and predicts prognosis after liver transplantation.[16-19]

If a nodule > 1 cm is found on ultrasound, quadruple-phase computed tomography (CT) or magnetic resonance imaging (MRI) is recommended.[3] Quadruple-phase CT is used to differentiate HCC, which is usually supplied by the hepatic artery, from normal liver tissue, which is mainly supplied by the portal vein. HCC is characterized by arterial phase enhancement and portal venous washout at the time the majority of the liver is enhanced. If either the CT or MRI shows the typical characteristics of HCC, then patients should be managed as per regular guidelines (e.g., Barcelona Clinic Liver Cancer [BCLC] staging classification[20]), without biopsy diagnosis. Biopsy of the lesion is recommended only in selected cases if there is an atypical radiologic appearance; this is because there are concerns with liver biopsy. False negative biopsies are common in clinical practice and may lead to delays in both diagnosis and treatment.[21] Tumor seeding along the biopsy tract occurs in 1%-5% of cases, but coaxial biopsy may decrease this rate.[22] Seeding may exclude the patient from consideration of curative treatments, such as resection or transplant. If radiologic appearance and biopsy results are nondiagnostic or if the lesion is <1 cm, short-term follow-up with ultrasound (or CT/MRI if patient is listed for a transplant) in 3-4 months is recommended to assess growth of the lesion.
Singal studied 446 patients with cirrhosis who were prospectively enrolled for 6-monthly ultrasound and AFP.[23] They excluded the first 6 months to avoid lead-time bias. After a median of 3.5 years, 41 patients were identified with HCC, 73.2% of whom had early lesions (BCLC stage 0-B) with the same percentage within Milan criteria and 80.5% within University of California, San Francisco criteria. They found an annual HCC incidence of 2.8% and a cumulative incidence at 3 and 5 years of 5.7% and 9.1%, respectively. The sensitivity of AFP and ultrasound was 90%, which was greater than either alone. However, screening came at a cost: 36 patients with high AFP had normal MRI and CT and 34 patients had a lesion on ultrasound that was not identified from MRI or CT.

Another retrospective study compared 6-monthly and yearly ultrasounds versus no screening in 269 patients with cirrhosis and HCC (Table 1).[24] Those HCC patients who had appropriate screening had smaller lesions (70% within Milan criteria) compared to 37% for those screened yearly and 7% who had no screening. In addition, 3-year survival was better in 6-monthly (39%) screening versus yearly (27%) or no screening (12%). Among 821 Italian HCC patients who were studied retrospectively, no difference was found between 6- and 12-monthly screening compared to no screening.[25] However, a later prospective study from the same group confirmed the benefit of 6-monthly screening over 12-monthly screening in 649 Italian patients with cirrhosis.[26] As shown in Table 1, in those patients with 6-monthly screening, 70% were within Milan criteria compared to 58% of those screened yearly being within Milan criteria (P < 0.001). Screening more frequently (3 versus 6 months) increased detection of small focal lesions but not of HCC.[27] Systematic reviews and meta-analysis of surveillance studies in patients with cirrhosis showed that those who had routine screening usually had earlier stage HCC, were more likely to be candidates for curative treatment, and had better survival compared to unscreened patients.[28, 29]

Table 1. Efficacy of Screening for HCC in Patients with Cirrhosis

Ultrasound Surveillance Interval
Study Design 1st Author(Ref)Every 6 MonthsEvery 12 MonthsNo Screening
nWithin Milan (% treatable)Survival (% or median)nWithin Milan (% treatable)Survival (% or median)nWithin Milan (% treatable)Survival (% or median)
  1. a Compared to every 6-month screening *P < 0.001;
  2. b P = 0.03.
  3. c Total n included in study was 9,373 in every 6-month arm and 9,443 in no screening arm.
Retrospective Stravitz[24]17270%3 yr: 39%4837%3 yr: 27%597%3 yr: 12%
Retrospective Trevisani[25]21569%36 mos15560%34 mos45131%14 mos
Prospective Santi[26]51070% (82%)45 mos13958%a (70%)30 mosbNot studied
Prospective Zhang[12]86c45% (79%)1 yr: 66% 5 yr: 46%Not studied67c0% (49%)1 yr: 31% 5 yr: 0%

How well do we screen?
Studies from Europe and the United States show that less than 30% of patients with cirrhosis receive screening. In one study of 904 patients with cirrhosis in a US safety net hospital, less than 2% had biannual ultrasounds, 13% had annual ultrasounds, and 67% had only one ultrasound in 3 years.[30] Lower surveillance was noted in the uninsured patients and in African Americans. Surveillance was highest in those who had a yearly visit to a hepatologist, followed by a visit to a primary care doctor; both were better than no follow-up visit.[30] Two large, recent, retrospective studies of patients in the VHA[31] and with commercial insurance[32] found that twice yearly ultrasound screening in patients with cirrhosis was performed 20%-30% of the time. In the VHA study, some of the strongest predictors of not receiving screening included fewer visits with a subspecialist (gastrointestinal/hepatology/infectious disease), increased distance from a patient's home to the nearest VHA center, and a longer time between the date the ultrasound was ordered and the date it was requested to be performed.

Screening of HCV patients after cure
Treatment of hepatitis C markedly decreases the risk of HCC but does not eradicate it. To emphasize this, a study of 33,000 VHA patients identified 10,827 patients who achieved sustained virologic response (SVR) with interferon-based therapies; of those who achieved SVR, 100 developed new HCC.[33] The annual incidence rate of HCC in those with SVR was 0.33% per year compared to 1.32% per year in those without SVR. The predictors of developing HCC in this cohort were cirrhosis at SVR (odds ratio, 6.69; confidence interval, 4.3-10.4), age over 65 years (4.51; 2.0-10.4), age 55-64 years (2.04; 1.3-3.2), Hispanic race compared to Caucasians (2.3; 1.1-1.8), diabetes mellitus (1.8; 1.2-2.9), and alcohol (1.68; 1.08-2.6).

Thus, patients who have SVR or are cured of their hepatitis C are still at risk of developing HCC, need to be monitored, and should not be discharged from their doctor's practice. Literature over the past year has noted HCC occurring or recurring after SVR in response to direct acting antivirals. Uncontrolled studies reported early recurrence within 6-12 months of SVR,[34, 35] but the Agence Nationale de Recherche sur le Sida reported no difference in HCC incidence in those treated with interferon-based therapies versus direct-acting antivirals.[36] Whether all oral direct-acting antiviral therapy is associated with an increased risk of cancer is not clear, and further long-term randomized studies are required.

In summary, there is an increasing prevalence of HCC with the aging of patients with hepatitis C, the increase of nonalcoholic fatty liver disease, as well as hepatitis B. There is much discussion about screening patients without cirrhosis as these patients can develop HCC. However, this opinion piece highlights that the major problem worldwide is how poorly we appropriately screen and diagnose HCC in patients with cirrhosis. What is most important is to diagnose cirrhosis early so that screening can be initiated because patients with cirrhosis are those with the highest risk of HCC. The outcome of HCC is influenced by the failure to diagnose cirrhosis, the absence of surveillance, and the delay in follow-up and treatment. Screening appropriately leads to early diagnosis, which leads to better management options, a higher proportion of treatable lesions, and better outcomes, including survival.


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