Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort.

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014-October 2015). In total, 208 patients were included: 98 (47%) treatment-experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

Simeprevir in combination with sofosbuvir in treatment-naïve and -experienced patients with hepatitis C virus genotype 4 infection: a Phase III, open-label, single-arm study (PLUTO).

BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. AIM: To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. METHODS: Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. RESULTS: Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. CONCLUSIONS: Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807].

Effectiveness and safety of ombitasvir, paritaprevir, ritonavir ± dasabuvir ± ribavirin: An early access programme for Spanish patients with genotype 1/4 chronic hepatitis C virus infection.

Over the last 5 years, therapies for hepatitis C virus (HCV) infection have improved significantly, achieving sustained virologic response (SVR) rates of up to 100% in clinical trials in patients with HCV genotype 1. We investigated the effectiveness and safety of ombitasvir/paritaprevir/ritonavir±dasabuvir in an early access programme. This was a retrospective, multicentre, national study that included 291 treatment-naïve and treatment-experienced patients with genotype 1 or 4 HCV infection. Most patients (65.3%) were male, and the mean age was 57.5 years. The mean baseline viral load was 6.1 log, 69.8% had HCV 1b genotype, 72.9% had cirrhosis and 34.7% were treatment-naïve. SVR at 12 weeks posttreatment was 96.2%. Four patients had virological failure (1.4%), one leading to discontinuation. There were no statistical differences in virological response according to genotype or liver fibrosis. Thirty patients experienced serious adverse events (SAEs) (10.3%), leading to discontinuation in six cases. Hepatic decompensation was observed in five patients. Four patients died during treatment or follow-up, three of them directly related to liver failure. Multivariate analyses showed a decreased probability of achieving SVR associated with baseline albumin, bilirubin and Child-Pugh score B, and a greater probability of developing SAEs related to age and albumin. This combined therapy was highly effective in clinical practice with an acceptable safety profile and low rates of treatment discontinuation.

Efficacy and Safety of Therapy With Simeprevir and Sofosbuvir in Liver Transplant Recipients Infected by Hepatitis C Virus Genotype 4: Cohort Spanish Society of Liver Transplantation Cohort.

BACKGROUND: Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of 2nd-generation direct-acting antivirals (DAAs), and more data are needed to help guide treatment decisions. We still have even fewer data concerning liver transplant patients. Simeprevir (SIM) and sofosbuvir (SOF) combination is useful to treat this genotype. The aim of this study was to know the efficacy and safety of the combination SIM + SOF ± ribavirin (RBV) in a group of liver transplant patients with HCV genotype 4 infection in Spain in real life. METHODS: This was a multicenter retrospective study, including 28 HCV genotype 4 patients from 11 liver transplant centers who were treated with SIM + SOF ± RBV. We included in the analysis demographic, clinical, and virologic data and details of serious adverse events (SAEs), including mortality rate 6 months after treatment. RESULTS: All patients were male, mean age 52 ± 9.43 years, and 50% were IL28B CT and 37.5% TT; 46.42% of them were pretreated and 76.9 were null responders. Fibrosis stage 4 was found in 38.7% of patients; in 67.8% of those cases the diagnosis of fibrosis was made with the use of Fibroscan, in 21.4% by liver biopsy. The average Fibroscan was 13.86 KPa. The average Model for End-Stage Liver Disease (MELD) score of cirrhotic patients was 10.9 and the Child-Pugh score was A in 70%, B in 20%, and C in 10%. We included RBV in 75% of patients, and treatment duration was 12 weeks in all patients. The sustained virologic response at week 12 (SVR12) was 95.23%. There were no discontinuations due to SAEs, but the mortality rate at 6 months after treatment was 7.14%. All deceased patients were cirrhotic, Child C, and with an average MELD score of 20. CONCLUSIONS: The combination SIM + SOF ± RBV to treat HCV genotype 4 in liver transplant patients is an option with high rates of SVR12 and very safe, similarly to genotype 1. There was no treatment-related mortality, but when it is administered in advanced stages of fibrosis it may not be enough to prevent mortality associated with cirrhotic hepatitis C recurrence after transplantation.

Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program.

In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/µL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.

Prevalence and severity of hepatopulmonary syndrome and its influence on survival in cirrhotic patients evaluated for liver transplantation.

The prevalence of hepatopulmonary syndrome (HPS) and its influence on survival before and after liver transplantation (LT) remain controversial. Additionally, the chronology of post-LT reversibility is unclear. This study prospectively analyzed 316 patients with cirrhosis who were evaluated for LT in 2002-2007; 177 underwent LT at a single reference hospital. HPS was defined by a partial pressure of arterial oxygen (PaO2 ) <70 mmHg and/or an alveolar-arterial oxygen gradient (A-a PO2 ) ≥20 mmHg in the supine position and positive contrast echocardiography. The prevalence of HPS was 25.6% (81/316 patients), and most patients (92.6%) had mild or moderate HPS. High Child-Pugh scores and the presence of ascites were independently associated with HPS. Patients with and without HPS did not significantly differ in LT waiting list survival (mean 34.6 months vs. 41.6 months, respectively; log-rank, p = 0.13) or post-LT survival (mean 45 months vs. 47.6 months, respectively; log-rank, p = 0.62). HPS was reversed in all cases within 1 year after LT. One-fourth of the patients with cirrhosis who were evaluated for LT had HPS (mostly mild to moderate); the presence of HPS did not affect LT waiting list survival. HPS was always reversed after LT, and patient prognosis did not worsen.

Evaluation of clinical safety of conversion to Advagraf therapy in liver transplant recipients: observational study.

OBJECTIVE: To present the correlation between dosage and plasma concentration of tacrolimus and the consequences for short-term hepatorenal function of conversion to Advagraf (tacrolimus extended-release capsules) in liver transplant recipients. PATIENTS AND METHODS: This observational study on adult liver transplant recipients examined tacrolimus levels after conversion to Advagraf therapy. Mean (SD) patient age was 51 (44-59) years. Conversion occurred at 43 (19-85) months posttransplantation, and follow-up was 193 (106.5-243.25) days. Dosage was adjusted milligram for milligram. Levels of tacrolimus, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and creatinine were recorded on the day before conversion to Advagraf and 1, 3, 6, and months afterward. RESULTS: Of the 79 patients in whom therapy was converted to Advagraf, 31 (39.2%) had alcoholic cirrhosis, 19 (24.1%) had viral disease, 10 (12.7) had mixed disease, 8 (10.1%) had cholestatic disease, 4 (5.1%) had metabolic disease, and 7 (8.8%) had other diseases. Despite no modification of Advagraf dosage during follow-up in most patients, mean tacrolimus levels decreased from the first month after conversion; however, at 6 months after conversion, they tended to equal the initial value. Renal function and liver biochemistry values demonstrated no significant change during follow-up. CONCLUSION: Although tacrolimus levels decreased initially after conversion to Advagraf therapy, 1:1 conversion is safe for hepatorenal function in liver transplant recipients.

Liver transplantation for hepatocellular carcinoma: results of a multicenter study with common priorization criteria.

OBJECTIVE: To evaluate the results of liver transplantation (OLT) performed for hepatocellular carcinoma (HCC) among a multicenter cohort of patients with predefined common inclusion and priorization criteria. PATIENTS AND METHODS: Over a 5-year period (January 2002-December 2006), 199 HCC patients underwent OLT in four centers in Andalusia. The morphological (Milan) inclusion criteria were priorized in two consecutive periods, according to the Model for End-stage Liver Disease score: group I, 53 patients (HCC < 2 cm = 24 points; > or = 2 cm or multinodular = 29 points) and group II, 146 cases (HCC < 3 cm without priorization; HCC > or = 3 cm or multinodular = 18 points). RESULTS: Among the 199 HCCs, 186 (93.5%) subjects were transplanted and 13 (6.5%) were excluded. There were 18 cases (9.7%) where the diagnosis was incidental and 168 were known HCC cases; 144 (85.7%) complied with the Milan criteria (Milan+); 24 (14.3%) exceeded there criteria (Milan-). According to preoperative imaging, the number of nodules and tumor mean sizes among the excluded-Milan+ and Milan- groups-were 1.8/5.3 cm, 1.4/3.5 cm, and 2.3/6.7 cm, respectively (P < .001). Percutaneous treatment during listing was delivered to 55% of the excluded cases: 49% of Milan+ and 96% of Milan-. The median time on the list was 88 days for known HCC (53 days for group I, and 97 days for group II), and 172 days for the incidental HCCs. Staging (pTNM) was correct in 64% of cases: 23% were understaged and 13% were overstaged. Overall mortality within the first 90 days was 9%, and transplant patient survival at 5 years was 61%. No differences were observed in survival rates between both study periods, although there were differences between the Milan+ (65%) and Milan- (23%) groups (P < .04). In addition, the difference in the recurrence rates was also significant between the Milan+ (7%), Milan- (24%), and the incidental (25%) groups (P < .02). CONCLUSIONS: A common priorization policy of HCC for OLT based on morphological criteria results in a low exclusion rate on the waiting lists (6.5%). The Milan criteria are still a good cutoff to stratify the risk of recurrence, despite preoperative tumor staging being correct in only two-thirds of cases.

Response to a vaccination schedule with 4 doses of 40 microg against hepatitis B virus in cirrhotic patients evaluated for liver transplantation.

We conducted a retrospective study to evaluate the response to recombinant hepatitis B vaccine after 4 intramuscular doses (40 microg) administered at 0, 1, 2, and 6 months in 157 cirrhotic patients who were liver transplant candidates. Seventeen nonresponders were revaccinated with the same schedule. We studied the association between the following variables and the vaccine response: age, gender, etiology of cirrhosis, diabetes, severity of liver disease (Child-Pugh class and Model for End-Stage Liver Disease [MELD] score), and the number of administered doses. The response rates were: 1 dose, 40% (2/5); 2 doses, 0% (0/7); 3 doses, 32.7% (16/49); and 4 doses, 31.3% (30/96) of patients. The median hepatitis B surface antibody (anti-HBs) titer was 45 mU/mL (range, 11-620 mU/mL). The response rate to revaccination was 41.2% (median anti-HBs titer, 88 mU/mL; range, 18-190 mU/mL). Diabetics showed a lower response rate than nondiabetic patients (17.2% vs 35.3%; P = .046). No association was observed between the response rate to vaccine and the other variables. In conclusion, the response rate to hepatitis B vaccine reached a little more than 30% in cirrhotic patients who received 3 or 4 doses. No higher response rate was observed among patients who received 4 doses. Diabetes was associated with a lower response rate. Anti-HBs seroconversion rates were not associated with the other variables. Revaccination may significantly increase the response rate to hepatitis B vaccine in cirrhotic patients, and may be considered in nonresponders after the third dose. Early vaccination against HBV should be considered in such patients.

Prevalence of hepatitis A and B markers and vaccine indication in cirrhotic patients evaluated for liver transplantation in Spain.

Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is generally recommended for patients with chronic liver disease and those evaluated for liver transplantation in the absence of immunity. HAV and HBV infections after liver transplantation are frequent and associated with a worse prognosis. The data suggest that the number of patients with chronic liver disease without naturally acquired immunity against HAV and HBV is substantial, and that new vaccination strategies are needed. The aim of this study was to determine the level of immunity from hepatitis A and B infections and the need for HBV and HAV vaccination among cirrhotic patients evaluated for liver transplantation. We studied HBV and HAV serological markers (HbsAg, anti-HBc, anti-HBs, IgG anti-HAV) in 451 cirrhotic patients evaluated for liver transplantation to investigate the association with gender, age, and etiology of cirrhosis. Negative HBV markers were observed in 57% of patients with 43% displaying one positive HBV marker: HBsAg (+), 9.5%; anti-HBc (+)/anti-HBs (-), 11.5%; anti-HBc (-)/anti-HBs(+), 4.2%; anti-HBc(+)/anti-HBs(+), 17.7%. HBV vaccine indication established in 68.5% of patients was greater among women and hepatitis C virus-negative patients. No differences were observed in age or cause of cirrhosis. HAV vaccination indicated in 6.7% of patients (IgG anti-HVA-negative) was greater among patients with negative HBV markers (9.3% vs 3.3%, P = .018) and younger patients (25.3% of patients

Lack of association of recipient MCP-1 gene promoter polymorphism with acute graft rejection after orthotopic liver transplantation.

Acute graft rejection after orthotopic liver transplantation (OLT) is associated with leukocyte infiltration of the graft. Monocyte chemoattractant protein-1 (MCP-1) is a beta-chemokine involved in the attraction and accumulation of mononuclear granulocytes toward sites of inflammation. A biallelic polymorphism (G/A) at position -2518 of the MCP-1 gene has been described. Cells obtained from individuals with the GG or AG genotypes have been found to produce more MCP-1 than those obtained from individuals with the AA genotype. The goal of this study was to assess the possible association between this polymorphism and susceptibility to acute graft rejection after OLT. One hundred fifty Caucasian liver transplant recipients from the South of Spain underwent genotyping using a polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP). No significant differences were observed when patients with versus without acute rejection episodes were compared for the distribution of -2518 MCP-1 genotypes. The present study supports the lack of involvement of polymorphism at position -2518 (A/G) of the MCP-1 gene on the susceptibility to acute allograft rejection among OLT recipients.

Results of an upper endoscopy protocol in liver transplant candidates.

OBJECTIVE: our aims is to understand endoscopic findings from a preoperative systematic study of patients with hepatic cirrhosis who were candidates for transplantation and their impact on a protocol for primary and secondary prophylaxis of variceal haemorrhage. PATIENTS AND METHODS: this study involves a retrospective evaluation of upper digestive tract lesions detected before inclusion and a prospective evaluation of new episodes of variceal haemorrhage, associated mortality rates, and factors that are likely to be involved in the development of this condition. Primary prophylaxis with beta-blockers was considered indicated in cases of varices of grande II or greater or with signs associated with increased risk. Secondary prophylaxis was essentially always associated with medical and endoscopic treatment. RESULTS: of 134 patients, there were 9 deaths, with a median time on the waiting list of 3 months. Of all patients, 33.6% presented with high risk oesophageal varices, 11.2 % with gastric varices, 42.6% with portal hypertensive gastropathy, and 26.9% with peptic lesions. Primary prophylaxis was indicated in 33 of 90 patients, and was initiated in almost half of the cases as a results of the study. Optimum fulfiment of the pre-established objectives was 75.3%. The incidence of new haemorrhagic events due to varices was 10.4% and accounted for almost half of the deaths during the monitoring period. The only statistically significant predictive factors were the presence of gastrict varices and previous history. CONCLUSION: upper endoscopy should play a role in the preoperative examination of liver transplant candidates due to the significant impact it has on subsequent management.

Splenic abscesses caused by Actinomyces meyeri in a patient with autoimmune hepatitis.

We report a case of actinomycosis with uncommon localizations that was due to Actinomyces meyeri. Although penicillin is the standard treatment for this condition, our patient was treated successfully with imipenem. Actinomyces organisms are important constituents of the normal flora of mucous membranes and are considered opportunistic pathogens; these organisms may produce infection after local trauma, surgery, or aspiration. The mains forms of actinomycosis are cervicofacial, thoracic, and abdominal; most cases are due to Actinomyces israelii, whereas other Actinomyces species are occasionally implicated. Actinomycosis usually occurs in immunocompetent persons, but may occur in persons with diminished host defenses.

Solitary ileocolic arteriovenous malformation: spongostan and silk therapeutic embolisation.

A debilitated patient with liver cirrhosis and poor haemostasis had a severe lower gastrointestinal haemorrhage. A superior mesenteric arteriogram revealed an early persistent and promiment draining vein in the ileocolic artery. Two fragments of Spongostan and silk were used to embolise the bleeding artery and the haemorhage ceased immediately. No infarction of the embolised area was observed and the bleeding was controlled.

Hepatotoxicity due to lysine salt of bendazac.

BACKGROUND: The lysine salt of bendazac is a non-steroidal anti-inflammatory agent, and it is marketed exclusively for the treatment of cataracts. We report two cases of possible hepatotoxicity due to the use of bendazac lysine. METHODS: Laboratory tests, serologic tests, abdominal sonography and scan were performed to study liver disease. RESULTS: Reversible increases of the hepatic enzymes were found in both cases. Anemia was also found in one of the cases (case 1). CONCLUSIONS: Abnormal liver test results could be related to a possible liver injury attributed to the use of bendazac lysine.

Low protein concentration in cirrhotic ascites is related to low ascitic concentrations of immunoglobulins G and A.

OBJECTIVE: To analyse the differences in ascitic and serum levels of immunoglobulins and albumin between two groups of cirrhotic patients (with ascitic total protein levels higher and lower than 10 g/l). DESIGN: A prospective study. PATIENTS AND METHODS: We studied 39 cirrhotic patients with sterile ascites. The patients were classified into two groups: group A (18 patients) comprised those with an ascitic total protein level less than 10 g/l and group B (21 patients) those with an ascitic total protein level higher than 10 g/l. Ascitic and serum levels of albumin and immunoglobins G, A and M were analysed. RESULTS: Ascitic immunoglobulin G and A levels in group B were higher than ascitic immunoglobulin G and A levels in group A. Ascitic levels of these immunoglobulins correlated linearly with ascitic total protein levels. The serum levels of immunoglobulins G and A in groups A and B were not significantly different. Ascitic and serum immunoglobulin M concentrations in the two groups were similar. Transfer of immunoglobulins G and A and albumin from plasma to ascites seemed to be similar in group B. Transfer of immunoglobulins G and A seemed to be impaired in group A. Differences in ascitic immunoglobulin levels between groups A and B were also observed in the presence of diuretic treatment. Differences in ascitic immunoglobulin levels were related to the Child-Pugh score. CONCLUSION: Patients with a low ascitic total protein level show low ascitic immunoglobulin G and A concentrations. The low ascitic immunoglobulin G and A levels could be related to an impairment in the transfer of these immunoglobulins from plasma in those patients who have poor liver function. Ascitic immunoglobulin M is not related to ascitic total protein, and its origin is not clear. The putative transfer of immunoglobulin M to the peritoneal cavity is not related to the mechanism of transfer of albumin or of immunoglobulins G and A from serum. The physiological significance of ascitic immunoglobulin M is unclear.