Development and validation of a scoring system to predict response to obeticholic acid in primary biliary cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. METHODS: We used data from the Italian RECAPITULATE (N 441) and the IBER-PBC (N 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS), or also after 6 months of treatment (ORS+). Multivariable Cox's regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (ALP/ULN<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or NORMAL RANGE criteria (NR: normal ALP, ALT and bilirubin) up to 24 months. RESULTS: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were of 0.75, 0.78 and 0.72 for POISE, ALP/ULN<1.67 and NR response, which raised to 0.83, 0.88, 0.81 with ORS+, respectively. The respective performances in validation were of 0.70, 0.72 and 0.71 for ORS, and 0.80, 0.84, 0.78 for ORS+. Results were consistent across groups with mild/severe disease. CONCLUSIONS: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC.

Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy.

BACKGROUND AND AIMS: The landscape in primary biliary cholangitis (PBC) has changed with the advent of second-line treatments. However, the use of obeticholic acid (OCA) and fibrates in PBC-related cirrhosis is challenging. We assessed the impact of receiving a second-line therapy as a risk factor for decompensated cirrhosis in a real-world population with cirrhosis and PBC, and identify the predictive factors for decompensated cirrhosis in these patients. APPROACH AND RESULTS: Multicenter study enrolling 388 patients with PBC-cirrhosis from the Spanish ColHai registry. Biopsy (20%), ultrasound (59%), or transient elastography (21%) defined cirrhosis, and the presence of varices and splenomegaly defined clinically significant portal hypertension (CSPH). Paris-II and PBC OCA international study of efficacy criteria determined the response to ursodeoxycholic acid (UDCA), fibrates (n=93), and OCA (n=104). The incidence of decompensated cirrhosis decreased for UDCA versus OCA or fibrates in the real-world population, but they were similar considering the propensity score-matched cohort (UDCA 3.77 vs. second-line therapy 4.5 100 persons-year, respectively), as patients on second-line therapy exhibited advanced liver disease. Consequently, GGT, albumin, platelets, clinically significant portal hypertension, and UDCA response were associated with a decompensating event. OCA response (achieved in 52% of patients) was associated with bilirubin (OR 0.21 [95% CI: 0.06-0.73]) and AST (OR 0.97 [95% CI: 0.95-0.99]), while fibrate response (achieved in 55% of patients) with AST [OR 0.96 (95% CI: 0.95-0.98]). In patients treated with OCA, drug response (sHR 0.23 [95% CI: 0.08-0.64]), diabetes (sHR 5.62 [95% CI: 2.02-15.68]), albumin (sHR 0.34 [95% CI: 0.13-0.89]), and platelets (sHR 0.99 [95% CI: 0.98-1.00]) were related to decompensation. In patients treated with fibrate, drug response (sHR 0.36 (95% CI: 0.14-0.95]), albumin (sHR 0.36 (95% CI: 0.16-0.81]), and clinically significant portal hypertension (sHR 3.70 (95% CI: 1.17-11.70]) were associated with decompensated cirrhosis. CONCLUSIONS: Advanced PBC, rather than OCA and fibrates, was found to be associated with decompensating events. Therefore, biochemical and clinical variables should be considered when making decisions about the management of these drugs. Moreover, a positive response to OCA and fibrates reduced the risk of decompensation.

Hospital-based screening outperforms primary care screening as a means of achieving hepatitis C virus micro-elimination.

AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.

Tenofovir Disoproxil Fumarate Reduces the Severity of COVID-19 in Patients with Chronic Hepatitis B.

BACKGROUND AND AIMS: HIV-positive patients on tenofovir hydroxyl fumarate (TDF)/emtricitabine have a lower risk of COVID-19 and hospitalization than those given other treatments. Our aim was to analyze the severity of COVID-19 in patients with chronic hepatitis B (CHB) on TDF or entecavir (ETV). METHODS: Spanish hospital databases (n = 28) including information regarding adult CHB patients on TDF or ETV for the period February 1st to November 30th 2020 were searched for COVID-19, defined as a positive SARS-CoV-2 polymerase chain reaction, and for severe COVID-19. RESULTS: Of 4736 patients, 117 had COVID-19 (2.5%), 67 on TDF and 50 on ETV. Compared to patients on TDF, those on ETV showed (p < 0.05) greater rates of obesity, diabetes, ischemic cardiopathy, and hypertension. COVID-19 incidence was similar in both groups (2.3 vs. 2.6%). Compared to TDF, patients on ETV more often (p < 0.01) had severe COVID-19 (36 vs. 6%), required intensive care unit (ICU) (10% vs. 0) or ventilatory support (20 vs. 3%), were hospitalized for longer (10.8 ± 19 vs. 3.1 ± 7 days) or died (10 vs. 1.5%, p = 0.08). In an IPTW propensity score analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage, TDF was associated with a sixfold reduction in severe COVID-19 risk (adjusted-IPTW-OR 0.17, 95%CI 0.04-0.67, p = 0.01). CONCLUSION: Compared to ETV, TDF seems to play a protective role in CHB patients with SARS-CoV-2 whereby the risk of severe COVID-19 is lowered.

Patients with severe mental illness and hepatitis C virus infection benefit from new pangenotypic direct-acting antivirals: Results of a literature review.

INTRODUCTION: Hepatitis C virus (HCV) infection is a global health problem that can results in cirrhosis, hepatocellular carcinoma and even death. HCV infection is 3-20-fold more prevalent among patients with versus without severe mental illness (SMI), such as major depressive disorder, personality disorder, bipolar disorder and schizophrenia. Treatment options for HCV were formerly based on pegylated interferon alpha, which is associated with neuropsychiatric adverse events, and this contributed to the exclusion of patients with SMI from HCV treatment, elimination programmes, and clinical trials. Moreover, the assumption of poor adherence, scant access to healthcare and the stigma and vulnerability of this population emerged as barriers and contributed to the low rates of treatment and efficacy. METHODS: This paper reviews the literature published between December 2010 and December 2020 exploring the epidemiology of HCV in patients with SMI, and vice versa, the effect of HCV infection, barriers to the management of illness in these patients, and benefits of new therapeutic options with pangenotypic direct antiviral agents (DAAs). RESULTS: The approval of DAAs has changed the paradigm of HCV infection treatment. DAAs have proven to be an equally efficacious and safe option that improves quality of life (QoL) in patients SMI. CONCLUSIONS: Knowledge of the consequences of the HCV infection and the benefits of treatment with new pangenotypic DAAs among psychiatrists can increase screening, referral and treatment of HCV infection in patients with SMI.

Cystic fibrosis with liver involvement in adults has a benign course. Results from a tertiary referral center cohort.

BACKGROUND: Cystic Fibrosis Liver Disease is a poorly understood entity, especially in adults, in terms of its real prevalence, natural history and diagnostic criteria, despite being the most important extrapulmonary cause of mortality. The aim was to evaluate the prevalence, characteristics and potential risk factors of liver disease in adults with cystic fibrosis, according to two diagnostic criteria accepted in the scientific literature. METHODS: Patients were recruited in a tertiary referral hospital, and laboratory, ultrasound, non-invasive liver fibrosis tests (AST to Platelet Ratio Index; Fibrosis-4 Index) and transient elastography (Fibroscan) were performed. The proportion of patients with liver disease according to the Debray and Koh criteria were evaluated. RESULTS: 95 patients were included, 48 (50.5%) females, with a mean age of 30.4 (28.6-32.2) years. According to the Debray criteria, 6 (6.3%) patients presented liver disease. According to the Koh criteria, prevalence increased up to 8.4%, being statistically different from the 25% value described in other published series (p = 0.005). Seven (7.5%) presented ultrasonographic chronic liver disease. Eleven (13%) presented liver fibrosis according to the APRI score; 95 (100%) had a normal FIB-4 value. Mean liver stiffness value was 4.4 (4.1-4.7) kPa. FEV1 (OR=0.16, p 0.05), meconium ileus (OR=14.16, p 0.002), platelets (Pearson coefficient -0.25, p 0.05) and younger age (Pearson coefficient -0.19, p 0.05) were risk factors. CONCLUSIONS: Prevalence and severity of liver disease in adult cystic fibrosis patients were lower than expected. Meconium ileus, platelets, age and respiratory function were confirmed as risk factors associated to cystic fibrosis liver disease.

Evolution of HCV associated porphyria cutanea tarda after HCV sustained virologic response by direct acting antivirals.

OBJECTIVES: Porphyria cutanea tarda (PCT) is common and usually associated with HCV chronic infection and HFE polymorphisms. Since DAA IFN-free regimens availability, SVR for HCV is nearly a constant and we wonder whether HCV SVR determine PCT evolution. METHODS: Retrospective observational study including patients with HCV associated PCT from the Gastroenterology and Infectious Diseases Departments at our Hospital, treated with DAA (Apr/2015-Apr/2017). Clinical variables of PCT were collected at PCT diagnosis, after PCT treatment, before DAA use and after SVR achievement. UROD activity and C282Y/H63D polymorphisms were registered. SPSS 22.0. RESULTS: 13 HCV-PCT patients included: median age 52.5 years; 4 females; 8 HCV/HIV co-infected (all on undetectable viral load). Classical PCT factors: 12 smoked, 9 alcohol abuse, 6 former IDU. 10 type I PCT and 1 type II PCT. HFE polymorphism: 2 cases with C282Y/H63D; H63D polymorphism in 8. PCT manifestations resolved with PCT treatment in 4 patients, almost completely in 7 patients, 1 patient referred stabilization and one worsened. After DAA treatment all the residual lesions resolved, what always led to specific treatment interruption. CONCLUSIONS: Our series of cases of HCV-associated PCT shows that SVR after DAA treatment leads to PCT resolution. Porphyrin levels are not needed after ending PCT specific treatment interruption when there are no residual skin lesions in HCV-associated PCT.

Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid.

BACKGROUND: Obeticholic acid (OCA) was recently approved as the only on-label alternative for patients with primary biliary cholangitis (PBC) with intolerance or suboptimal response to ursodeoxycholic acid (UDCA). However, few data are available outside clinical trials. AIM: To assess the effectiveness and safety of OCA in a real-world cohort of patients with non-effective UDCA therapy. METHODS: Open-label, prospective, real-world, multicentre study, enrolling consecutive patients who did not meet Paris II criteria, from 18 institutions in Spain and Portugal. Effectiveness was assessed by the changes in GLOBE and UK-PBC scores from baseline. POISE and Paris II criteria were evaluated after 12 months of OCA . Liver fibrosis was evaluated by FIB-4 and AST to platelet ratio index (APRI). RESULTS: One hundred and twenty patients were eligible, median time since PBC diagnosis 9.3 (4.0-13.8) years, 21.7% had cirrhosis, and 26.7% received had previous or concomitant treatment with fibrates. Seventy-eight patients completed at least 1 year of OCA. The Globe-PBC score decreased to 0.17 (95% CI 0.05 to 0.28; P = 0.005) and the UK-PBC score decreased to 0.81 (95% CI -0.19 to 1.80; P = 0.11). There was a significant decrease in alkaline phosphatase of 81.3 U/L (95% CI 42.5 to 120; P < 0.001), ALT 22.1 U/L (95% CI 10.4 to 33.8; P < 0.001) and bilirubin 0.12 mg/dL (95% CI 0 to 0.24; P = 0.044). FIB-4 and APRI remained stable. According to the POISE criteria, 29.5% (23 out of 78) achieved response. The adverse events rate was 35%; 11.67% discontinued (8.3% due to pruritus). CONCLUSIONS: This study supports data from phase III trials with significant improvement of PBC-Globe continuous prognostic marker score among OCA-treated patients with good tolerability.

Acute hepatitis due to olmesartan: an uncommon entity.

We report the case of a hypertensive 54-year-old female who had been under treatment with olmesartan (40 mg daily) for a month. She was referred due to hypertransaminasemia and also reported asthenia and a 7 kg weight loss.

Real-world evidence of the effectiveness of ombitasvir-paritaprevir/r ± dasabuvir ± ribavirin in patients monoinfected with chronic hepatitis C or coinfected with human immunodeficiency virus-1 in Spain.

AIM: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. MATERIAL AND METHODS: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. RESULTS: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. CONCLUSIONS: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb-V and dialysis in Spanish clinical practice - Vie-KinD study.

BACKGROUND AND AIMS: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. MATERIAL AND METHODS: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. RESULTS: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision. CONCLUSIONS: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.

Infection with multiple hepatitis C virus genotypes detected using commercial tests should be confirmed using next generation sequencing.

Current HCV genotyping methods may have some limitations in detecting mixed infections. We aimed to determine the accuracy of genotyping and the detection of mixed-genotype infections using the Abbott-RealTime HCV Genotype II assay (Abbott-RT-PCR) in comparison with a Roche-Next Generation Sequencing assay (Roche-NGS). Plasma samples collected from 139 HCV-infected patients tested with Abbott-RT-PCR, 114 with single genotype (GT) and 25 with mixed GTs were genotyped using Roche-NGS. Roche-NGS confirmed all single GTs obtained with Abbott-RT-PCR. One case of Abbott GT 4 was found as GT 1a using Roche-NGS. Genotype 5 was confirmed using Roche-NGS in 75% cases (3 out of 4 cases). Twenty-five patients were identified as having mixed HCVinfections using Abbott-RT-PCR. The concordance between Abbott-RT-PCR and Roche-NGS was 76% (19 out of 25 cases). Three mixed-GT infections identified with the Abbott assay (two (1b + 4); one (1a + 3)) were reported as pure 1b using Roche-NGS. Very divergent results were found for the other three samples. When compared to Roche-NGS, Abbott-RT-PCR has performed excellently for the determination of patients infected with single GTs. For patients that are categorized as having a mixed infection using Abbott-RT-PCR, we recommend an NGS assay as a confirmation test.

Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: Results from the Spanish HEPA-C real-world cohort.

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real-world HCV patient cohort. HEPA-C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA-C between December 2016 and May 2017, and treated with EBR/GZR with at least end-of-treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19-92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post-treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real-world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.

String sign of Kantor in a patient with Crohn's disease.

We report the case of a 29-year-old male with structuring ileocolic Crohn's disease (CD), diagnosed in 2007 and treated with oral azathioprine, oral mesalazine and intravenous infliximab, without any other surgical or medical history of interest. He presented to the Emergency Room with abdominal distention and pain, nausea, vomiting and motility problems of a three-day duration. An abdominal computerized tomography using intravenous contrast was performed.

Interferon-related genetic markers of necroinflammatory activity in chronic hepatitis C.

INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.

Liver metastasis from neuroendocrine carcinoma after the use of the new direct-action antivirals against hepatitis C virus in a patient with past history of hepatocellular carcinoma.

The use of the new direct-action antivirals against hepatitis C virus provides very high viral eradication rates. However, various recently published articles recommend caution with their use after the appearance of some cases of de novo tumors (originated in hepatic and extra-hepatic locations) and a possible shorter time period of recurrence of hepatocellular carcinomas previously treated with surgery or loco-regional therapies. The sudden drop of the number of natural killer cells secondary to the use of these new medicines has been suggested as one of the possible mechanisms responsible for this process. However, due to the controversy concerning this subject and the absence of long-term follow-up studies in clinical practice, caution is needed before definitive conclusions are settled. We present the case report of a patient diagnosed of chronic liver disease secondary to hepatitis C virus infection and a past history of hepatocellular carcinoma in complete remission after radiofrequency ablation. He was treated with the new direct-action antivirals reaching sustained viral response. Six months later, the patient was diagnosed with liver metastasis from a small-cell neuroendocrine tumor of unknown primary site.