Cohort Of Hepatitis C Virus Patients Research Articles

Pilot model of hepatitis C virus micro-elimination in high-risk populations in Hong Kong: Barriers and facilitators

Although the general seroprevalence of hepatitis C virus (HCV) infection in Hong Kong is <0.5 %, Hong Kong is still striving for HCV elimination owing to barriers in care cascade encompassing linkage-to-care (LTC), treatment initiation and adherence. We aimed to evaluate the feasibility of a pilot model of micro-elimination to strengthen the HCV care cascade for high-risk groups in Hong Kong. We initiated the pilot Conquering Hepatitis vIa Micro-Elimination (CHIME) program which adopts an integrated care approach involving outreach visits to halfway house or drug rehabilitation centers run by non-governmental organizations. Participants with history of injection drug use (PWID), recreational drug use, or imprisonment were included. We performed point-of-care test for anti-HCV with reflex HCV RNA testing. LTC with government-subsidized direct acting antiviral was provided to viremic participants. We compared the impact on the care cascade with a cohort of HCV patients (17.8 % PWID) under usual care. 396 participants (62.9 % PWID) were screened and 187 (47.2 %) were viremic, of which 29.8 % had cirrhosis. Proportion with LTC, treatment initiation and adherence were 76.5 % and 63.7 %, 90.9 % and 85.8 %, and 90.0 % and 92.2 %, for the CHIME program and usual care, respectively. The CHIME program was significantly associated with higher odds of LTC (OR 1.797, 95 % CI 1.221-2.644). Non-engagement in care (affecting 37.9 % participants with HCV viremia) was associated with unemployment (OR 2.165, 95 % CI 1.118-4.190). The pilot CHIME program demonstrated feasibility of an integrated approach to consolidate the HCV care cascade in high-risk populations in Hong Kong.

Liver Disease Outcomes after Sustained Virological Response in Patients with Chronic Hepatitis C Infection Treated with Generic Direct-Acting Antivirals.

The introduction of generic direct-acting antivirals (DAAs) in Egypt is associated with a superior cure rate of hepatitis C virus (HCV) infection. However, the course of progressive liver damage and developing liver related complications in patients with sustained virologic response (SVR) remain unclear. This study was designed to examine the long-term outcomes of generic DAA-induced virological cure in a real-life cohort of HCV patients with or without comorbid schistosomiasis. We prospectively enrolled a cohort of 506 recently cured HCV patients (437 Child-Pugh class A [Child-A] and 69 Child-Pugh class B [Child-B]). All patients were clinically evaluated at different time points during a 2-year follow-up (November 2018 to February 2021). Over the course of treatment and follow-up, 77 (15.2%) patients (42 [9.6%] Child-A and 35 [50.7%] Child-B) experienced complications at different time points. The overall mortality rate was approximately 1/1,000 person-years. The incidence of hepatic insufficiency was approximately 5.5/1,000 person-years, and that of de novo hepatocellular carcinoma (HCC) was approximately 8.3/1,000 person-years. A sustained improvement in liver indices up to 2 years of follow-up was observed. In the Cox regression model, pretreatment decompensated cirrhosis predicted the occurrence of adverse liver events and HCC after therapy. In conclusion, in HCV patients with advanced cirrhosis or coexisting hepatic schistosomiasis, generic DAA-induced SVR remains robust with favorable clinical outcomes although the risk of hepatocarcinogenesis cannot be eliminated. Surveillance of patients with treated HCV infection is an important aspect of postcure care for early detection and management of liver disease-related adverse events.

Performance of simple serum-based tests to exclude cirrhosis prior to hepatitis C treatment in non-hospital settings in Australia.

Current guidelines suggest using transient elastography (TE) or aspartate aminotransferase to platelet ratio index (APRI) score <1 to exclude cirrhosis prior to commencing treatment for hepatitis C virus (HCV). Recently, fibrosis-4 (FIB-4) <0.93 has been shown to have a high negative predictive value (NPV) for the presence of cirrhosis. To assess FIB-4 and APRI in a cohort of HCV patients and to validate FIB-4 <0.93 in populations of HCV-infected individuals with differing cirrhosis prevalence, including secondary care, primary care and prisons. From our treatment database, we identified patients with complete data (n = 793). We calculated FIB-4 and APRI and correlated this with the presence of cirrhosis, determined by TE. We analysed the performance of FIB-4 and APRI using area under the receiver operating curve analysis. We calculated sensitivity, specificity, positive predictive value, NPV and number of patients misclassified using published cut-offs in populations with varying cirrhosis prevalence. FIB-4 was superior to APRI for the diagnosis of cirrhosis (area under the receiver operating curve 0.868 vs 0.802). In secondary care (cirrhosis prevalence 32%), APRI <1 had a NPV of 80% and misclassified 14% of patients. FIB-4 <0.93 had a NPV of 97% and misclassified 1%. In primary care and prison (cirrhosis prevalence 13% and 8%), the NPV for APRI <1 was 93% and 96%, respectively, but 5% of patients with cirrhosis were misclassified. FIB-4 <0.93 had excellent NPV in both primary care (97%) and prisoners (100%). FIB-4 <0.93 is highly efficient at ruling out cirrhosis in HCV patients and allows TE to be appropriately avoided, thereby streamlining treatment algorithms.

Delays and Gaps in Progressing Through the Hepatitis C Virus Cascade of Care: An Underserved Safety-net Hospital Experience.

Background and ObjectiveWhile highly effective hepatitis C virus (HCV) therapies exist, gaps in the cascade of care remain. Disparities in the HCV cascade are prominent among underserved safety-net populations. We aim to evaluate the HCV cascade among an urban safety-net cohort of HCV patients.MethodsWe retrospectively evaluated adults with chronic HCV to determine rates of linkage to care (LTC), retention to care, and receiving HCV treatment from 2002 to 2018. Comparisons between groups utilized Chi-square testing; comparisons of median time to LTC and HCV treatment were evaluated with Student’s t-test and analysis of variance.ResultsAmong 600 chronic HCV patients (60.7% male, 20.7% non-Hispanic white, 49.2% African American, 92.5% treatment naïve, 26.8% cirrhosis), successful LTC within one year of HCV diagnosis was 57.7%, among which, 91.6% were successfully retained into care. In those with successful LTC, 72.6% received HCV treatment, 91.8% completed treatment, and 89% achieved SVR12. Women with HCV experienced longer delays from LTC to HCV treatment (331 vs. 206 days in men, P < 0.05), as did African Americans (280 vs. 165 days in non-Hispanic whites, P < 0.05). Compared to the non-Hispanic whites, HCV treatment was lower in African Americans (70.4% vs. 74.4%, P < 0.05).ConclusionWomen with HCV experienced significant delays along the HCV cascade, with median time of over 2 years from diagnosis to treatment. African Americans also experienced significant delays along the HCV cascade of care. However, sex and race/ethnicity were not found to be significant predictors of overall LTC or treatment.

Circulating IL-13 Is Associated with De Novo Development of HCC in HCV-Infected Patients Responding to Direct-Acting Antivirals

Simple SummaryChronic hepatitis C virus infection is one of the major risk factors for the development of hepatocellular carcinoma. New direct-acting antivirals substantially improved the cure rate of hepatitis C, but the incidence of hepatitis C virus-related hepatocellular carcinoma remains high. To identify the immune profile associated with the risk for hepatocellular carcinoma, we investigated a cohort of patients who developed de novo hepatocellular carcinoma following direct-acting antiviral treatment in comparison to controls who did not develop hepatocellular carcinoma. Our results can improve clinical management prior to the development of hepatocellular carcinoma.Direct-acting antivirals (DAAs) are highly effective in targeting hepatitis C virus (HCV) infections, but the incidence of HCV-related hepatocellular carcinoma (HCC) remains still high. In this study, we investigated a cohort of HCV-infected patients treated with DAAs who were followed up for 4 years after sustained virological response (SVR) achievement. Patients who developed de novo HCC following DAA treatment were compared to matched controls who did not develop HCC. These control patients were selected based on DAA treatment, sex, age, fibrosis status, and platelet counts. We evaluated serum levels of 30 immune mediators before, during, at the end of, and three months after DAA treatment using Luminex technology. We identified the immune factors associated with de novo HCC occurrence following DAA treatment. Specifically, interleukin (IL)-4 and IL-13 levels were significantly higher before start of the DAA treatment in the serum of patients who later developed HCC than in controls and stayed higher at each subsequent time point. Least absolute shrinkage and selection operator (LASSO) regression revealed IL-13 as the only strong factor associated with HCC development in this cohort of HCV patients. The difference was observed already at baseline of DAA treatment, which confirms the existence of a specific immune profile in these patients who later develop HCC.

Is positivity for hepatitis C virus antibody predictive of lower risk of death in COVID-19 patients with cirrhosis?

Liver injury has been reported in coronavirus disease 2019 (COVID-19) cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated. Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus (HCV) infection, in particular. To this end, we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic; these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts (sofosbuvir/velpatasvir), with either liver disease (various severities; n = 1319) or cirrhosis (n = 208). Among the COVID-19 patients, 10 had cirrhosis (3%), including 7 of metabolic origin and 3 of viral origin. Mortality among the COVID-19 patients was 27.1%, with 70% of those with cirrhosis of metabolic etiology having died. Cirrhosis, older age, low white blood cell count and lymphocyte count being identified as risk predictors of death [odds ratio (OR) = 13.7, 95% confidence interval (CI): 2.59-83.01, P = 0.006; OR = 1.05, 95%CI: 1.03-1.08, P = 0.0001; OR = 1.09, 95%CI: 1.36-1.16, P = 0.001; OR = 0.61, 95%CI: 0.39-0.93, P = 0.023, respectively]. In the two cohorts of HCV patients, COVID-19 diagnosis was made in 0.07% of those with liver disease and 1% of those with cirrhosis. Thus, the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy. Amongst the COVID-19 patients, pre-existing metabolic cirrhosis appears to be associated with higher mortality, while HCV antibodies may be suggestive of “protection” against COVID-19.

Depression-free after Interferon-α exposure indicates less incidence of depressive disorder: A longitudinal study in Taiwan

IFN-α-induced depression in patients undergoing hepatitis C virus (HCV) treatment provides powerful support for the inflammation hypothesis of depression. Most studies have focused on the occurrence of depressive symptoms, but there has been no study yet in depression-free HCV patients receiving IFN-α. We hypothesized that HCV patients who did not develop depression after IFN-α exposure might have a lower incidence of depressive disorders after the IFN-α treatment. We conducted a twelve-year population-based cohort study of chronic HCV patients who received IFN-α therapy. The data were obtained from the Taiwan National Health Insurance Research Database. The study cohort was patients without any depressive disorder nor antidepressant use before and during IFN-α therapy. They were matched randomly by age, sex income and urbanization at a ratio of 1:4 with the control cohort of HCV patients without IFN-α therapy. The follow-up started after the last administration of IFN-α, and the primary outcome was the incidence of depressive disorders after IFN-α therapy. A total of 20,468 depression-free subjects were identified from records of HCV patients receiving IFN-α therapy. Patients without IFN-α-induced depression were associated with a significantly lower incidence (per 10,000 person-years) of new-onset depressive disorders (126.8, 95% Confidential Interval [CI] of 118.5-135.6) as compared to the control cohort (145.2, 95% CI of 140.0-150.6) (p<0.001). After adjusting for age, sex, income, urbanization and comorbid diseases, the crude hazard ratio for the incident depressive disorder was 0.87 (95% CI, 0.80-0.87) and the adjusted hazard ratios was 0.79 (95% CI, 0.72-0.87) for IFN-α-induced depression-free subjects as compared to the controls. Our study indicates that IFN-α treated depression-free patients have a lower risk for depressive disorders. This hypothesized mechanism might derive from an IFN-α-induced resilience factor as yet to be defined. Our study might suggest a new possibility for a new pharmacological strategy against depression.

Cost-Effectiveness Analysis of Early Treatment of Chronic HCV with Sofosbuvir/Velpatasvir in Italy.

Chronic Hepatitis C virus (cHCV) is a major health issue worldwide. New effective direct-acting anti-viral (DAA) drugs such as the combination sofosbuvir/velpatasvir, represent an important turning point, given the high sustained virologic response (SVR) rates associated with their use. To estimate the cost and effects of two different treatment strategies based on sofosbuvir/velpatasvir. Strategy 1: treating all patients, including those in the early stages of fibrosis; Strategy 2: reserving treatments for patients at more advanced stages of disease (≥ F3). The analysis compares the incremental cost-effectiveness ratio (ICER) of Strategy 1 versus Strategy 2 in a cohort of HCV-infected patients and a cohort of hepatitis C virus (HCV)-human immunodeficiency virus (HIV) patients. A Markov model simulating the natural history of the disease was built considering a 60-year time horizon and two cohorts of 1000 patients aged ≥ 35years. Disease morbidity was classified according to the METAVIR classification. The robustness of the model was tested using deterministic and probabilistic sensitivity analyses (PSA). In both cohorts, Strategy 1 results in higher resource consumption and a greater number of quality-adjusted life-years (QALYs) compared with Strategy 2. The ICERs for the cohort of HCV patients and the cohort of co-infected HCV/HIV patients ranged between €15,555-74,804/QALY and €10,708-55,138/QALY, respectively, depending on the assumed cost of the treatment. In the PSA, the ICER distribution remained below the threshold of €30,000/QALY in 96 and 97% of the scenarios in the cohorts of HCV and HCV/HIV patients, respectively. Extending the treatment of HCV to patients at an early stage of HCV infection is estimated to be cost effective from the perspective of the Italian Healthcare System.

The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease.

Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.

Efficacy and safety of direct-acting antiviral therapy in previous hard-to-treat patients with recurrent hepatitis C virus infection after liver transplantation: a real-world cohort.

BackgroundRecurrent hepatitis C virus (HCV) infection after liver transplantation (LT) has been a frequent and relevant problem in the past two decades. This analysis evaluated the efficacy and safety of new interferon (IFN)-free direct-acting antiviral (DAA) therapies in a large real-world cohort of HCV patients after LT.MethodsWe retrospectively analyzed a cohort of 157 patients infected with HCV who underwent deceased donor LT between 1997 and 2014. Patient survival, outcome, and side effects of antiviral therapy were assessed.ResultsSurvival with recurrent HCV genotype 1 (GT1) infection was inferior to other HCV GTs (P=0.01). The overall sustained virological response (SVR) rate with new DAA therapy was 94.6% (n=37). Patients with both GT1 and other GTs reached SVR rates >90%. We noticed a few side effects, mainly caused by ribavirin, and only one discontinuation in DAA-treated patients.ConclusionDAA therapy was effective and safe in previous hard-to-treat patients after LT in this real-world cohort.

Impact of virus eradication in patients with compensated hepatitis C virus-related cirrhosis: competing risks and multistate model.

No published study to date has provided a careful analysis of the effects of a sustained viral response (SVR) on the outcomes of patients with compensated hepatitis C virus (HCV)-related cirrhosis in relation to the degree of portal hypertension. Therefore, we estimated the impact of achieving SVR on disease progression, hepatocellular carcinoma (HCC) development and mortality in a large cohort of HCV patients with cirrhosis with or without oesophageal varices (OVs) at the start of antiviral therapy. A total of 535 Caucasian patients were prospectively recruited to this study. All patients had a clinical or histological diagnosis of compensated HCV-related cirrhosis and underwent interferon-based therapy. Competing risks and a multistate model were analysed according to the presence or absence of OVs at baseline. Compared to patients without SVR, a greater proportion of patients who achieved SVR showed no liver disease progression after 10 years (36.3% vs. 61.3% of patients without baseline OVs; 29.6% vs. 64.3% of patients with baseline OVs). Achievement of SVR was significantly associated with reduced occurrence rates of de-novo OVs, hepatic decompensation and HCC. Compared to patients without SVR, patients with SVR had lower likelihoods of liver-related death at 10 years (20.6% vs. 10.3% of patients without baseline OVs; 50.5% vs. 21.8% of patients with baseline OVs). In patients with compensated HCV-related cirrhosis with or without OVs at baseline, SVR is associated with reduced disease progression and liver-related mortality.

Are selective serotonin reuptake inhibitors associated with hepatocellular carcinoma in patients with hepatitis C?

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for patients with chronic hepatitis C virus (HCV) infection. Research suggests that serotonin promotes the development and growth of hepatocellular carcinoma (HCC). We tested the hypothesis whether exposure to SSRIs is associated with an increased risk of HCC in HCV patients. Patients who entered the United States Veterans Affairs (VA) Hepatitis C Clinical Case Registry in 2000 to 2009 were analyzed. During the 8 years of follow-up, 36,192 patients filled at least 1 SSRI prescription. Cases of HCC were identified by diagnosis codes (ICD-9 155.0). Multivariable Cox regression analyses estimated adjusted HCC hazard ratios (HRs) for SSRI-exposed versus SSRI-unexposed subjects and categories of average SSRI doses. The annual incidence of HCC in the VA registry cohort of 109,736 patients was 0.5% and significantly greater in the 8% with cirrhosis at baseline (HR = 5.2; 95% CI, 4.7-5.7). There was no evidence for significant interactions between the effect of SSRI-exposure and cirrhosis. Baseline characteristics of the exposed (n = 36,192) and unexposed (n = 73,544) subjects were similar. The median (interquartile range [IQR]) follow-up period after SSRI-exposure began was 44 (20-74) months with 18 (3-49) months between the first and last prescription. The median average SSRI dose during follow-up expressed as a fraction of initial recommended doses for depression was 0.94 (IQR, 0.5 to 1.3). The risk of HCC was not significantly increased after SSRI exposure (HR = 0.96; 95% CI, 0.87-1.05) or with increasing SSRI doses. Analysis of a large cohort of HCV patients did not support the hypothesis that SSRIs increase the risk of developing HCC.

All-Cause Mortality and Liver-Related Outcomes Following Successful Antiviral Treatment for Chronic Hepatitis C

Antiviral therapy for the hepatitis C virus (HCV) reduces all-cause and liver-related morbidity and mortality. Few studies are available from populations with multiple medical and psychiatric comorbidities where the impact of successful antiviral therapy might be limited. The purpose of this study was to determine the effect of sustained virologic response (SVR) on all-cause and liver-related mortality in a cohort of HCV patients treated in an integrated hepatitis/mental health clinic. This was a retrospective review of all patients who initiated antiviral treatment for chronic HCV between January 1, 1997 and December 31, 2009. Cox regression analysis was used to determine factors involved in all-cause mortality, liver-related events and hepatocellular carcinoma. A total of 536 patients were included in the analysis. Median follow-up was 7.5 years. Liver and non-liver-related mortality occurred in 2.7 and 5.0 % of patients with SVR and in 17.8 and 6.4 % of patients without SVR. In a multivariate analysis, SVR was the only factor associated with reduced all-cause mortality (HR 0.47; 95 % CI 0.26-0.85; p = 0.012) and reduced liver-related events (HR 0.23; 95 % CI 0.08-0.66, p = 0.007). Having stage 4 liver fibrosis increased all-cause mortality (HR 2.50; 95 % CI 1.23-5.08; p = 0.011). Thrombocytopenia at baseline (HR 2.66; 95 % CI 1.22-5.79; p = 0.014) and stage 4 liver fibrosis (HR 4.87; 95 % CI 1.62-14.53; p = 0.005) increased liver-related events. Despite significant medical and psychiatric comorbidities, SVR markedly reduced liver-related outcomes without a significant change in non-liver-related mortality after a median follow-up of 7.5 years.

GRP-121 Multidisciplinary Monitoring of Psychiatric Morbidity of HCV-Infected Patients Treated with Interferon and Ribavirin

BackgroundTreatment of hepatitis C virus (HCV) infection with pegylated interferon and ribavirin may induce psychiatric disorders, which may result in poor adherence and response to antiviral treatment.PurposeWe aimed to describe...

Fibrosis Progression in HCV Carriers with Mild Hepatitis Who Possess the High‐Repetition Variant of the DRD4 Gene, a Genetic Marker for Binge‐Drinking and Risk‐Seeking Behavior: A Longitudinal Study

Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome. A cohort of HCV patients with normal or near-normal aminotransferases (N=128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N=128) and related to liver histology. HRV allele frequencies were 0.19 in patients and 0.16 in controls (p=0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p=0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p=0.002) and stage (p=0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR=1.06, 95% CI 1.02 to 1.11) and HRV (OR=3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up. The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C.

The economic burden of advanced liver disease among patients with Hepatitis C Virus: a large state Medicaid perspective

BackgroundChronic hepatitis C virus (HCV) may progress to advanced liver disease (ALD), including decompensated cirrhosis and/or hepatocellular carcinoma (HCC). ALD can lead to significant clinical and economic consequences, including liver transplantation. This study evaluated the health care costs associated with ALD among HCV infected patients in a Medicaid population.MethodsUsing Florida Medicaid claims data, cases were patients with at least 1 diagnosis of HCV or prescription therapy for HCV (ribavirin plus interferon, peginterferon, or interferon alfacon-1) prior to an incident ALD-related diagnosis (“index event”) between 1999 and 2007. ALD-related conditions included decompensated cirrhosis, HCC, or liver transplant. A cohort of HCV patients without ALD (comparison group subjects) were matched 1-to-1 based on age, sex, and race. Baseline and follow-up were the 12 months prior to and following index, respectively; with both periods allowing for a maximum one month gap in eligibility. For both case and comparison patient cohorts, per-patient-per-eligible month (PPPM) costs were calculated as total Medicaid paid amount for each patient over their observed number of eligible months in follow-up, divided by the patient’s total number of eligible months. A generalized linear model (GLM) was constructed controlling for age, race, Charlson score, alcoholic cirrhosis, and hepatitis B to explore all-cause PPPM costs between study groups. The final study group included 1,193 cases and matched comparison patients (mean age: 49 years; 45% female; 54% white, 23% black, 23% other).ResultsThe majority of ALD-related diagnoses were for decompensated cirrhosis (92%), followed by HCC (6%) and liver transplant (2%). Cases had greater comorbidity (mean Charlson score: 3.1 vs. 2.3, P < 0.001). All-cause inpatient use up to 1-year following incident ALD diagnosis was significantly greater among cases with ALD (74% vs. 27%, P < 0.001). In the GLM, cases had 2.39 times greater total adjusted mean all-cause PPPM costs compared to the comparison group ($4,956 vs. $1,735 respectively; P < 0.001). Among cases, mean total unadjusted ALD-related costs were $1,356 PPPM, which were largely driven by inpatient costs ($1,272).ConclusionsOur results suggest that among patients diagnosed with HCV, the incremental costs of developing ALD are substantial, with inpatient stays as the main driver of these increased costs.

Understanding the Role of PNPLA3 Genetic Variants in Patients with Chronic Hepatitis C Infection

In 2008, in an attempt to identify genetic determinants of liver steatosis, Romeo et al. ran an independent genomewide association study on 2,121 patients enrolled in the Dallas Heart Study that had hepatic fat content assessed by proton magnetic resonance spectroscopy [1]. By concentrating just on nonsynonymous sequence variations the authors were able to discover a variation (rs738409 C[G) at position 148 in the patatin-like phospholipase-3 (PNPLA3) gene as the strongest determinant of steatosis in patients. The genetic polymorphism encodes an isoleucineto-methionine substitution. The PNPLA3 gene encodes a 481 amino acid protein of unknown function that belongs to the patatin-like phospholipase family; the progenitor of this family, patatin, has nonspecific lipid acyl hydrolase activity. Following this breakthrough discovery, several candidate gene studies have demonstrated that the G allele of PNPLA3 single nucleotide polymorphism (SNP) influences liver fat accumulation, is associated with disease severity in adult and pediatric populations with NAFLD, and ultimately increases the risk of NASH [2–5]. These results did not go unnoticed among colleagues working in the hepatitis C virus (HCV) field, as several studies were designed to assess the clinical role of the PNPLA3 polymorphisms in patients with chronic hepatitis C. The reasons for this interest are many fold. First, steatosis is known to negatively impact the natural history of HCV infection as it accelerates progression to cirrhosis [6, 7]. Second, liver steatosis has been shown to be a negative moderator of treatment outcome to interferon (IFN)-based therapies, with patients showing a fatty liver achieving lower sustained virological response rates across all HCV genotypes [8]. Third, with respect to the plethora of clinical trials currently investigating future potential anti-HCV drugs, the identification of a further genetic polymorphism able to influence treatment outcome would have an enormous impact in the design of future studies [9]. Among the first to demonstrate the impact of the PNPLA polymorphism in patients with HCV infection were the studies by Valenti et al. and Trepo et al. who, by analyzing large cohorts of HCV patients in Europe, almost simultaneously reported the G allele of rs738409 SNP to be associated not only with the presence of histologically determined liver steatosis, but also with the presence of cirrhosis and accelerated fibrosis progression [10, 11]. Ginanni-Corradini et al. further expanded these findings by reporting an increased rate of hepatocellular carcinoma (HCC) development in patients with the GG genotype of rs738409 in a cohort of 222 HCV patients [12]. Indeed by multivariate analysis the GG genotype was an independent factor associated with HCC development carrying a 2.23 odds ratio. Taken together these data rather unequivocally correlate the G allele of the PNPLA3 SNP with a worse prognosis of chronic hepatitis C. On the other hand the first studies were not able to solve if the G allele of the PNPLA3 SNP had an impact on IFNbased treatment efficacy. Indeed Valenti et al. were able to show a modest effect only in HCV-1 patients, with GG patients achieving a 10 % SVR rate compared to the 36 % obtained by the CG/CC counterpart, while Trepo et al. could not replicate these findings in their cohort. These discrepant results are not surprising given the extreme heterogeneity of the cohorts in terms of known moderators of treatment outcome such as disease severity, HCV A. Aghemo (&) A M Migliavacca Center for Liver Diseases, First Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milan, Italy e-mail: alessio.aghemo@policlinico.mi.it