Tami Daugherty

Sofosbuvir and simeprevir combination therapy in the setting of liver transplantation and hemodialysis

We report safety, tolerability, and 12‐week sustained virologic response with half‐standard dose sofosbuvir and standard‐dose simeprevir combination therapy in a hepatitis C virus genotype 1a‐infected liver transplant recipient on hemodialysis – uncharted territory for sofosbuvir‐based therapy. The patient was a non‐responder to prior treatment with pegylated interferon plus ribavirin. Sofosbuvir efficacy was maintained despite pill‐splitting and administration of half‐standard dose, 200 mg per day. No drug–drug interactions were noted with tacrolimus‐based immunosuppression. Laboratory tests remained stable or improved during therapy. Our observation, if reproduced in a larger study, may lead to significant improvement in clinical outcomes and cost savings in this patient population.

The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.

The pathologic liver changes in chronic heart failure have been characterized mostly based on autopsy series and include sinusoidal dilation and congestion progressing to pericellular fibrosis, bridging fibrosis, and ultimately to cardiac cirrhosis or sclerosis. Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes. We report the pathologic and clinical findings in liver explants from six patients who underwent combined heart–liver transplantation. We also report preoperative liver biopsy findings from 21 patients who underwent heart transplantation without simultaneous liver transplantation. We staged the changes related to chronic passive congestion as follows: stage 0—no fibrosis; stage I—pericellular fibrosis; stage II—bridging fibrosis; and stage III—regenerative nodules. Nineteen biopsies showed fibrosis with bridging fibrosis in 13 and regenerative nodules in 6. Fifteen patients were alive at 1 year post transplant. Only three patients had a post-operative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these patients all showed at least stage II fibrosis. These patients survived for 3, 6, and 10 months after cardiac transplant. The presence of bridging fibrosis was not significantly associated with post-operative survival (P=0.336) or post-operative liver failure (P=0.257). We conclude that patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation. Because the pattern of fibrosis due to passive congestion is highly variable throughout the liver, a diagnosis of cirrhosis, which implies fibrosis and regenerative nodules throughout the liver, should be made with great caution on biopsy.

Incidence of hepatocellular carcinoma among US patients with cirrhosis of viral or nonviral etiologies.

BACKGROUND & AIMS We aimed to identify risk factors for hepatocellular carcinoma (HCC) in patients with cirrhosis in the United States. We performed a prospective study to identify associations between etiologies of cirrhosis and ethnicity with HCC incidence. METHODS We used convenience sampling to select a cohort of 379 patients with cirrhosis who visited the liver clinic at the Stanford University Medical Center from 2001 to 2009 (65% male, 75% white or Hispanic, and 20% Asian). Study end points were HCC diagnosis by histology or noninvasive criteria, liver transplantation, or last screening without HCC. Patients were followed up, with ultrasound or computed tomographic imaging analyses and measurements of serum levels of α-fetoprotein, approximately every 6 months, for a median time of 34 months (range, 6-99 mo). RESULTS The etiologies of cirrhosis in the cohort were 68% hepatitis C, 7% hepatitis B, and 25% nonviral. Forty-four patients (12%) were diagnosed with HCC during the follow-up period. Patients with cirrhosis related to viral hepatitis had a statistically significantly higher incidence of HCC than those with nonviral diseases in Kaplan-Meier analysis (P = .04). There was no statistically significant difference in HCC incidence between Asian and non-Asian patients. In a multivariate Cox proportional hazards model that included age, sex, ethnicity, etiology, and Child-Pugh-Turcotte score, viral cirrhosis was associated significantly with HCC, compared with nonviral cirrhosis (hazard ratio, 3.6; 95% confidence interval, 1.3-10.1; P = .02) but Asian ethnicity was not. CONCLUSIONS In a diverse cohort of patients in the United States with cirrhosis, a viral etiology of cirrhosis was associated with increased incidence of HCC, but Asian ethnicity was not. These findings indicate the importance of cirrhosis etiology in determining risk for HCC.

Mutations in HBV DNA Polymerase Associated With Nucleos(t)ide Resistance Are Rare in Treatment-naive Patients

BACKGROUND & AIMS Prior studies have detected hepatitis B virus (HBV) DNA polymerase mutations in treatment-naive patients. However, most of these studies used either direct polymerase chain reaction sequencing, which detects these mutations with low levels of sensitivity, or patient cohorts that were not well-characterized. We investigated the prevalence of HBV mutations in DNA polymerase by using a line probe assay. METHODS In a prospective, cross-sectional study, we enrolled 198 treatment-naive patients with chronic hepatitis B (52.5% male; mean age, 41 years) from February 2009 to May 2011 from 3 gastroenterology and liver clinics in Northern California. Exclusion criteria included infection with hepatitis C or D viruses or human immunodeficiency virus. All patients completed a questionnaire (to determine demographics, history of liver disease, prior treatments, family medical history, drug and alcohol use, and environmental risk factors for hepatitis) that was administered by a research coordinator; mutations in HBV DNA polymerase were detected by using the INNO-LiPA HBV DR v.3 assay. RESULTS Most patients were Vietnamese (48.5%) or Chinese (36.4%) and were infected with HBV genotypes B (67.5%) or C (24.2%). Mutations in HBV DNA polymerase were found in 2 patients (1%), rtI233V (n = 1) and rtM250M/L (n = 1). CONCLUSIONS In a multicenter prospective study of treatment-naive patients with chronic hepatitis B, we detected mutations in HBV DNA polymerase in only 1%. Because of the low prevalence of these mutations and the uncertain clinical significance of such quasispecies, routine HBV DNA polymerase mutation analysis cannot be recommended before initiation of antiviral therapy for treatment-naive patients with chronic hepatitis B. The analysis requires further molecular and clinical studies.

Prospective study of risk factors for hepatitis C virus acquisition by Caucasian, Hispanic, and Asian American patients

Summary.  Commonly known risk factors for infection with hepatitis C virus (HCV) include blood transfusion, injection drug use, intranasal cocaine use, and body tattoos. We hypothesized that Asian Americans infected with HCV may not identify with these established risk factors present in Caucasians and Hispanics, and our aim was to conduct a survey of risk factors in HCV‐infected patients in these ethnic groups. In this prospective study, 494 patients infected with HCV completed a detailed risk assessment questionnaire at a liver centre in Northern California from 2001 to 2008. Among subjects participating in this study, 55% identified themselves as Caucasian, 20% as Hispanic, and 25% as Asian. Asian Americans were older, less likely to smoke or consume alcohol, and have a family history of cancer compared with Caucasians and Hispanics. The laboratory profiles were similar, and genotype 1 was the most common infection in all groups (74–75%). The great majority of Caucasians (94%) and Hispanics (86%) identified with commonly known risk factors, which was in contrast to 67% of Asians (P < 0.0001). The most common risk factors in Asians were blood transfusions (50%) and acupuncture (50%). Furthermore, 74% of Caucasians and 66% of Hispanics identified more than one major risk factor, while only 20% of Asians reported having more than one risk factor (P < 0.0001). Survey for established risk factors for acquisition of HCV may be more appropriate for risk assessment of Caucasians and Hispanics, but not for Asian Americans. These findings may guide the development of HCV screening in our increasingly diverse population.

Real-world experience with interferon-free, direct acting antiviral therapies in Asian Americans with chronic hepatitis C and advanced liver disease.

Abstract Real-life data on interferon (IFN)-free direct acting antiviral (DAA) therapies for chronic hepatitis C (CHC) is limited for Asian Americans. To evaluate sustained virologic response (SVR) and adverse events (AE) in Asian Americans treated with sofosbuvir (SOF)-based, IFN-free DAA therapies. This is a retrospective study of 110 consecutive Asian Americans with HCV genotypes 1 to 3 or 6 treated with IFN-free SOF-based regimens for 8 to 24 weeks between February 2014 and March 2016 at a university center in Northern California. Mean age was 63 ± 12 years, mean BMI was 25 ± 6 (kg/m2), and about half (52%) were male. Most patients were infected with HCV genotype 1 (HCV-1, 64%), followed by HCV-2 (14%), HCV-6 (13%), and HCV-3 (8%). Half had cirrhosis, and the majority of these (67%) had decompensation. Overall SVR12 was 93% (102/110), and highest among patients without cirrhosis, liver transplant, or HCC (100%, 37/37). SVR12 was lower among patients with HCC (82%, 14/17), decompensated cirrhosis (84%, 31/37), or liver transplant (89%, 17/19), regardless of treatment and genotype. Most common AEs were anemia (25%), fatigue (20%), and headache (12%). Anemia was highest in patients receiving SOF/RBV (67%). There was 1 treatment-unrelated serious adverse effect (SAE). There were 7 dose reductions due to anemia or fatigue from RBV and 2 treatment discontinuations due to fatigue or loss of insurance authorization. This real-life cohort of Asian American CHC patients treated with IFN-free SOF-based therapies showed high overall treatment response and good tolerability, despite very high rates of advanced disease and prior treatment failure.

Both HCV and HBV are Major Causes of Liver Cancer in Southeast Asians

The incidence of hepatocellular carcinoma (HCC) is higher in Asian Americans than in other ethnicities. While hepatitis B virus (HBV) is common, hepatitis C virus (HCV) is more prevalent in some subgroups. Our goal was to determine the etiology of liver disease associated with HCC in subgroups of Asian Americans. This was an analysis of 510 Asian HCC patients at a US medical center. Patients were identified using ICD9 diagnosis. Multivariate logistic regression was used to study predictors of HCV as the cause of HCC. Patients were Southeast Asian, Chinese, and Korean, with similar gender, age, and foreign-born status. Southeast Asians had a similar proportion of HBV- and HCV-related HCC, while Chinese and Korean patients had a higher proportion of HBV-related HCC. HCC was usually associated with HBV in Chinese and Korean patients, but both HCV and HBV were important associations in Southeast Asians.

Recurrent Pyogenic Cholangitis

A 38-year-old Vietnamese male was admitted to Stanford Hospital in December 2008 for management of worsening right upper quadrant and flank pain. He first developed symptoms of epigastric and right upper quadrant pain at 14 years of age while living in Vietnam, and was diagnosed with peptic ulcer disease. After immigrating to the United States at 19 years of age, he continued to experience abdominal pain and underwent cholecystectomy for treatment of presumed symptomatic cholelithiasis. Continued attacks of abdominal pain, fever, and jaundice ultimately led to the diagnosis of recurrent pyogenic cholangitis, and he underwent a Roux-en-Y hepatico-jejunostomy. Over the next ten years, he was hospitalized multiple times for repeated episodes of cholangitis with the subsequent development of left-sided intrahepatic biliary strictures. In 2004 a metal stent was placed in his left main intrahepatic duct to treat a dominant stricture. Several months later, he developed an obstruction of the stent that could not be managed with medical therapy, and underwent a left hepatic lobe resection with revision of the hepaticojejunostomy. His postoperative course was complicated and resulted in a four-month hospitalization. He remained relatively asymptomatic until 2007, when evaluation of another episode of cholangitis revealed the interim development of right-sided intrahepatic strictures and intrahepatic stones (Fig. 1). Interventional radiologists extracted the stones and placed an internal-external biliary drain. A subsequent computed tomography (CT) scan suggested cirrhosis and portal hypertension. Upper endoscopy was performed and revealed grade 1 non-bleeding esophageal varices and mild portal hypertensive gastropathy. The patient was then referred to Stanford for evaluation for liver transplantation for presumed secondary biliary cirrhosis. Over the ensuing two years, he was hospitalized multiple times for continued episodes of cholangitis and sepsis complicated by resistant organisms, including vancomycin-resistant enterococcus. He was managed with intravenous antibiotics and percutaneous transhepatic catheter drainages and stone extractions. After a symptom-free period of several months, a transhepatic cholangiogram in October 2008 revealed no obstruction or stones, and the external biliary drain was removed. Two months later in December 2008, the patient returned to Stanford with worsening right upper quadrant and flank pain. Physical examination revealed marked tenderness in the right upper quadrant. A CT scan of the abdomen and pelvis demonstrated a 3 9 2 cm lowattenuation lesion in the posterior right hepatic lobe suggesting the presence of an evolving hepatic abscess (Fig. 2). Interventional radiology determined that the lesion was too small to drain percutaneously, and the patient was treated with intravenous ceftriaxone for six weeks. A follow-up CT scan demonstrated resolution of the abscess, and the patient is currently awaiting liver transplantation.

Effectiveness and tolerability of simeprevir and sofosbuvir in nontransplant and post-liver transplant patients with hepatitis C genotype 1.

Hepatitis C virus genotype 1a (HCV‐1a), prior treatment, cirrhosis and post‐transplant status are historically associated with poor treatment responses. The new oral direct‐acting agents appear to be effective and safe in these patients.

Acute liver failure at 26 weeks' gestation in a patient with sickle cell disease

Orthotopic liver transplantation (OLT) for acute liver failure (ALF) during pregnancy is an uncommon occurrence with variable outcomes. In pregnancy‐related liver failure, prompt diagnosis and immediate delivery are essential for a reversal of the underlying process and for maternal and fetal survival. In rare cases, the reason for ALF during pregnancy is either unknown or irreversible, and thus OLT may be necessary. This case demonstrates the development of cryptogenic ALF during the 26th week of pregnancy in a woman with sickle cell disease. She underwent successful cesarean delivery of a healthy male fetus at 27 weeks with concurrent OLT. This report provides a literature review of OLT in pregnancy and examines the common causes of ALF in the pregnant patient. On the basis of the management and outcome of our case and the literature review, we present an algorithm for the suggested management of ALF in pregnancy. Liver Transpl 15:1236–1241, 2009.