CATIE News

26 September 2019 

FDA—Rare cases of liver injury with some hepatitis C treatments

  • The U.S. drug regulator has issued a safety alert about three hepatitis C treatments
  • The FDA advises doctors to use Maviret, Vosevi and Zepatier only in certain patients
  • When used appropriately, the treatments work and are generally safe

Exposure to hepatitis C virus (HCV) leads to this virus infecting the liver. In cases where the infection becomes chronic, HCV causes persistent inflammation in the liver. This inflammation results in healthy liver tissue dying and being replaced with scar tissue. Gradually, over many years (usually decades), scarring spreads across the liver until the entire organ becomes injured. As the amount of scar tissue accumulates, the liver is less able to function and complications ensue, including severe fatigue, internal bleeding, serious abdominal infections, kidney injury, problems thinking clearly and liver failure. The presence of scar tissue also increases the risk of liver cancer.

In Canada and other high-income countries, HCV treatment is usually widely available and consists of taking pills once daily, often for between eight and 12 weeks. When HCV treatments are used as indicated by regulatory agencies, they tend to result in high cure rates (95% or greater) and are generally safe.

Three of the HCV treatments approved in Canada and other high-income countries are as follows:

  • Maviret (sold as Mavyret in the U.S.) – a combination of the drugs glecaprevir + pibrentasvir
  • Vosevi – a combination of the drugs sofosbuvir + velpatasvir + voxilaprevir
  • Zepatier – a combination of the drugs elbasvir + grazoprevir

The American Food and Drug Administration (FDA) has recently issued a safety alert about the rare occurrence of serious liver injury in people who have used these treatments. Specifically, the agency has received details that some people who used these treatments developed “worsening liver function or liver failure.”

The FDA reminds care providers and patients that these treatments are not to be used in “patients with moderate to severe liver impairment.”

Trends in cases

The FDA stated that it is aware of 63 people with HCV who have been affected by the previously mentioned treatments. According to the FDA:

“In many of the reported cases, liver failure occurred in patients who had signs and symptoms of moderate to severe liver impairment or other serious problems and should not have been treated with these medicines.” This liver impairment was graded as Child-Turcotte-Pugh B or C; more details about this grading system appear toward the end of this report.

In some cases, patients were reported to have “no cirrhosis or [symptoms of] cirrhosis with mild liver impairment [Child-Turcotte-Pugh A]” despite evidence of severe liver injury.

“In addition, some cases had other significant pre-existing risk factors such as liver cancer, [excess intake of alcohol], or serious medical illnesses associated with serious liver problems. These factors may have contributed to clinical worsening of liver function or liver failure during treatment with these hepatitis C medicines.”

“In most cases, liver failure or [serious symptoms of cirrhosis] typically occurred within the first four weeks of starting treatment.”

The agency noted that Maviret, Vosevi and Zepatier are “FDA-approved to treat chronic hepatitis C in patients without liver impairment or with mild liver impairment [Child-Turcotte-Pugh A]. Clinical trials in patients with [no symptoms of cirrhosis] or mild liver impairment [Child-Turcotte-Pugh A] have shown that these medicines are well tolerated and highly effective.”

Advice for healthcare professionals

The FDA advises that “healthcare professionals should continue to prescribe Maviret, Vosevi or Zepatier as indicated in the prescribing information for patients without liver impairment or with mild liver impairment [Child-Turcotte-Pugh A].”

The FDA also recommends the following:

“Assess severity of liver disease at baseline and closely monitor for signs and symptoms of worsening liver function such as increases in liver enzymes, jaundice, ascites, encephalopathy and variceal hemorrhage.”

“Assessment of baseline liver disease and close monitoring are especially important in those with pre-existing significant liver problems or risk factors, such as hepatocellular carcinoma or [excess intake of alcohol], which can also contribute to clinical worsening of liver function or liver failure during treatment.”

“Discontinue these medicines in patients who develop signs and symptoms of liver decompensation or as clinically indicated.”

Advice for patients

The FDA stated that “patients should be aware that the risk of serious liver injury is rare. However, you should contact your health care professional right away if you develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or light-colored stools, as these may be signs of liver injury.”

“If you have liver impairment or other pre-existing risk factors that can worsen liver function such as a history of [excess intake of alcohol], you should talk with your health care professional about the benefits and risks of the medicine.”

“Do not stop taking these medicines without first talking with your health care professionals because stopping treatment early can lead to inadequate treatment, which could allow your HCV to come back. Over time, this could result in progression to severe liver disease and its complications, including cirrhosis, liver cancer and death. These medicines have been widely used and are safe and effective in patients without liver impairment or in those with mild liver impairment for whom they are indicated.”

Technical notes

1. Protease inhibitors

The agency noted that all three treatments previously mentioned contain an HCV protease inhibitor. Although not stated by the agency, protease inhibitors require processing by the liver so they can be broken down and eliminated from the body. In cases where people with chronic HCV infection have moderate to severe liver injury, it is possible, likely even, that their livers will be highly dysfunctional and not able to break down the protease inhibitor and, therefore, these drugs could accumulate in the body, potentially causing toxicity.

2. Grading severe liver disease and the likelihood of survival

In cases of cirrhosis (severe liver injury and scarring of the liver), it is useful for doctors to know the likelihood of patient survival in the short and medium term so that interventions can be prioritized.

Doctors have developed a scoring system called Child-Turcotte-Pugh (CTP) for this purpose. CTP takes into account cirrhosis-related symptoms and certain lab test results. The more severe the symptoms and the greater the abnormality in lab test results, the greater the CTP score. Entering these into an equation produces a score that has a relatively high predictive value.

CTP takes into account the following factors:

  • HCV brain-related problems (encephalopathy)
  • whether or not fluid is accumulating in the abdomen (ascites)
  • analyses of lab tests focusing on the concentrations of bilirubin and albumin
  • the time it takes for blood to clot

CTP scores are graded and have the following implications:

  • CTP category A (5 to 6 points) – people have a 100% chance of surviving for one year and an 80% chance of surviving for a subsequent year
  • CTP category B (7 to 9 points) – people have an 81% chance of surviving for one year and a 57% chance of surviving for a subsequent year
  • CTP category C (10 to 15 points) – people have a 45% chance of surviving for one year and a 35% chance of surviving for a subsequent year

—Sean R. Hosein

REFERENCES:

  1. Food and Drug Administration. FDA warns about rare occurrence of serious liver injury with use of hepatitis C medicines Mavyret, Zepatier and Vosevi in some patients with advanced liver disease. Drug Safety Communications. 28 August 2019.
  2. Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: The model for end-stage liver disease – should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Alimentary Pharmacology & Therapeutics. 2005 Dec;22(11-12):1079-89.
  3. Dienstag JL. Chapter 334. Chronic Hepatitis. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; 2018.