To evaluate the ability of pretreatment liver stiffness measurements (pLSM) to predict hepatocellular carcinoma (HCC), incident decompensation and all-cause mortality in chronic hepatitis C (CHC) ...patients who achieved sustained virological response (SVR) after treatment with direct-acting antivirals (DAAs).
773 CHC patients with SVR after DAA treatment and no prior liver complications were identified retrospectively. Optimized cut-off of 17.5 kPa for incident HCC was selected by maximum Youden's index. Patients were grouped by pLSM: <10 kPa reference, 10-17.4 kPa and ≥17.5 kPa. Primary outcomes were incident hepatocellular carcinoma and secondary outcomes were incident decompensated cirrhosis and all-cause mortality, analyzed using cox-regression.
Median follow-up was 36 months and 43.5% (336) had cirrhosis (LSM>12.5 kPa). The median pLSM was 11.6 kPa (IQR 6.7-17.8, range 2.5-75) and pLSM of <10 kPa, 10-17.4 kPa and 17.5-75 kPa was seen in 41.5%, 32.2% and 26.3%. During a median follow-up time of 36 months, 11 (1.4%) developed HCC, 14 (1.5%) developed decompensated cirrhosis, and 38 (4.9%) patients died. A pLSM of 17.5 kPa identified patients with a high risk of HCC with a negative predictive value of 98.9% and incidence rate of HCC in the 17.5-75 kPa group of 1.40/100 person years compared to 0.14/100 person years and 0.12/100 person years in the 10-17.4 kPa and <10 kPa groups, p<0.001.
Pretreatment LSM predicts risk of HCC, decompensation and all-cause mortality in patients with SVR after DAA treatment. Patients with a pLSM <17.5 kPa and no other risk factors for chronic liver disease appear not to benefit from HCC surveillance for the first 3 years after treatment. Longer follow-up is needed to clarify if they can be safely excluded from post treatment HCC screening hereafter.
A national survey for chronic hepatitis C has not been performed in Denmark and the prevalence is unknown. Our aim was to estimate the prevalence of chronic hepatitis C from public registers and the ...proportion of these patients who received specialized healthcare.
Patients with a diagnosis of chronic hepatitis C were identified from four national registers: a laboratory register, the Hospital Discharge Register, a clinical database of chronic viral hepatitis and the Register of Communicable Diseases. The total population diagnosed with hepatitis C was estimated by capture-recapture analysis. The population with undiagnosed hepatitis C was derived from the national register of drug users by comparing diagnosed and tested persons.
A total of 6,935 patients diagnosed with chronic hepatitis C were identified in the four registers and the estimated population diagnosed with the disease was 9,166 persons (95% C.I. interval 8,973 - 9,877), corresponding to 0.21% (95% CI 0.21%-0.23%) of the Danish population over 15 years of age. The prevalence was highest among persons 40-49 years old (0.39%) and males (0.28%). It was estimated that 40% of the diagnosed patients lived in the capital region, and 33.5% had attended specialised healthcare. It was estimated that 46% of hepatitis C patients had not been diagnosed and the total population with chronic hepatitis C in Denmark was 16,888 (95% C.I. 16,474-18,287), corresponding to 0.38% (95% CI 0.37-0.42) of the population over 15 years of age.
The estimated prevalence of chronic hepatitis C in Denmark was 0.38%. Less than half of the patients with chronic hepatitis C in Denmark have been identified and among these patients, one in three has attended specialised care.
Objective: Detecting significant fibrosis and cirrhosis remains important in treatment and follow-up of patients with chronic hepatitis C Infection (CHC). The aim of this study was to assess the ...ability of PRO-C3 to identify significant fibrosis (Ishak score ≥3) and cirrhosis (Ishak score ≥5) both as a single test and as a part of algorithms.
Materials and methods: PRO-C3 was assessed in baseline samples from the NORDynamIC trial. 270 patients were stratified into groups according to baseline biopsy. Baseline APRI, FIB-4 and GUCI scores were available for comparison in 232 patients.
Results: PRO-C3 increased with Ishak scores (p = .001). Area under the curve (AUC) for significant fibrosis was 0.75 (95% CI 0.68-0.81) and 0.76 (95% CI 0.68-0.84) for cirrhosis. FIB-4, APRI and GUCI had similar AUCs. In a PRO-C3 algorithm including age, platelet count, body mass index (BMI) and international normalised ratio (INR), the diagnostic efficacy improved to 0.85 (CI 0.80-0.89) and 0.90 (IQR 0.84-0.96) for significant fibrosis and cirrhosis, respectively.
Conclusions: In our study, PRO-C3 was an independent predictor of fibrosis stage, and may play an important role in managing CHC patients.
Background Chronic hepatitis C (CHC) can be eliminated as a public health threat by meeting the WHO targets: 90% of patients diagnosed and 80% treated by 2030. To achieve and monitor progress towards ...elimination, an updated estimate of the size of the CHC population is needed, but Denmark has no complete national CHC register. By combining existing registers in 2007, we estimated the population living with CHC to be 16,888 (0.38% of the adult population). Aim To estimate the population living with diagnosed and undiagnosed CHC in Denmark on 31 December 2016. Among additional aims were to estimate the proportion of patients attending specialised clinical care. Methods People with diagnosed CHC were identified from four national registers. The total diagnosed population was estimated by capture-recapture analysis. The undiagnosed population was estimated by comparing the register data with data from two cross-sectional surveys. Results The population living with diagnosed CHC in Denmark was 7,581 persons (95%CI: 7,416–12,661) of which 6,116 (81%) were identified in the four registers. The estimated undiagnosed fraction was 24%, so the total CHC infected population was 9,975 corresponding to 0.21% of the adult population (95%CI: 9,758–16,659; 0.21%-0.36%). Only 48% of diagnosed patients had received specialised clinical care. Conclusion CHC prevalence in Denmark is declining and 76% of patients have been diagnosed. Linking diagnosed patients to care and increasing efforts to test people with former or current drug use will be necessary to achieve CHC elimination.
Background. Knowledge about mortality rates (MRs) in patients with chronic hepatitis C (CHC) with cirrhosis is limited. This study aimed to estimate all-cause MRs among patients with CHC with or ...without cirrhosis in Denmark compared with the general population. Methods. Patients registered in the Danish Database for Hepatitis B and C with CHC and a liver fibrosis assessment were eligible for inclusion. Liver fibrosis was assessed by means of liver biopsy, transient elastography, and clinical cirrhosis. Up to 20 sex- and age-matched individuals per patient were identified in the general population. Data were extracted from nationwide registries. Results. A total of 3410 patients with CHC (1014 with cirrhosis), and 67 315 matched individuals were included. Adjusted MR ratios (MRRs) between patients with or without cirrhosis and their comparison cohorts were 5.64 (95% confidence interval CI, 4.76–6.67) and 1.94 (1.55–2.42), respectively. Cirrhosis among patients was associated with an MRR of 4.03 (95% CI, 3.43–4.72). A cure for CHC was associated with an MRR of 0.64 (95% CI, 0.40–1.01) among cirrhotic patients and 2.33 (1.47–3.67) compared with the general population. Conclusions. MRs were high among patients with CHC with or without cirrhosis compared with the general population. Curing CHC was associated with a reduction in MR among cirrhotic patients, but the MR remained higher than the general population.
Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk ...of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5-6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = -12.17+ (age × 0.11) + (BMI (kg/m(2)) × 0.23) + (D7-lathosterol (μg/100 mg cholesterol)×(-0.013)) + (Platelet count (x10(9)/L) × (-0.018)) + (Prothrombin-INR × 3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86-0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82-0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.
The present study evaluated the impact of variations in the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) on treatment outcome in patients with hepatitis C virus (HCV) genotype 2/3 ...infection receiving peginterferon‐α2a and lower, conventional 800 mg daily dose of ribavirin. Previous studies using higher, weight‐based ribavirin dosing report that patients carrying polymorphisms encoding reduced predicted ITPase activity show decreased risk of ribavirin‐induced anemia but increased risk of thrombocytopenia, with no impact on elimination of virus. In all, 354 treatment‐naïve HCV genotype 2/3‐infected patients, enrolled in a phase III trial (NORDynamIC), were genotyped for ITPA (rs1127354 and rs7270101). Homo‐ or heterozygosity at Ars1127354 or Crs7270101, entailing reduced ITPase activity, was observed in 37% of patients and was associated with increased likelihood of achieving sustained virological response (SVR) (P = 0.0003 in univariate and P = 0.0002 in multivariate analyses) accompanied by a reduced risk of relapse among treatment‐adherent patients. The association between ITPA variants and SVR remained significant when patients were subdivided by the 12‐ and 24‐week treatment duration arms, HCV genotype, fibrosis stage, and IL28B genotype, and was not secondary to improved adherence to therapy or less pronounced anemia. Gene variants predicting reduced predicted ITPase activity were also associated with decreased risk of anemia (P < 0.0001), increased risk of thrombocytopenia (P = 0.007), and lower ribavirin concentrations (P = 0.02). Conclusion: These findings demonstrate a novel ribavirin‐like association between polymorphisms at ITPA and treatment efficacy in chronic hepatitis C mediated by reduced relapse risk. We hypothesize that patients (63%) being homozygous for both major alleles, leading to normal ITPase activity, may benefit more from the addition of ribavirin to present and future treatment regimens for HCV in spite of concomitant increased risk of anemia. (Hepatology 2014;59:2131–2139)
Non-invasive methods are the first choice for liver fibrosis evaluation in chronic liver diseases, but few studies investigate the ability of combined methods to predict outcomes.
591 chronic ...hepatitis C patients with baseline liver stiffness (LSM) by FibroScan and hyaluronic acid measurements were identified retrospectively. The patients were grouped by baseline LSM: < 10kPa, 10-16.9kPa, and 17-75kPa. Primary outcomes were all-cause mortality and liver-related mortality, analyzed using cox regression and competing risk regression models, respectively.
Median follow-up was 46.1 months. Prevalence of cirrhosis at baseline was 107/591 (18.1%). Median LSM was 6.8kPa (IQR 5.3-11.6) and divided into groups, 404/591 (68.4%) had a LSM < 10kPa, 100/591 (16.9%) had a LSM between 10-16.9kPa and 87/591 (14.7%) had a LSM between 17-75kPa. There were 69 deaths, 27 from liver-related disease. 26 patients developed cirrhosis and 30 developed complications of cirrhosis. The mortality rate in the 17-75kPa group was 9.7/100 person-years, compared to 2.2/100 person-years and 1.1/100 person-years in the 10-16.9kPa and <10kPa groups (p<0.005). Liver-related mortality increased 10-fold for each group (p<0.005). Cirrhotic complications occurred almost exclusively in the 17-75kPa group, with an incidence of 10.3/100 person-years, compared to 1.8/100 person-years and 0.2/100 person-years in the 10-16.9kPa and <10kPa groups (p<0.005). Median hyaluronic acid in the 17-75kPa group was approximately 200ng/mL. Patients with a LSM 17-75kPa had significantly higher risks of death, liver-related death, and complications to cirrhosis if their hyaluronic acid measurement was more than or equal to 200ng/mL at baseline, with hazard ratios of 3.25 (95% CI 1.48-7.25), 7.7 (95% CI 2.32-28), and 3.2 (95% CI 1.35-7.39), respectively.
The combination of LSM and circulating hyaluronic acid measurements significantly improved prognostic ability, relative to LSM alone. Combined static and dynamic markers of liver fibrosis could provide superior risk prediction.
Hepatic steatosis in HCV patients has been postulated as a risk factor associated with a higher frequency of fibrosis and cirrhosis. A single genetic variant, PNPLA3 I148M, has been widely associated ...with increased hepatic steatosis. Previous studies of the PNPLA3 I148M sequence variant in HCV infected individuals have reported an association between this variant and prevalence of steatosis, fibrosis, and cirrhosis. To evaluate the impact of PNPLA3 I148M variant on metabolic traits and treatment response in HCV genotype 2 and 3 infected patients.
Three hundred and eighty-two treatment naïve HCV genotype 2 or 3 infected patients were included in a phase III, open label, randomized, multicenter, investigator-initiated trial (the NORDynamIC study), in which pretreatment liver biopsies were mandatory. PNPLA3I148M genotyping was performed in a total of 359 Caucasian patients.
In HCV genotype 2 infected patients carrying the PNPLA3 148M allele, there was significantly increased insulin resistance (P = 0.023) and lower viral load (P = 0.005) at baseline as well as the first seven days of antiviral treatment. These results were not observed in HCV genotype 3 infected patients.
Our results suggest a possible association between the PNPLA3 148M allele and insulin resistance as well as baseline viral load in HCV genotype 2, but not in genotype 3.
Patients with chronic hepatitis C may have advanced fibrosis at first evaluation. Using the European Association for the Study of the Liver (EASL) definition (FibroScan® >9.5 kPa) for "late presenter ...for care" (LP), we found that 32% (169 of 527) of patients were LP. Being a LP was associated with increasing age and a history of alcohol overuse.
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