Cost Effectiveness of Hepatocellular Carcinoma Surveillance After a Sustained Virologic Response to Therapy in Patients With Hepatitis C Virus Infection and Advanced Fibrosis.

Hepatitis C virus (HCV)-related cirrhosis increases the risk for hepatocellular carcinoma (HCC). After a sustained virologic response (SVR) to anti-HCV therapy, the risk of HCC is reduced but not eliminated. Recent developments in antiviral therapy have increased rates of SVR markedly. Guidelines recommend indefinite biannual ultrasound surveillance after SVR for patients with advanced fibrosis before treatment. Surveillance for HCC is cost effective before anti-HCV treatment; we investigated whether it remains so after SVR. We developed a Markov model to evaluate the cost effectiveness of biannual or annual HCC ultrasound surveillance vs no surveillance in 50-year-old patients with advanced fibrosis after an SVR to anti-HCV therapy. Parameter values were obtained from publications and expert opinions. Primary outcomes were quality-adjusted life-years (QALYs), costs, and the incremental cost-effectiveness ratios (ICERs). With a constant 0.5% annual incidence of HCC, biannual and annual surveillance resulted in ICERs of $106,792 and $72,105 per QALY, respectively, with high false-positive rates. When surveillance was limited to patients with cirrhosis, but not F3 fibrosis, biannual surveillance likely was cost effective, with ICERs of $48,729 and $43,229 per QALY after treatment with interferon and direct-acting antiviral agents, respectively. In patients with F3 fibrosis, the incidence of HCC was 0.3% to 0.4% per year, leading to an ICER of $188,157 per QALY for biannual surveillance. If HCC incidence increases with age, surveillance becomes more cost effective but remains below willingness-to-pay thresholds only for patients with cirrhosis or with pretreatment aspartate aminotransferase to platelet ratio index greater than 2.0 or FIB-4 measurements greater than 3.25. Sensitivity analyses identified HCC incidence and transition rate to symptomatic disease without surveillance as factors that affect cost effectiveness. In a Markov model, we found HCC surveillance after an SVR to HCV treatment to be cost effective for patients with cirrhosis, but not for patients with F3 fibrosis.

Farhang Zangneh H ，Wong WWL ，Sander B ，Bell CM ，Mumtaz K ，Kowgier M ，van der Meer AJ ，Cleary SP ，Janssen HLA ，Chan KKW ，Feld JJ ... -  《-》

Duration and cost-effectiveness of hepatocellular carcinoma surveillance in hepatitis C patients after viral eradication.

Successful treatment of chronic hepatitis C with oral direct-acting antivirals (DAAs) leads to virological cure, however, the subsequent risk of hepatocellular carcinoma (HCC) persists. Our objective was to evaluate the cost-effectiveness of biannual surveillance for HCC in patients cured of hepatitis C and the optimal age to stop surveillance. We developed a microsimulation model of the natural history of HCC in individuals with hepatitis C and advanced fibrosis or cirrhosis who achieved virological cure with oral DAAs. We used published data on HCC incidence, tumor progression, real-world HCC surveillance adherence, and costs and utilities of different health states. We compared biannual HCC surveillance using ultrasound and alpha-fetoprotein for varying durations of surveillance (from 5 years to lifetime) vs. no surveillance. In virologically cured patients with cirrhosis, the incremental cost-effectiveness ratio (ICER) of biannual surveillance remained below $150,000 per additional quality-adjusted life year (QALY) (range: $79,500-$94,800) when surveillance was stopped at age 70, irrespective of the starting age (40-65). Compared with no surveillance, surveillance detected 130 additional HCCs in 'very early'/early stage and yielded 51 additional QALYs per 1,000 patients with cirrhosis. In virologically cured patients with advanced fibrosis, the ICER of biannual surveillance remained below $150,000/QALY (range: $124,600-$129,800) when surveillance was stopped at age 60, irrespective of the starting age (40-50). Compared with no surveillance, surveillance detected 24 additional HCCs in 'very early'/early stage and yielded 12 additional QALYs per 1,000 patients with advanced fibrosis. Biannual surveillance for HCC in patients cured of hepatitis C is cost-effective until the age of 70 for patients with cirrhosis, and until the age of 60 for patients with stable advanced fibrosis. Individuals who are cured of hepatitis C using oral antiviral drugs remain at risk of developing liver cancer. The value of lifelong screening for liver cancer in these individuals is not known. By simulating the life course of hepatitis C cured individuals, we found that ultrasound-based biannual screening for liver cancer is cost-effective up to age 70 in those with cirrhosis and up to age 60 in those with stable advanced fibrosis.

Mueller PP ，Chen Q ，Ayer T ，Nemutlu GS ，Hajjar A ，Bethea ED ，Peters MLB ，Lee BP ，Janjua NZ ，Kanwal F ，Chhatwal J ... -  《-》

Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada.

Evidence is limited on hepatocellular carcinoma (HCC) risk after sustained virological response (SVR) to interferon-based treatment of hepatitis C virus (HCV) infection. We evaluated the effect of SVR on the risk of HCC and estimated its incidence in post-SVR HCV patients from a large population-based Canadian cohort. The British Columbia Hepatitis Testers Cohort includes individuals tested for HCV between 1990-2013 linked with data on their medical visits, hospitalizations, cancers, prescription drugs and mortality. Patients receiving interferon-based HCV treatments were followed from the end of treatment to HCC diagnosis, death or December 31, 2012. We examined HCC risk among those who did and did not achieve SVR using multivariable proportional hazard models with the Fine and Gray modification for competing risks. Of 8147 individuals who received HCV treatment and were eligible for analysis, 4663 (57%) achieved SVR and 3484 (43%) did not. Each group was followed for a median of 5.6years (range: 0.5-12.9) for an HCC incidence rate of 1.1/1000 person-years (PY) among the SVR and 7.2/1000 PY among the no SVR group. The HCC incidence rate was higher among those with cirrhosis (SVR: 6.4, no SVR: 21.0/1000 PY). In the multivariable model, SVR was associated with a lower HCC risk (subdistribution hazard ratio [SHR]=0.20, 95% CI: 0.13-0.3), while cirrhosis (SHR=2.61, 95% CI: 1.68-4.04), age ⩾50years, being male and genotype 3 infection were associated with a higher HCC risk. Among those who achieved SVR, cirrhosis, age ⩾50years and being male were associated with a higher HCC risk. SVR after interferon-based treatment substantially reduces but does not eliminate HCC risk, which is markedly higher among those with cirrhosis and age ⩾50years at treatment initiation. Treatment of patients at an advanced fibrosis stage with new highly effective drugs will warrant continued surveillance for HCC post-SVR. We assessed the effect of successful hepatitis C treatment with older interferon-based treatment on the occurrence of liver cancer (hepatocellular carcinoma) and found that successful treatment prevents liver cancer. However, more people with cirrhosis and older age continued to develop liver cancer after successful treatment. Thus, treatment with new drugs among those with cirrhosis will require continued monitoring for liver cancer.

Janjua NZ ，Chong M ，Kuo M ，Woods R ，Wong J ，Yoshida EM ，Sherman M ，Butt ZA ，Samji H ，Cook D ，Yu A ，Alvarez M ，Tyndall M ，Krajden M ... -  《-》

Dynamic Evaluation of Liver Fibrosis to Assess the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis C Who Achieved Sustained Virologic Response.

Liver fibrosis is an important risk factor for the development of hepatocellular carcinoma (HCC) after sustained virologic response (SVR) in patients with persistent hepatitis C virus (HCV) infection. However, as the degree of liver fibrosis changes following the eradication of HCV after SVR, it is unclear whether the prediction of HCC development based on liver fibrosis at baseline remains valid. In 522 patients who achieved SVR by interferon-based anti-HCV therapy, the Fibrosis-4 Index for Liver Fibrosis (FIB-4 index) was updated annually by recalculation based on laboratory values after SVR. The incidence of HCC was reassessed annually based on the updated FIB-4 index. The percentage of patients with mild liver fibrosis (FIB-4 index <1.45) increased annually after SVR, whereas the percentage of patients with advanced liver fibrosis (FIB-4 index ≥3.25) decreased. The incidences of HCC based on the FIB-4 index remained constant between the time of SVR and subsequent annual updates. No patients developed HCC after SVR if the FIB-4 index decreased to <1.45. The FIB-4 index retained its predictive ability for the risk of HCC when recalculated after SVR, despite the decrease in patients with high FIB-4 index values. Dynamic assessment of the FIB-4 index can be useful in the surveillance of HCC after SVR. Patients with a FIB-4 index <1.45 did not develop HCC even by the regression from advanced fibrosis after SVR. Further studies will be necessary to confirm these findings, which may result in a decrease in the number of patients in whom surveillance is required.

Toyoda H ，Tada T ，Yasuda S ，Mizuno K ，Ito T ，Kumada T ... -  《-》

Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication.

The risk of hepatocellular carcinoma (HCC) is reduced but not eradicated among patients with hepatitis C virus (HCV)-induced advanced hepatic fibrosis who attained sustained viral response (SVR). We aimed to assess the risk of cirrhosis-related complications in this specific group of patients. Data from previously reported Western cohort studies including patients with chronic HCV infection and bridging fibrosis or cirrhosis who attained SVR were pooled for survival analyses on the individual patient level. The primary endpoint was HCC and the secondary endpoint was clinical disease progression, defined as liver failure, HCC or death. Included were 1000 patients with SVR. Median age was 52.7 (IQR 45.1-59.7) years, 676 (68%) were male and 842 (85%) had cirrhosis. Median follow-up was 5.7 (IQR 2.9-8.0) years. Fifty-one patients developed HCC and 101 had clinical disease progression. The cumulative 8-year HCC incidence was 1.8 (95% CI 0.0-4.3) among patients with bridging fibrosis and 8.7% (95% CI 6.0-11.4) among those with cirrhosis (p=0.058). Within the cirrhosis group, the 8-year HCC incidence was 2.6% (95% CI 0.0-5.5) among patients <45years, 9.7% (95% CI 5.8-13.6) among patients from 45-60years, and 12.2% (95% CI 5.3-19.1) among patients >60years of age at start of therapy (p=0.006). Multivariable Cox analyses indicated that higher age, lower platelet count and diabetes mellitus were independently associated with development of HCC. After 8years 4.2% (95% CI 0.1-8.3) of patients with bridging fibrosis and 15.8% (95% CI 12.3-19.3) of patients with cirrhosis experienced clinical disease progression (p=0.007). Patients with HCV-induced cirrhosis and SVR showed an annual risk of approximately 1% for HCC and 2% for clinical disease progression. Therefore, to prevent HCC surveillance, chronic HCV infection should preferably be treated before cirrhosis has developed. Patients with cirrhosis who were able to eradicate their chronic HCV infection remain at substantial risk of primary liver cancer. The risk of liver cancer increases with higher age, laboratory makers suggesting more severe liver disease, and presence of diabetes mellitus. Also after successful antiviral therapy patients with HCV-induced cirrhosis should thus remain included in follow-up for early detection of liver cancer.

van der Meer AJ ，Feld JJ ，Hofer H ，Almasio PL ，Calvaruso V ，Fernández-Rodríguez CM ，Aleman S ，Ganne-Carrié N ，D'Ambrosio R ，Pol S ，Trapero-Marugan M ，Maan R ，Moreno-Otero R ，Mallet V ，Hultcrantz R ，Weiland O ，Rutter K ，Di Marco V ，Alonso S ，Bruno S ，Colombo M ，de Knegt RJ ，Veldt BJ ，Hansen BE ，Janssen HLA ... -  《-》