Last reviewed: March 2020
Last updated: October  2019
22 Oct 2019

FDA warns direct-acting antivirals can cause serious liver injury in patients with advanced liver disease

The US Food and Drug Administration (FDA) has received reports of rare cases of worsening liver function or liver failure in patients with chronic hepatitis C who have moderate-to-severe hepatic impairment and are treated with certain direct-acting antivirals. In most cases, liver failure or hepatic decompensation occurred within 4 weeks of starting treatment. Some cases have led to death.

The drugs involved include:

  • Elbasvir/grazoprevir

  • Glecaprevir/pibrentasvir

  • Sofosbuvir/velpatasvir/voxilaprevir.

It is important to note that these drugs are not indicated in patients with moderate-to-severe hepatic impairment (Child-Pugh B or C), and most of the reported cases were in patients who should not have been prescribed these drugs because they had signs and symptoms of advanced liver disease (or other serious liver problems) prior to starting treatment. Worsening liver function improved and symptoms resolved in most patients after stopping the drug.

When prescribing these drugs, assess the severity of liver disease at baseline and monitor the patient for clinical signs and symptoms of worsening liver function (e.g., increases in liver enzymes, ascites, jaundice, variceal haemorrhage, encephalopathy) during treatment. This is especially important in patients with pre-existing serious liver problems or risk factors that can contribute to clinical worsening of liver function during treatment (e.g., hepatocellular carcinoma, alcohol abuse). These drugs should not be prescribed in patients with a history of prior hepatic decompensation. Discontinue use of these drugs in patients who develop evidence of hepatic decompensation or as clinically indicated.

These drugs are considered to be safe and effective in patients with no hepatic impairment or mild hepatic impairment (Child-Pugh A) and can be prescribed as indicated.

The FDA has previously issued a similar warning about ombitasvir/paritaprevir/ritonavir ± dasabuvir.[58]

See Management: approach

See Management: treatment algorithm

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History and exam

Other diagnostic factors

  • constitutional symptoms
  • jaundice
  • ascites
  • signs of hepatic encephalopathy
  • extrahepatic manifestations

Risk factors

  • unsafe medical practices
  • intravenous or intranasal drug use
  • blood transfusion or organ transplant
  • birth between 1945 and 1965
  • heavy alcohol use
  • interleukin (IL)-28B gene polymorphism
  • HIV
  • incarceration/institutionalisation
  • haemodialysis
  • healthcare work
  • tattoos
  • multiple sex partners
  • infected mother (for fetus)
  • male sex

Diagnostic investigations

1st investigations to order

  • enzyme immunoassay or hepatitis C antibodies
  • nucleic acid amplification tests (NAATs)
  • serum aminotransferases
  • viral genotyping
More 1st investigations to order

Investigations to consider

  • non-invasive tests of liver fibrosis or elasticity
  • liver biopsy
More investigations to consider

Treatment algorithm


Professor of Medicine

Division of Liver Diseases

Mount Sinai Hospital

New York



JA declares that he has no competing interests.

Dr Jawad Ahmad would like to gratefully acknowledge Dr Brian L. Pearlman, the previous contributor to this topic.

Peer reviewersVIEW ALL

Assistant Professor

Digestive Disease and Liver Transplant

Yale University



AL has participated in an advisory board meeting with Gilead and Janssen, and is a primary investigator for Merck’s C-Surfer trial.

Director of Hepatology and Medical Director of Liver Transplantation

Associate Professor of Medicine

Strong Memorial Hospital

University of Rochester



BM belongs to the paid speaker’s bureau for pharmaceutical companies Gilead (maker of ledipasvir/sofosbuvir), AbbVie (maker of Viekira Pak® - ombitasvir/paritaprevir/ritonavir and dasabuvir), Merck, and Salix.

Consultant Hepatologist

Bradford Teaching Hospitals Foundation Trust




SM has received sponsorship and has sat on advisory boards for BMS, Gilead, AbbVie, and Merck.

Consultant Hepatologist

Nottingham University Hospitals NHS Trust



SR is an advisory board (paid) member for AbbVie, Gilead, Janssen, and MSD.

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