Siegfried R. Erb

Fatal reactivation of hepatitis B post-chemotherapy for lymphoma in a hepatitis B surface antigen-negative, hepatitis B core antibody-positive patient: Potential implications for future prophylaxis recommendations

In the absence of prophylaxis, the reactivation of hepatitis B in oncology patients who are hepatitis B carriers is a well-known and often fatal complication of chemotherapy. The current recommendations in Canada and the USA are that patients who are positive for hepatitis B surface antigen (HBsAg) receive antiviral prophylaxis prior to chemotherapy. We report a 67-year-old man with B-cell lymphoma who developed hepatitis B reactivation following chemotherapy with cyclophosphamide, adriamycin, vincristine, prednisone and rituximab. Pre-chemotherapy, the patient was negative for HBsAg, positive for hepatitis B core antibody (anti-HBc) and weakly positive for hepatitis B surface antibody. Despite treatment with lamivudine, the patient died of fulminant hepatic failure. Our experience indicates that patients who are negative for HBsAg but positive for anti-HBc are still at risk for reactivation of latent hepatitis B during and after chemotherapy and may be considered for prophylaxis.

Predictors of relapse to significant alcohol drinking after liver transplantation

BACKGROUND End-stage alcoholic liver disease is common, with many of these patients referred for liver transplantation (LT). Alcohol relapse after LT can have detrimental outcomes such as graft loss and can contribute to a negative public perception of LT. OBJECTIVE To identify factors that predict the recurrence of harmful alcohol consumption after LT. METHODS A total of 80 patients who underwent LT for alcoholic cirrhosis or had significant alcohol consumption in association with another primary liver disease, from July 1992 to June 2006 in British Columbia, were retrospectively evaluated by chart review. Several demographic-, psychosocial- and addiction-related variables were studied. Univariate and multivariate logistic regression analyses were used to test possible associations among the variables studied and a return to harmful drinking after LT. RESULTS The relapse rate of harmful alcohol consumption post-liver transplant was 10%, with two patient deaths occurring directly as a result of alcohol relapse. Univariate analysis revealed relapse was significantly associated with pretransplant abstinence of less than six months (P=0.003), presence of psychiatric comorbidities (P=0.016), female sex (P=0.019) and increased personal stressors (P=0.044), while age at transplant of younger than 50 years approached significance (P=0.054). Multivariate logistic regression analysis revealed the following independent factors for relapse: pretransplant abstinence of less than six months (OR 77.07; standard error 1.743; P=0.013) and female sex (OR 18.80; standard error 1.451; P=0.043). CONCLUSION The findings of the present study strongly support a required minimum of six months of abstinence before LT because duration of abstinence was found to be the strongest predictor of recidivism. Female sex, younger age at transplant and psychiatric comorbidities were also associated with relapse to harmful drinking.

Drug Interactions With Direct-Acting Antivirals for Hepatitis C: Implications for HIV and Transplant Patients

Objective: Review pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C (HCV) infection and interactions with concomitant immunosuppressant and antiretroviral therapies (ART). Data Sources: MEDLINE (1948-January 2015), EMBASE (1964-January 2015), International Pharmaceutical Abstracts (1970-January 2015), Google, and Google Scholar were searched combining the terms simeprevir, sofosbuvir, ledipasvir, daclatasvir, paritaprevir, ABT-450, ombitasvir, dasabuvir, pharmacokinetics, drug interaction, drug metabolism, HIV, antiretroviral, immunosuppressant, transplant. Articles, conference proceedings, abstracts, and product monographs were reviewed. Study Selection and Data Extraction: Literature on pharmacokinetic or pharmacodynamic interactions with DAAs and immunosuppressants or ART was considered for inclusion. Pertinent information was extracted and summarized in the review. In the absence of data, pharmacokinetic and pharmacodynamic principles were used to predict the likelihood of interactions. Data Synthesis: DAA pharmacokinetics are reviewed and drug interaction data are presented with provision of management strategies. Fixed-dose combination paritaprevir/ritonavir/ombitasvir plus dasabuvir is most susceptible to drug interactions with immunosuppressants and ART mainly due to the influence of ritonavir on multiple enzymes. Simeprevir is also prone to drug interactions because of cytochrome P450(CYP) 3A4, CYP1A2, P-glycoprotein, and OATP1 involvement and is not recommended for use in combination with several HIV antiretrovirals (ARVs). Close therapeutic drug monitoring of calcineurin inhibitors is required with concomitant simeprevir. Few clinically significant interactions are expected with sofosbuvir or ledipasvir. Limited data suggest that daclatasvir may be coadministered with immunosuppressants but requires dose adjustments with certain ARVs. Conclusions: None of the DAAs are completely free of drug interactions. Awareness and management of drug interactions is critical to optimize outcomes and minimize adverse effects in these patient populations.

Case report: multiple hepatic and pulmonary haemangioblastomas--a new manifestation of von Hippel-Lindau disease.

Capillary haemangioblastomas rarely occur outside the central nervous system and have not been described previously in the lung or liver. We describe such lesions developing in a patient with von Hippel-Lindau complex who previously had cerebellar and spinal haemangioblastomas resected.

Postliver transplant allograft reinfection with a lamivudine-resistant strain of hepatitis B virus: Long term follow-up

Lamivudine is a nucleoside analogue with efficacy in the suppression of hepatitis B viral (HBV) replication. In a previously reported study, lamivudine was administered to patients with chronic, actively replicating HBV infection who subsequently underwent liver transplantation. Patients became serum HBV DNA-negative in response to lamivudine before transplantation, which was continued in the post-transplant period. Two of four patients surviving the immediate postoperative period developed allograft reinfection 240 and 409 days post-transplant. The strain of the reinfecting virus was analyzed, and a mutation in the YMDD region of the viral polymerase conferring resistance to lamivudine was discovered. The long term follow-up of these two patients is reported. The first patient developed ascites 16.5 months after allograft reinfection. A transjugular liver biopsy performed 18 months after the emergence of the lamivudine-resistant strain revealed cirrhosis and lobular hepatitis without rejection. The gradient between hepatic vein wedged and free pressures was 13 mmHg, consistent with portal hypertension. The second patient, 16 months after allograft reinfection with the lamivudine-resistant strain, is without clinical evidence of portal hypertension, although liver enzymes remain elevated. Both patients were given a trial of famciclovir, which did not significantly suppress HBV viremia. In conclusion, lamivudine-resistant HBV strains with the YMDD mutation may have an aggressive clinical course with rapid progression to cirrhosis. Famciclovir did not appear to be an effective rescue agent in these two patients.

A review of direct-acting antivirals for the treatment of hepatitis C in patients with advanced chronic kidney disease

Historically, standard treatment of hepatitis C virus (HCV) infection in patients with renal impairment has been limited by low cure rates and poor tolerability. The introduction of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV with impressive cure rates >90% and low rates of adverse events. Despite these major advancements, treatment of patients with HCV and advanced chronic kidney disease (CKD) is a major challenge due to the lack of efficacy and safety data in this patient population. The purpose of this review is to summarize the available data for efficacy and safety of the following DAAs in treating HCV patients with advanced Stage 4 and 5 CKD: simeprevir, sofosbuvir, ledipasvir, ombitasvir, paritaprevir, dasabuvir, grazoprevir, elbasvir and daclatasvir.

Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence

Abstract:  Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post‐transplant HBIG delivery. We report our experience of a 60‐yr‐old man for whom liver transplantation was performed for chronic HBV. HBIG was administered intramuscularly during the anhepatic phase of surgery. The finding of a portal vein thrombosis requiring repeated thrombectomy necessitated chronic anticoagulation. Post‐operatively, HBIG was administered subcutaneously, in four separate injections, for a daily dose of 2170 IU along with continued lamivudine dosing. Hepatitis B surface antibody (anti‐HBs) titres reached a serum concentration of >500 IU/L by seven d post‐transplant and approximately 1000 IU/L by nine d post‐transplant. Five months post‐transplant, with continued combination of subcutaneous HBIG and lamivudine, there has been no recurrent HBV infection and anti‐HBs titres have been at target levels. Our experience suggests that subcutaneous delivery of HBIG may be a feasible consideration when intramuscular/intravenous dosing is not possible.

Indications for liver transplantation in British Columbia's Aboriginal population: a 10-year retrospective analysis.

OBJECTIVES To study the indications for liver transplantation among British Columbias First Nation population. MATERIALS AND METHODS A retrospective analysis of the British Columbia Transplant Societys database of Aboriginal and non-Aboriginal liver transplant recipients from 1989 to 1998 was undertaken. For primary biliary cirrhosis (PBC), the transplant assessment database (patients with and without transplants) was analyzed using a binomial distribution and compared with published census data regarding British Columbias proportion of Aboriginal people. RESULTS Between 1989 and 1998, 203 transplantations were performed in 189 recipients. Fifteen recipients were Aboriginal (n=15; 7.9%). Among all recipients, the four most frequent indications for liver transplantation were hepatitis C virus (HCV) infection (n=57; 30.2%), PBC (n=34; 18.0%), alcohol (n=22; 11.6%) and autoimmune hepatitis (n=14; 7.4%). Indications for liver transplantation among Aboriginal people were PBC (n=8; 53.3%; P<0.001 compared with non-Aboriginal people), autoimmune hepatitis (n=4; 26.67%; P=0.017), acute failure (n=2; 13.3%) and HCV (n=1). Among all patients referred for liver transplantation with PBC (n=43), 29 (67.44%) were white and 11 (25.6%) were Aboriginal. A significant difference was found between the proportion of Aboriginal people referred for liver transplantation and the proportion of Aboriginal people in British Columbia (139,655 of 3,698,755 [3.8%]; 1996 Census, Statistics Canada) (P<0.001). CONCLUSIONS Aboriginal people in British Columbia are more likely to be referred for liver transplantation with a diagnosis of PBC but are less likely to receive a liver transplant because of HCV or alcohol than are non-Aboriginal people.

Post-surgical shunt hepatopulmonary syndrome in a case of non-cirrhotic portal hypertension: lack of efficacy of shunt reversal.

Hepatopulmonary syndrome, a consequence of significant liver disease and portal hypertension, is thought to be secondary to the effects of vasoactive substances, normally inactivated in the liver, on the pulmonary vasculature. We report a patient with preserved hepatic function who underwent a decompressive surgical porto-systemic shunt for non-cirrhotic portal hypertension. This patient developed hepatopulmonary syndrome with dyspnoea and oxygen desaturation 2 years post-surgical shunt. Over the next 7 years, the patients respiratory function became increasingly impaired although hepatic function remained preserved. Because of the hypothesized role of porto-systemic shunting in the aetiology of this syndrome, the surgical shunt was successfully reversed angiographically. No improvement in dyspnoea or oxygen saturation occurred and liver transplantation was undertaken. Six months post-transplant, the patient has decreased his oxygen requirements and is free of dyspnoea. Our experience supports the causal role of porto-systemic shunting in the pathogenesis of hepatopulmonary syndrome but suggests that merely decreasing the extent of porto-systemic shunting is not beneficial. Liver transplantation remains the only reliable therapeutic modality available to these patients.

CASE REPORT: Post-Liver Transplant Crohn's Disease: Graft Tolerance but Not Self-Tolerance?

Inflammatory bowel disease (IBD) rarely occurs de novo after liver transplantation, and when it does usually presents as ulcerative colitis in patients transplanted for primary sclerosing cholangitis. We present two patients who developed de novo Crohns colitis two and three years after liver transplant for primary biliary cirrhosis (PBC) and chronic hepatitis B infection, respectively. Both were on maintenance immunosuppression with a calcineurin inhibitor and azathioprine with no evidence of allograft rejection. Investigations for enteric and opportunistic infection were negative. In the nontransplant setting, the development of IBD is likely multifactorial with an immune origin. In our cases, the immunosuppression was titrated to minimal levels when IBD developed. Clearly, although a significant degree of allograft tolerance can occur, autoimmune diseases can still develop elsewhere, suggesting selective immune tolerance.