Kalyan R. Bhamidimarri

An Algorithm for Risk Assessment and Intervention of Mother to Child Transmission of Hepatitis B Virus

BACKGROUND & AIMS Despite immunoprophylaxis, mother to child transmission (MTCT) of hepatitis B virus (HBV) still occurs in infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We analyzed methods of risk assessment and interventions for MTCT. METHODS We reviewed 63 articles and abstracts published from 1975-2011 that were relevant to MTCT; articles were identified using the PubMed bibliographic database. RESULTS Administration of HB immunoglobulin and HB vaccine to infants at birth (within 12 hours), followed by 2 additional doses of vaccines within 6-12 months, prevented approximately 95% of HBV transmission from HBsAg-positive mothers to their infants. However, HBV was still transmitted from 8%-30% of mothers with high levels of viremia. It is important to assess the risk for MTCT and identify mothers who are the best candidates for intervention. The most important risk factor is maternal level of HBV DNA >200,000 IU (10(6) copies)/mL; other factors include a positive test result for the HB e antigen, pregnancy complications such as threatened preterm labor or prolonged labor, and failure of immunoprophylaxis in prior children. Antiviral therapy during late stages of pregnancy is the most effective method to reduce transmission from mothers with high levels of viremia, but elective cesarean section might also be effective. Antepartum administration of HB immunoglobulin, giving infants a double dose of HB vaccine, or avoiding breastfeeding had no impact on MTCT. CONCLUSIONS HBsAg-positive mothers should be assessed for risk of MTCT, and infants should receive immunoprophylaxis. Pregnant women with levels of HBV DNA >200,000 IU/mL should be considered for strategies to reduce the risk for MTCT. We propose an algorithm for risk assessment and patient management that is based on a review of the literature and the opinion of a panel of physicians with expertise in preventing MTCT.

Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients

Recurrent hepatitis C virus (HCV) infection occurs universally in the allograft in the absence of effective antiviral therapy before liver transplantation (LT). Antiviral therapy with sofosbuvir and simeprevir has proven to be highly effective and well tolerated in the nontransplant setting for treatment of HCV genotype 1 infection; therefore, we sought to evaluate the efficacy and safety of this regimen in LT recipients with recurrent HCV infection. This was a retrospective analysis of a single‐center treatment protocol of patients with HCV genotype 1 infection who received a 12‐week combination regimen of sofosbuvir and simeprevir. Sixty‐one patients (35 with genotype 1a and 26 with genotype 1b) completed treatment with simeprevir and sofosbuvir. Three patients received additional ribavirin. Laboratory data and clinical assessments performed at the baseline, on treatment, at the end of treatment, and 12 weeks after the completion of antiviral therapy [sustained virological response at 12 weeks (SVR12)] were analyzed. The median time after LT was 5.4 years [interquartile range (IQR), 1.9‐8.4 years], and tacrolimus was the most commonly used immunosuppressive agent (80.3%). Overall, SVR12 was achieved in 93.4% [95% confidence interval (CI), 84%‐97%] of LT recipients treated with 12 weeks of sofosbuvir and simeprevir. When they were analyzed according to the HCV subtype, LT recipients with genotype 1b had a 100% SVR12 rate (95% CI, 87%‐100%), whereas SVR12 was 89% (95% CI, 74%‐95%) for those with genotype 1a. Advanced fibrosis (METAVIR F3‐F4) was associated with diminished antiviral efficacy in LT recipients with genotype 1a [SVR12, 67% (95% CI, 39%‐86%); P = 0.01]. Overall, the incidence of adverse events (AEs) was low, and no severe AEs occurred during treatment. In conclusion, treatment with a 12‐week regimen of sofosbuvir and simeprevir was well tolerated and resulted in a high SVR12 rate for LT recipients with recurrent HCV genotype 1 infection. Genotype 1a patients with advanced fibrosis of the allograft were more likely to relapse. Liver Transpl 21:823‐830, 2015.

Transplantation of kidneys from hepatitis C-positive donors into hepatitis C virus-infected recipients followed by early initiation of direct acting antiviral therapy: A single-center retrospective study

The availability of direct acting antiviral agents (DAA) has transformed the treatment of hepatitis C virus (HCV) infection. The current study is a case series that reports the outcomes from a cohort of twenty‐five HCV‐infected ESRD patients who received a kidney from an anti‐HCV‐positive deceased organ donor followed by treatment with DAAs in the early post‐transplant period. Time to transplantation and the efficacy of DAA therapy as measured by sustained viral response at 12 weeks were assessed. The median waiting time from original date of activation on the United Network Organ Sharing (UNOS) waiting list until transplantation was 427 days; however, the median time from entering the patient into UNetsm for a HCV‐positive offer until transplantation was only 58 days. The 25 patients were started on antiviral treatment early post‐transplant (median 125 days) and 24 of 25 (96%) achieved a sustained virologic response at 12 weeks. Tacrolimus dose adjustments were required during antiviral treatment in 13 patients to maintain therapeutic levels. Accepting a kidney from an anti‐HCV‐positive deceased donor shortened the waiting time for HCV‐infected kidney transplant candidates. We recommend that kidneys from anti‐HCV‐positive donors should be considered for transplant into HCV‐infected recipients followed by early post‐transplant treatment with DAA agents.

Drug-Induced Cholestasis

Drug-induced cholestasis manifests as an acute self-limiting injury or as a chronic perpetuating injury, resulting in duct loss and cirrhosis. The number of drugs implicated in drug-induced cholestasis grows every year as new drugs are developed and approved. Other agents such as herbals, nutritional supplements, and complementary and alternative medicines are also reported to cause cholestatic liver injury. Recent literature on molecular transporters involved in bile transport has improved our understanding of patterns of drug-induced liver injury and the mechanisms of cholestasis. This article summarizes the probable offending drugs, and the diagnosis and management of drug-induced cholestasis.

Hispanics With Primary Biliary Cirrhosis Are More Likely to Have Features of Autoimmune Hepatitis and Reduced Response to Ursodeoxycholic Acid Than Non-Hispanics

BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is a cholestatic disease that predominantly affects middle-aged Caucasian women. Studies have suggested that PBC has a more aggressive course in individuals of Hispanic ancestry. We investigated the clinical presentation and progression of PBC in an ethnically diverse population. METHODS We performed a cross-sectional study, analyzing data from Hispanic (n = 70) and non-Hispanic patients (n = 134) with PBC seen at the University of Miami/Jackson Memorial Hospital from January 1, 2000, through December 31, 2011. We compared demographics, clinical presentation, response to therapy, and outcomes between the groups. RESULTS Age at diagnosis, antimitochondrial antibody positivity, frequency of advanced histologic stage, use and dose of ursodeoxycholic acid (UDCA), and the presence of pruritus or fatigue were similar between groups. Hypothyroidism was less frequent among Hispanics (16% vs 29% in non-Hispanics; P = .04). Hispanic subjects were more likely to have overlap syndrome of PBC and autoimmune hepatitis than non-Hispanics (31% vs 13%; P = .002). After a median follow-up period of 3.65 years, a greater percentage of Hispanics had ascites (24% vs 12%; P = .03) and variceal bleeding (20% vs 7%; P = .01), although there were no differences in the number of deaths or liver transplants. Of 204 total patients, 180 received UDCA for at least 1 year. A lower proportion of Hispanic patients had a biochemical response to treatment (60% vs 88%; P < .0001). Independent predictors of poor biochemical response were younger age at diagnosis and Hispanic ethnicity. CONCLUSIONS In a cross-sectional study, patients of Hispanic ethnicity with PBC had an increased prevalence of overlap syndrome, reduced response to UDCA treatment, and more frequent complications of portal hypertension than non-Hispanic patients.

Liver Transplant for Cholestatic Liver Diseases

Cholestatic liver diseases include a group of diverse disorders with different epidemiology, pathophysiology, clinical course, and prognosis. Despite significant advances in the clinical care of patients with cholestatic liver diseases, liver transplant (LT) remains the only definitive therapy for end-stage liver disease, regardless of the underlying cause. As per the United Network for Organ Sharing database, the rate of cadaveric LT for cholestatic liver disease was 18% in 1991, 10% in 2000, and 7.8% in 2008. This review summarizes the available evidence on various common and rare cholestatic liver diseases, disease-specific issues, and pertinent aspects of LT.

Multivisceral Transplantation : Where Do We Stand?

Intestinal transplantation is the definitive therapy for patients with irreversible intestinal failure and can be combined with transplantation of other abdominal organs, such as stomach, spleen, and pancreas with or without liver. There is an increasing trend in the volume of intestinal and multivisceral transplantation in the past few decades and there is also increasing trend in patient and graft survival primarily due to improved patient selection, advances in immunosuppression, and improved perioperative management. This review summarizes the various key elements in patient selection, types of grafts, and updates in the perioperative management involved in multivisceral transplantation.

Noninvasive Markers to Assess Liver Fibrosis

Chronic liver disease represents a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depends on the amount and progression of liver fibrosis with time and the risk of development of cirrhosis. Historically, liver biopsy was considered to be the gold standard for the detection of fibrosis. Nevertheless, liver biopsy is an invasive procedure that has limitations in terms of patient acceptance, risk-benefit ratio, cost-effectiveness, and its availability in various geographic regions. Moreover, it is a questionable gold standard due to significant sampling error and intraobserver and interobserver variability. These limitations have led to the development of noninvasive techniques for assessing the presence and the degree of liver fibrosis. This review aims to revise the most recent data from the literature about noninvasive methods useful in the evaluation of liver fibrosis.

Reply: To PMID 25825070.

Recently, Tavio et al. described a distinctive approach to treat hepatitis C virus (HCV) infection in 2 individuals undergoing liver transplantation (LT): initiation of antiviral therapy during the anhepatic phase. During LT, HCV RNA diminishes substantially, with the nadir typically observed from 7 to 24 hours after revascularization of the graft. In part, this is because of the removal of the recipient liver and HCV RNA distribution in the graft, but also, it is because of massive volume shifts and replacement as part of the LT procedure. Continued production of virions after native hepatectomy has been attributed to extrahepatic HCV reservoirs, but this has not been definitively shown. Tavio et al. propose to capitalize on the low levels of HCV RNA during the anhepatic phase by initiating antiviral therapy during this time and possibly be able to avoid de novo infection of the graft. In a previous issue of Liver Transplantation, we presented the sustained virological response (SVR) rates in HCV genotype 1–infected LT recipients treated with 2 direct-acting antivirals (DAAs), sofosbuvir and simeprevir, for 12 weeks. Our treatment protocol at the University of Miami was to wait at least 3 months after LT before starting antiviral therapy, and most of the patients included in our study were years away from LT (median, 5.4 years). Overall, an SVR of 93.4% was achieved. Therapy of pretransplant patients with poorly compensated liver disease (Child-TurcottePugh class C) is still an area of ongoing investigation. In hepatocellular carcinoma, where timing of LT is more reliable, Curry et al. achieved a 96% SVR (25 of 26) in patients receiving sofosbuvir and ribavirin who had been HCV RNA undetectable for at least 30 days before LT. Thus, treatment of medically stable patients both before and after transplant has been shown to have impressive rates of SVR. Despite major improvements in surgical technique, the perioperative period of LT remains a guarded period for the patient. Complications such as delayed graft function and acute renal injury may occur unpredictably, thus the safety of using agents dependent on their function could add unneeded risk to HCV treatment. Additionally, systemic absorption and pharmacokinetics of DAAs are unknown in the immediate post-LT period and early withdrawal or gaps in treatment might potentially create emergent resistance-associated variants, which may ultimately complicate therapy or result in multidrug resistance. Although novel protocols assessing the optimal timing for starting antiviral therapy after LT will continue to emerge, we advocate delaying HCV therapy after LT until the patient’s clinical course has stabilized, at least until well-designed clinical trials demonstrate equivalence or superiority in safety and efficacy of earlier therapeutic approaches.

Clinical Features of Chronic Hepatitis B in Treatment-naive Asian Patients With Positive HBeAg and Coexisting Precore and/or Basal Core Promoter Mutations

Background: Precore or/and basal core promoter (PC/BCP) mutations are frequently detected in hepatitis B e antigen (HBeAg)-negative patients, but little is known about their clinical significance in HBeAg-positive patients. Aim: To characterize and report the clinical features of treatment-naive chronic hepatitis B patients who are HBeAg positive and harbor PC and/or BCP mutations. Patients and Methods: Consecutive treatment-naive patients with chronic hepatitis B between 2004 and 2014 were enrolled. Clinical characteristics were compared based on the stratification of HBeAg status and the presence of PC/BCP mutations. In addition, subset analysis in HBeAg-positive cohort was performed to compare clinical features of patients with and without PC/BCP mutations Results: Of the 267 patients enrolled from 3 centers, 177 were HBeAg positive and 90 HBeAg negative. When compared with HBeAg-negative patients, HBeAg-positive patients were significantly younger in mean age (37.93 vs. 44.40; P<0.001), had higher levels of median ALT (51 vs. 30.5 U/mL; P<0.001), higher levels of mean HBV DNA (7.50±1.48 vs. 5.10±1.44 log10 copies/mL; P<0.001), and lower frequency of detectable PC/BCP mutations (60.45% vs. 93.33%; P<0.001), but had significantly higher frequency of BCP when mutations were detected (37.85% vs. 22.22%; P=0.013). Among HBeAg-positive patients, when compared with patients with wild type, those with PC/BCP mutations were significantly older (30.63 vs. 42.71; P<0.001), had higher median ALT levels (29.5 vs. 73 U/mL; P<0.001), but there was no significant association with mean HBV DNA levels (7.96 vs. 7.20 log10 copies/mL; P=0.865) or HBV genotype (P=1.000). In the multivariate analysis, only age and ALT were independently associated with PC/BCP mutations in HBeAg-positive patients, but there was no association with HBV genotype or DNA. Conclusions: PC/BCP mutants were frequent (up to 60%) in treatment-naive HBeAg-positive patients and were associated with distinct clinical characteristics when compared with patients with wild type or HBeAg negative. Future large studies are needed to substantiate the long-term clinical outcomes when PC/BCP mutations are detected in HBeAg-positive patients as it may impact the natural history or treatment response in such patients.