Toxicity and risks from drug-to-drug interactions of new antivirals for chronic hepatitis C.

The new direct acting antivirals (DAAs), defined as those drugs that are effective in combinations without interferon, have totally changed HCV treatment and probably in few years will also totally change global landscape of advanced liver diseases. The advantage of DAAs is a low-risk/high-benefit ratio. Although overall adverse events during DAAs treatment are limited in frequency and severity, some toxicity issues emerged during the first years of real-life experience with these drugs. Another peculiar characteristic of present DAAs is a high probability of interaction with other "common-use" drugs, such as anti-hypertensive, anti-platelet, antiarrhythmic and cholesterol lowering agents. Above all, special attention should be paid in older patients and in those belonging to special populations, who more frequently require the concomitant use of polytherapy.

Folate in gastrointestinal health and disease.

OBJECTIVE: Folate has heterogeneous functions and is involved in several activities in both animal and human body. It is an important constituent of our organism, and its bioavailability is mainly dependent from the correct function of our gastrointestinal tract. Our aim is to describe what happens to folate homeostasis in gastrointestinal health and disease, analyzing the alterations of folate metabolism in some specific conditions of intestinal and liver impairment. DISCUSSION: Folate absorption and metabolization involve the small intestine and the liver; in conditions of gastrointestinal tract disease (i.e. celiac disease, liver disease) folate function may be compromised with important consequences on the whole organism. Moreover, folate deficiency may produce gastrointestinal alterations too. For this reason, the gastrointestinal tract could be the responsible but also the victim of folate deficiency. CONCLUSIONS: The presence of folate deficiency should always be assessed in patients with a gastrointestinal disease. Further studies are needed to assess the role of folates in gastrointestinal tract diseases and in other gynecologic, neurologic, psychiatric, cardiovascular, ophthalmic and neoplastic diseases. Folates supplementation could be considered, in the future, as an effective complimentary therapy in several pathologic conditions.

Seroconversion of HBsAg in HBeAg positive and HBeAg negative patients with chronic HBV treated with entecavir: a case series.

We report a case series of three HBeAg positive and five HBeAg negative patients (7 males, mean age 50.6 +/- 14.6 years) with chronic HBV infection experiencing seroconversion after treatment with entecavir (0.5 mg/day or 1 mg/day), initiated in 2007. Overall, the mean time to HBsAg clearance was 9.4 +/- 4.5 months. Seroconversion occurred in all patients, after a mean time of 8.0 +/- 3.7 months. In HBeAg negative patients, mean time to HBsAg clearance and to seroconversion were 9.2 +/- 5.9 and 6.8 +/- 4.0 months, respectively. In HBeAg positive patients, mean time to HBsAg clearance and to seroconversion were 9.7 +/- 0.6 months and 10.0 +/- 2.6 months, respectively. In this case series, seroconversion was maintained and was observed both in HBeAg positive patients and in HBeAg negative patients. Therefore, it may be preliminarily suggested that treatment with entecavir could be associated to HBsAg seroconversion in a short period of time, in both HBeAg positive and HBeAg negative HBV patients.

Late development of splenic artery aneurysm after orthotopic liver transplantation: a case report.

Splenic artery aneurysm (SAA) is a rare complication after orthotopic liver transplantation (OLT). Although SAAs are often incidental findings, in some cases they present with signs and symptoms of abdominal mass or intra-abdominal hemorrhage. The diagnosis requires Doppler ultrasound and confirmation with computed tomography, magnetic resonance, or angiography. Endovascular techniques are preferred to surgery for the treatment of most SAAs. A variable interval from 6 days to 11 years has been reported between OLT and the diagnosis of SAA, justifying a lifelong scheduled surveillance of abdominal vessels by ultrasound after OLT. Herein we have reported a case of SAA that developed 16 years after OLT. This pathological condition was totally asymptomatic. Only routine abdominal ultrasound allowed its detection and subsequent successful treatment.

Orthotopic liver transplantation after successful treatment with anti-CD20 monoclonal antibody (rituximab) for severe steroid-resistant autoimmune hemolytic anemia: a case report.

Chronic hepatitis C virus (HCV) infection has been associated with a wide number of immunologic disorders, ranging from clinically silent laboratory abnormalities (eg, autoantibody positivity) to severe systemic diseases (eg, cryoglobulinemic vasculitis). Autoimmune hemolytic anemia (AIHA), due to the production of antibodies against erythrocyte membrane antigens, is an uncommon extrahepatic manifestation in the setting of chronic hepatitis C. Herein we have reported the case of a 57-year-old woman with decompensated HCV-related cirrhosis awaiting orthotopic liver transplantation (OLT) who experienced severe AIHA. After 1 month of treatment with prednisone (1 mg/kg body weight/d), there was no significant amelioration of anemia. Rituximab, an anti-CD20 monoclonal antibody that depletes B-lymphocytes reducing serum immunoglobulins, was initiated (375 mg/m(2) IV, weekly for 4 weeks) with a prompt, sustained increase in hemoglobin. The drug was well tolerated; it did not interfere with the course of the liver disease. Thirty-one months after rituximab therapy with resolution of AIHA, the patient successfully underwent OLT using immunosuppression with tacrolimus and low-dose steroids. The patient was discharged on postoperative day 36. No infectious event occurred in the postoperative period. At 18 months follow-up after OLT, there has been no infectious or hematological event. Our experience supported the safety of rituximab use in patients with advanced HCV-related liver disease before OLT.

Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients.

BACKGROUND: Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis. AIMS: To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients. METHODS: A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 microg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively. RESULTS: Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 (P < 0.01). At treatment week 4, 34 patients had undetectable HCV-RNA, 10 with genotype 1/4 and 24 with genotype 2/3. Of RVR patients, 24 achieved SVR (70.5%), 6 and 18 with genotypes 1 and non-1. At the multivariate analysis, only EVR, genotypes 2 and 3, and adherence to full course and dosage of therapy retained their independent predictive power, with corresponding ORs of 25.5 (95% CI 3.0-217.3), 4.2 (95% CI 1.2-15.3) and 9.1 (95% CI 2.2-38.0), respectively. CONCLUSION: In decompensated cirrhotic patients, anti-viral therapy with current regimens is feasible and associated with an overall SVR rate of 35.1%. Treatment ought to be pursued among patients who attain an EVR, and maintain a full course and dosage of therapy.

Donor risk index and organ patient index as predictors of graft survival after liver transplantation.

In liver transplantation the identification of risk factors and the risk quantification for each single case represent a field of great interest. There are donor-related and recipient-related risk factors. Donor risk index (DRI) was retrospectively calculated in 223 liver transplant cases. We did not include patients with preoperative diagnosis of hepatocarcinoma and retransplants. The cases were stratified into two classes according to the DRI (low risk, DRI<1.7, and high risk, DRI >or= 1.7). A new index, namely the organ patient index (OPI) was calculated adding the Model for End-stage Liver Disease (MELD) score to the DRI. Patients were stratified into two classes according to the OPI (low risk, OPI 2.85). The cases with low DRI (n=144) showed better survival than the cases with high DRI (n=82; P< .02). The cases with low OPI (n=173) showed better survival than cases with high OPI (n=50; P< .01). The OPI predicted outcomes better than DRI, increasing the gap in the long-term graft survival between the low- and the high-risk class. The inclusion of the MELD in the new index allowed better prediction of graft survival.

Treatment of chronic hepatitis C virus infection with pegylated interferon and ribavirin in cirrhotic patients awaiting liver transplantation.

Successful treatment of chronic hepatitis C virus (HCV) infection can prevent reinfection after orthotopic liver transplantation (OLT). Pegylated interferon (PEG-IFN) may ameliorate virological response (VR), making the risk-to-benefit ratio of therapy favorable in waiting list patients. From January 2001 to April 2006, we treated 15 HCV cirrhotics with PEG-IFN alpha-2b (1.5 microg/kg/week) and ribavirin (RIBA; >or=10.6 mg/kg/d). Their mean age was 51.5 years. There were 9 men. In 6 cases the genotype was 1b. With Child-Pugh scores >or=9 (range 9-12) and Model for End-Stage Liver Disease (MELD) scores >or=14 (range, 14-22). Adverse events occurred in all subjects: thrombocytopenia (<40,000/microL) in 8; neutropenia (<700/microL) in 10; anemia (Hb <8.5 g/dL) in 1; grade III hepatic encephalopathy in 2; pelvic infection in 1; variceal hemorrhage in 1; and hepatocellular carcinoma (HCC) recurrence in 1. Adverse events caused treatment withdrawal in 6 (40.0%) and RIBA and/or PEG-IFN dose reduction in 10 (66.6%). Early VR (EVR) was obtained in 9 subjects (60.0%), end-of-treatment (EOT) VR in 7 (46.6%), and sustained VR (SVR) in 3 (20.0%). Three subjects--2 nonresponder and 1 breakthrough--were transplanted at 25, 23, and 16 months after the EOT, respectively. Three subjects died at 6, 8, and 15 months after the EOT due to HCC, spontaneous bacterial peritonitis, and liver failure. Nine patients are awaiting OLT. The risk-to-benefit ratio is against PEG-INF and RIBA treatment of severely decompensated cirrhotics infected with genotype 1 awaiting OLT, but therapy is probably beneficial in genotype 2 subjects, due to an expected SVR rate of more than 40%. However, one must carefully consider the high risk for severe adverse events.

Acute decompensation and absence of brain and kidney dysfunction predict long-term efficacy of plasma exchange in hyper-bilirubinemic cirrhotic patients awaiting liver transplantation.

Various artificial liver support systems are currently used in patients with decompensated chronic liver disease or acute liver failure as a bridge to recovery or to orthotopic liver transplantation (OLT). Between June 2004 and September 2006, 9 subjects were treated with plasma exchange (PE) for acute decompensation on chronic liver disease or chronic decompensation in end-stage liver disease. All of them were awaiting OLT or were listed at the moment of decompensation. Grade II to III hepatic encephalopathy (HE) was present in 4 patients, significant renal dysfunction in 3 patients, and ascites in 6 patients. Baseline serum total bilirubin was 35.1+/-11.2 mg/dL (mean value+/-SD). The patients underwent a mean of 12.1 2-hour exchanges over 1 to 8 weeks. The 3 who recovered were alive after a mean follow-up of 22.7+/-10.3 months. There were 3 patients who underwent transplantation and 3 who died due to liver failure during treatment. Only subjects with acute decompensation and without HE or significant renal dysfunction survived without OLT. PE did not significantly modify the grade of HE or the renal function. PE seemed to be a safe, long-term, effective therapeutic option for acute decompensation among subjects with chronic liver disease without brain or renal dysfunction.

Donor-recipient MELD-based match in a patient who required three liver grafts in the era of nonstandard donors: case report.

In recent studies, nonstandard donors and high Model for End-stage Liver Disease (MELD) values have been indicated as risk factors for both graft survival and patient survival. A recent debate concerns which donor and recipient match guarantees the best results in terms of early and late survival. To emphasize the role of the donor-recipient match, we have reported herein a complex case of a patient who changed his preoperative risk status, being transplanted three times using donors of different risk levels. At each transplant, the patient moved to a higher MELD class: first transplant MELD=22; second transplant MELD=37; third transplant MELD=38. Only at the third transplant did the patient recover. Besides the liver, almost all his organs (kidneys, heart, lungs) recovered in a few weeks, as well. Unfortunately, severe cortical and subcortical brain damage remained a crucial limiting impairment, leading to death 5 months later, due to pulmonary infection, yet with a perfectly working liver. We underlined the role of donor factors to predict the outcome after liver transplantation in the MELD era.

A 5-year prospective study of the late resolution of chronic hepatitis C after antiviral therapy.

BACKGROUND: Persistence of hepatitis C virus (HCV) in serum is assured after any course of antiviral therapy that failed to obtain a sustained virological response. AIM: To evaluate the long-term effect on serum HCV-RNA of a course of pegylated-interferon and ribavirin therapy that was unable to obtain sustained response. METHODS: Serum HCV-RNA was determined at monthly intervals in 68 non-responders, breakthroughs or relapsers and in 52 naïve controls enrolled in a five-year study. RESULTS: Five genotype 2 or 3 patients (one non-responder, three breakthroughs, one relapser) cleared HCV-RNA after the end of therapy or relapse, and remained negative until the end of follow-up. HCV-RNA clearance rate in genotype 2 and 3 non-responders, breakthroughs or relapsers was higher than in controls with the same genotypes (22.7% vs. 0%; log-rank 9.62; P < 0.002). HCV-RNA at the end of treatment or at relapse was <10(5) IU/mL in the five subjects who cleared the virus and <10(4) IU/mL in four of them. None of genotype 1 or 4 subjects cleared HCV-RNA during follow-up. CONCLUSIONS: Late resolution of HCV infection is possible in genotype 2 or 3 patients with low viral load at the end of therapy or at relapse. In these subjects, HCV-RNA monitoring is advisable during the first year after therapy.

[An atypical bone metastasis of hepatocellular carcinoma: case report and review of the literature]. / Una metastasi ossea atipica in corso di epatocarcinoma: descrizione del caso clinico ed analisi della letteratura.

Bone metastases are a quite frequent complication of hepatocellular carcinoma (HCC). They are a substantial fraction (about 14-28%) of the metastatic locations of this neoplasm. Recent studies are indicative of the clinical usefulness of local therapy of HCC bone metastasis, expecially if they are single locations. The presence of a single bone metastasis does not seem to influence short term prognosis of the primary neoplasm and, furthermore, its treatment by radiation, chemio-embolization or surgery may obtain long-term pain control, without the side effects of analgesic drugs. Most frequently, bone metastases of HCC appear in the spine, femur, humerus or ribs. In the last years, some atypical locations, as jaws, gums and skull, were reported. In this paper, we report the case of a painful bone metastasis of HCC, localized at the second phalanx of the second finger of the right hand. To our knowledge, until now only two cases of HCC metastatic location at the bones of the hand have been reported. The lesion has been treated by surgical ablation, obtaining long-term pain remission and the withdrawal of the analgesic drugs. Few weeks later, another bone metastasis appeared, located at the second phalanx of the third finger of the same hand, indicating in this subject a peculiar "metastatic tropism".