Samir Shah

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

Minimal hepatic encephalopathy: Consensus statement of a working party of the Indian National Association for Study of the Liver

Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30–45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health‐related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party.

Steatosis Is an Independent Predictor of Relapse Following Rapid Virologic Response in Patients With HCV Genotype 3

BACKGROUND & AIMS It is recommended that patients with chronic hepatitis C virus (HCV) genotype 3 infections receive 24 weeks of treatment. A rapid virologic response (RVR; at week 4) predicts a sustained virologic response (SVR), although not all patients with an RVR achieve an SVR. We explored the relationships among hepatic steatosis, level of HCV RNA, relapse, and RVR in a phase 3 randomized controlled trial of 932 patients infected with HCV genotype 2 (n = 427) or 3 (n = 505) who received 24 weeks of therapy with interferon-α. METHODS In patients with an RVR (HCV RNA <43 IU/mL), the presence of an SVR was modeled using multivariate logistic regression as a function of age, sex, weight, body mass index, insulin resistance, steatosis, and levels of γ-glutamyl transpeptidase, alanine aminotransferase, liver fibrosis, and baseline HCV RNA. RESULTS RVR, SVR, and relapse rates among patients with HCV genotype 3 were 79.6%, 79.2%, and 15.6%, respectively; corresponding rates among patients with HCV genotype 2 were 86.7%, 84.3%, and 10.1%. An RVR had high predictive value for an SVR in patients with HCV genotypes 2 (88.9%) and 3 (88.1%). The strongest independent predictors of relapse in patients with genotype 3 and an RVR were steatosis (odds ratio 3.0; P = .003) and HCV RNA ≥400,000 IU/mL (odds ratio 2.5; P = .04). Relapse rates in patients with steatosis were 17.4% and 20.9% for low and high baseline levels of HCV RNA, respectively; corresponding rates in those without steatosis were 2.5% and 8.8%. CONCLUSIONS Steatosis was associated with significantly higher rates of relapse, irrespective of viral load, in patients infected with HCV genotype 3 who had an RVR. Further studies are needed to determine if longer treatment durations are effective in patients with an RVR and these risk factors.

Liver Transplantation: East versus West

Liver transplantation (LT) has evolved rapidly since the first successful liver transplant performed in1967. Despite a humble beginning, this procedure gained widespread acceptance in the western world as a suitable option for patients with end stage liver disease (ESLD) by the beginning of the 1980s. At present, approximately 25,000 liver transplants are being performed worldwide every year with approximately 90% one year survival. The techniques of living donor liver transplantation (LDLT) developed in East Asia in the 1990s to overcome the shortage of suitable grafts for children and scarcity of deceased donors. While deceased donor liver transplantation (DDLT) constitutes more than 90% of LT in the western world, in India and other Asian countries, most transplants are LDLT. Despite the initial disparity, outcomes following LDLT in eastern countries have been quite satisfactory when compared to the western programs. The etiologies of liver failure requiring LT vary in different parts of the world. The commonest etiology for acute liver failure (ALF) leading to LT is drugs in the west and acute viral hepatitis in Asia. The most common indication for LT due to ESLD in west is alcoholic cirrhosis and hepatitis C virus (HCV), while hepatitis B virus (HBV) predominates in the east. There is a variation in prognostic models for assessing candidature and prioritizing organ allocation across the world. Model for end-stage liver disease (MELD) is followed in United States and some European centers. Other European countries rely on the Child-Turcotte-Pugh (CTP) score. Some parts of Asia still follow chronological order of listing. The debate regarding the best model for organ allocation is far from over.

Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part I: Status Report of HCV Infection in India

Globally, around 150 million people are infected with hepatitis C virus (HCV). India contributes a large proportion of this HCV burden. The prevalence of HCV infection in India is estimated at between 0.5% and 1.5%. It is higher in the northeastern part, tribal populations and Punjab, areas which may represent HCV hotspots, and is lower in western and eastern parts of the country. The predominant modes of HCV transmission in India are blood transfusion and unsafe therapeutic injections. There is a need for large field studies to better understand HCV epidemiology and identify high-prevalence areas, and to identify and spread awareness about the modes of transmission of this infection in an attempt to prevent disease transmission.

Reversible Parkinsonism and T1W pallidal hyperintensities in acute liver failure

We report on a young woman who survived acute liver failure (ALF) without liver transplant. During the ALF, she developed a disabling, levodopa‐unresponsive, symmetrical Parkinsonism. This was characterized by severe bradykinesia, mild rigidity, mutism, and prominent gait impairment. Magnetic resonance imaging (MRI) showed bilateral T1W pallidal hyperintensities. Parkinsonism and MRI changes remitted in parallel with normalization of hepatic function. We implicate excessive pallidal manganese deposition secondary to ALF in the pathogenesis of this neuroradiological syndrome. Though hitherto unreported, we propose that Parkinsonism with T1W pallidal hyperintensities may not be uncommon in ALF.

Alisporivir plus ribavirin, interferon free or in combination with pegylated interferon, for hepatitis C virus genotype 2 or 3 infection

Alisporivir is a cyclophilin inhibitor with pan‐genotypic anti–hepatitis C virus (HCV) activity and a high barrier to viral resistance. The VITAL‐1 study assessed alisporivir as interferon (IFN)‐free therapy in treatment‐naïve patients infected with HCV genotype 2 or 3. Three hundred forty patients without cirrhosis were randomized to: arm 1, alisporivir (ALV) 1,000 mg once‐daily (QD); arm 2, ALV 600 mg QD and ribavirin (RBV); arm 3, ALV 800 mg QD and RBV; arm 4, ALV 600 mg QD and pegylated IFN (Peg‐IFN); or arm 5, Peg‐IFN and RBV. Patients receiving IFN‐free ALV regimens who achieved rapid virological response (RVR) continued the same treatment throughout, whereas those with detectable HCV RNA at week 4 received ALV, RBV, and Peg‐IFN from weeks 6 to 24. Overall, 300 patients received ALV‐based regimens. In arm 1 to arm 4, the intent‐to‐treat rates of sustained virological response (SVR) 24 weeks after treatment (SVR24) were from 80% to 85%, compared with 58% (n = 23 of 40) with Peg‐IFN/RBV. Per‐protocol analysis showed higher SVR24 rates in patients who received ALV/RBV, IFN‐free after RVR (92%; n = 56 of 61) than with ALV alone after RVR (72%; n = 13 of 18) or with Peg‐IFN/RBV (70%; n = 23 of 33). Both RVRs and SVRs to ALV IFN‐free regimens were numerically higher in genotype 3– than in genotype 2–infected patients. Viral breakthrough was infrequent (3%; n = 7 of 258). IFN‐free ALV treatment showed markedly better safety/tolerability than IFN‐containing regimens. Conclusions: ALV plus RBV represents an effective IFN‐free option for a proportion of patients with HCV genotype 2 or 3 infections, with high SVR rates for patients with early viral clearance. Further investigations of ALV in IFN‐free combination regimens with direct‐acting antiviral drugs deserve exploration in future trials. (Hepatology 2015;62:1013‐1023)

The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.

Management of hepatitis C virus infection in the Asia-Pacific region: an update

The Asia-Pacific region has disparate hepatitis C virus (HCV) epidemiology, with prevalence ranging from 0·1% to 4·7%, and a unique genotype distribution. Genotype 1b dominates in east Asia, whereas in south Asia and southeast Asia genotype 3 dominates, and in Indochina (Vietnam, Cambodia, and Laos), genotype 6 is most common. Often, availability of all-oral direct-acting antivirals (DAAs) is delayed because of differing regulatory requirements. Ideally, for genotype 1 infections, sofosbuvir plus ledipasvir, sofosbuvir plus daclatasvir, or ombitasvir, paritaprevir, and ritonavir plus dasabuvir are suitable. Asunaprevir plus daclatasvir is appropriate for compensated genotype 1b HCV if baseline NS5A mutations are absent. For genotype 3 infections, sofosbuvir plus daclatasvir for 24 weeks or sofosbuvir, daclatasvir, and ribavirin for 12 weeks are the optimal oral therapies, particularly for patients with cirrhosis and those who are treatment experienced, whereas sofosbuvir, pegylated interferon, and ribavirin for 12 weeks is an alternative regimen. For genotype 6, sofosbuvir plus pegylated interferon and ribavirin, sofosbuvir plus ledipasvir, or sofosbuvir plus ribavirin for 12 weeks are all suitable. Pegylated interferon plus ribavirin has been replaced by sofosbuvir plus pegylated interferon and ribavirin, and all-oral therapies where available, but cost and affordability remain a major issue because of the absence of universal health coverage. Few patients have been treated because of multiple barriers to accessing care. HCV in the Asia-Pacific region is challenging because of the disparate epidemiology, poor access to all-oral therapy because of availability, cost, or regulatory licensing. Until these problems are addressed, the burden of disease is likely to remain high.

Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part II: INASL Recommendations for Management of HCV in India.

The estimated prevalence of hepatitis C virus (HCV) infection in India is between 0.5 and 1.5% with hotspots showing much higher prevalence in some areas of northeast India, in some tribal populations and in certain parts of Punjab. Genotype 3 is the most prevalent type of infection. Recent years have seen development of a large number of new molecules that are revolutionizing the treatment of hepatitis C. Some of the new directly acting agents (DAAs) like sofosbuvir have been called game-changers because they offer the prospect of interferon-free regimens for the treatment of HCV infection. These new drugs have not yet been approved in India and their cost and availability is uncertain at present. Till these drugs become available at an affordable cost, the treatment that was standard of care for the whole world before these newer drugs were approved should continue to be recommended. For India, cheaper options, which are as effective as the standard-of-care (SOC) in carefully selected patients, are also explored to bring treatment within reach of poorer patients. It may be prudent to withhold treatment at present for selected patients with genotype 1 or 4 infection and low levels of fibrosis (F1 or F2), and for patients who are non-responders to initial therapy, interferon intolerant, those with decompensated liver disease, and patients in special populations such as stable patients after liver and kidney transplantation, HIV co-infected patients and those with cirrhosis of liver.