48uep6bbphidcol2|ID

48uep6bbphidvals|2998

48uep6bbph|2000F98CTab_Articles|Fulltext

In the last decade there has been significant change in the treatment strategy for hepatitis C. The sustained virological response is now achievable in over 95%¹. With the current available treatment, relapse is less common and even if it occurs, it manifests as virological and biochemical relapses. Hepatitis C relapse causing acute hepatitis is rare. Relapse of  hepatitis C causing acute on chronic liver failure is even a rarer possibility. We report a case where a patient with compensated cirrhosis was treated with 12 week directly acting antivirals (DAA) and he achieved end of treatment response. However, there was a relapse leading to liver failure within 15 days of stopping therapy. Although theoretically possible, hepatitis C flare leading to Acute on Chronic Liver Failure (ACLF) within 15 days of stopping therapy has not been documented previously.  

A 50 year old gentleman with no comorbid illness, no previous history of ethanol or complementary/alternative medicines and a body mass index of 20 kg/m², on a routine health checkup was diagnosed to have hepatitis C. He was referred for further management at our center in February. He denied any history of surgery or blood transfusion in past. He was completely asymptomatic. On evaluation he was found to have hemoglobin 12.4 g/dl (MCV 99.7 fl, RDW 15.2%) White cell count 5650 cells/cumm, platelets 105000 cells/cumm, PT-INR 1.41, AST 114, ALT 79, ALP 106, Serum Bilirubin  1.8 mg/dl (Conjugated 0.0 mg/dl, Delta 0.8 mg/dl), serum Albumin 3.2 g/dl, serum Globulin 3.9 g/dl, Creatinine 0.63 mg/dl and AFP was 9.6. His RNA load was 19639.7 IU/Ml and genotype turned out to be Genotype 3. Ultrasound showed altered liver parenchyma with prominent portal vein at 12 mm. On endoscopy, there were no varices. His work up for additional liver disease etiology was negative (Total Anti HBc, HBsAg, ANA, ASMA, Anti LKM1, Ceruloplasmin, Ferritin, IgG). He was started on combination of Sofosbuvir (400mg) and Velpatasvir (100mg) combination (NS5A RAS Y93H was not carried out). His viral RNA became negative at 4 weeks and at 12 weeks remained negative. He tolerated the therapy well and had not developed decompensation during the course of therapy. His Transaminases normalized at end of treatment. His hepatitis C treatment was deemed completed on achieving end of treatment response.

Fifteen days after finishing the hepatitis C treatment, he presented to out-patient clinic with anorexia, nausea, fatigue and developing jaundice. He was evaluated and found to have hemoglobin 12.8 g/dl, WCC 8250 cells/cumm, Platelets 103000 cells/cumm, bilirubin 13.7 mg/dl (Conjugated 7.6 mg/dl, Delta 3.7 mg/dl), AST 174 u/L, ALT 173 u/L, Albumin 2.7 g/dl, Globulin 4.5 g/dl, INR 1.84, Creatinine 0.73 mg/dl and Amylase 53 u/L. He was started on symptomatic therapy for acute hepatitis. His IgM HAV, IgM HEV, Total Anti HBc, HBsAg, CMV, EBV, HSV, VZV, ANA, AMA, ASMA and LKM turned out to be negative. His HCV RNA relapsed(65213 IU/ml) and the repeat Genotype study showed to be consistent with his original infection. He was restarted on Sofosbuvir and Velpatasvir again. Seven days after the onset, he developed ascites, edema and acute kidney injury (creatinine 1.7 mg/dl). He was evaluated for liver transplant. His septic screen turned out to be negative. He developed encephalopathy 5 days later and was intubated. Due to unavailability of a suitable living donor he progressed to multi organ failure and died a week later.

In India, HCV infection affects about 0.4%-0.7% of the population and is responsible for 20%-40% of cases with cirrhosis². The extremely low price of Direct Acting Antivirals (DAAs) with the cost of treating one patient being much below 50,000 INR, compared to US dollars 30,000 in high-income countries. This enables cheap and effective treatment of hepatitis C in India translating to sustained virological response in over 95% cases. Reactivation of hepatitis C, although seen in less than 5% cases overall, is expected to be higher in Genotype 3 cases with cirrhosis. Most of the reactivations are diagnosed by virological studies and less often by transaminitis. Even patients on immunosuppression therapy develop enhanced immunosuppression and do not develop severe hepatitis³. The reactivation being responsible for progression of compensated liver disease to ACLF is unusual and is indeed a rare event. Our patient had documented end of treatment response with undetectable viral RNA by PCR. Within 15 days patient developed symptomatic acute hepatitis and more than 4 log rise in viral RNA copies. Within a week of development of acute hepatitis he developed liver failure and went into multiorgan failure. 

Four DAAs including an NS5B inhibitor (sofosbuvir) and three NS5A inhibitors (ledipasvir, daclatasvir, and velpatasvir) are currently available in the Indian market. The patient was treated with the Sofosbuvir and Velpatasvir as the newer drugs are not available in India. Ribavirin could have been added, although recent guidelines mention 12 weeks of Sofosbuvir with Velpatasvir in Genotype 3 patients with compensated cirrhosis as adequate therapy⁴. This case highlights the importance of carrying out RAS study before the initiation of treatment which was not carried out by us at baseline. Besides, we do not know if prolonging the therapy could have helped.

Acute on Chronic Liver Failure (ACLF) defined by the Asia-Pacific Association for the Study of Liver (APASL)⁵ as acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease. The European Association for study of Liver⁶ disease defines ACLF as a syndrome in patients with chronic liver disease with or without previously diagnosed cirrhosis characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the international normalized ratio), and one or more extra-hepatic organ failures, that is associated with increased risk for mortality within a period of 28 days and up to 3 months from onset. Our patient qualified as ACLF as per the definitions of both the societies. None of the guidelines mention HCV flare as an etiology for ACLF, although possibility has been suggested. Most cases, it is believed to be caused by simultaneous reactivation of hepatitis B which was not the case in our patient as Total Anti HBc and HBsAg remained persistently negative. The rise in HCV RNA was the only positive finding documented in this patient. Even septic screen was negative in the early period.

Although an early liver biopsy and a baseline RAS Y93H analyses could have helped, it is not routinely practiced in India before treatment. 

To conclude, reactivation of Hepatitis C can be responsible for causing ACLF and one needs to be extra vigilant in patients of cirrhosis for such a relapse.