'Curing' Hepatitis C Is Not the End of Patient Care

Laird Harrison


August 12, 2019

Norah Terrault, MD, MPH, will never forget the patient who slipped away. He was in late middle age and had lived with hepatitis C for several decades before undergoing treatment. Antiviral drugs knocked out the virus, but his liver remained badly scarred.

And then the patient disappeared.

When Terrault saw him again, he had gained weight and returned to heavy drinking, both of which stressed his already damaged organ. An ultrasound revealed liver cancer.

"It brought home to us the importance of not losing track of patients," said Terrault, director of the viral hepatology center at the University of California, San Francisco.

During the past 15 years, direct-acting antiviral therapies have proven so effective that almost all chronic hepatitis C infections can be cured if appropriately treated. But these infections may have been undetected for many years, leaving patients with compromised livers. As a result, some run a high enough risk for cancer and other diseases that they will continue to need the help of a specialist.

"That care is important even though curing the disease does improve the health of the liver," says Paul Martin, MD, chief of gastroenterology and hepatology at the University of Miami in Florida. "You eradicate the hepatitis C, and as a result, there is healing of the hepatic tissue. But the risk for complications such as liver cancer probably never becomes zero in those patients."

The Best Strategies Start Before Treatment

Once hepatitis C is detected and the patient begins receiving care, the provider should determine the stage of disease before treatment, says Terrault. Liver biopsy is rarely necessary; the stage of fibrosis can be determined with noninvasive testing such as hepatic elastography.

Staging tests combine measurements of inflammation and fibrosis, and were developed and validated in untreated patients. Cutoff scores are used to define advanced fibrosis, including cirrhosis. Inflammation diminishes after cure, so most noninvasive tests performed at this point show an improvement without accurately reflecting fibrosis levels.

"A lot of the post-cure management is going to be dictated by the disease severity before you started therapy," says Nancy Reau, MD, a professor of transplant hepatology and gastroenterology at Rush University in Chicago, Illinois. "Patients who have no significant fibrosis will be returned to their primary care providers."

But patients with stage 3 or 4 fibrosis, or who are in danger of further liver damage, should remain in the care of a hepatologist or gastroenterologist, she says.

That includes patients with advanced fibrosis (F3 or F4) on staging tests before treatment, as they are at risk for hepatocellular carcinoma and decompensation, even with cure.

Alcohol use, steatosis, male sex, increased age, diabetes, coinfection with hepatitis B, and hemochromatosis are all risk factors for liver cancer, Reau points out.

For these patients, Terrault recommends surveillance with ultrasound and alpha-fetoprotein every 6 months. For patients with cirrhosis, she also recommends endoscopy and monitoring sodium, creatinine, total bilirubin, international normalized ratio, and albumin to determine model for end-stage liver disease and Child-Pugh scores. These tests can also monitor serial progression or improvement in patients with cirrhosis.

After Treatment Begins, When Is a Patient 'Cured'? 

For the pivotal trials leading to the approval of the current hepatitis C antiviral drugs, the researchers defined treatment success as an undetectable RNA level for the virus 12 weeks after completing the therapy, otherwise known as sustained virologic response (SVR) 12.

Relapses beyond SVR 12 are extremely rare. In a large study evaluating late relapse,[1] hepatitis C RNA was detected in just 12 of 3004 patients with SVR12 between weeks 12 and 24. Phylogenetic sequencing showed 7 to be new infections.

Still, providers should test for the virus at 24 to 48 weeks after the end of treatment (SVR24 or SVR48), Terrault says. When no hepatitis C RNA is detectable at SVR48, providers can confidently tell patients they are cured and do not need any further testing for hepatitis C. The exception to this, she says, is if a patient is determined to be at risk for reinfection.

Know Who Is at Risk for Reinfection and Treat Accordingly

Providers should advise patients that having antibodies for hepatitis C does not confer protection against reinfection. Antibody screening tests for hepatitis C are not useful in individuals who have already been infected and then treated, Reau points out.

"A hepatitis C antibody test remains positive after spontaneous clearance or cure through antiviral therapy," she says. "So if your patient is concerned about re-exposure, you have to look for the virus through polymerase chain reaction."

Providers should also counsel patients about avoiding exposure. Some risk factors for reinfection include injected illegal drugs, exposure through contaminated blood, and injections in substandard healthcare settings.

In one recent meta-analysis, hepatitis C virus-monoinfected patients at low risk for recurrence had a 1% rate of hepatitis C virus RNA positivity at 5 years compared with 11% among people at high risk, such as intravenous drug users and prisoners.[2]

Among people who inject drugs, the rate of reinfection is 2%-3% annually.[3] Similarly, about 3% of HIV-infected men who have sex with men are reinfected per year.[4] Men who have sex with men while taking prophylaxis for HIV may also run an increased risk for reinfection, Terrault says.

Terrault recommends annual hepatitis C testing for people who inject drugs, in HIV-positive men who have sex with men, as well as those with increased alanine aminotransferase levels.

There are also special considerations for those with advanced liver disease. Patients with cirrhosis should abstain from alcohol, Terrault says. Men with minimal or no cirrhosis should have fewer than 2 drinks a day, and women with no cirrhosis should have fewer than 1 drink a day; some evidence suggests even this might be too much, she adds. As well, marijuana may worsen fibrosis, so she recommends against daily use.

"We like to ensure that patients have immunity to hepatitis A and B, and if not, we advise vaccination," Martin adds.

Maintaining an ideal body weight can help reduce the risk for liver damage from fatty liver disease as well, Terrault notes. She also recommends informing patients about medications and herbs that can damage the liver.

"There is a lot to do on risk reduction," Reau says. "Make sure they use appropriate protection, if it's a man who has sex with men. Or if it's someone who engages in IV drug use, make sure that they connect with a needle exchange program, and try to get the patient into substitution therapy. But these individuals still have bad days, so try to emphasize that even one slip might increase the risk for hepatitis C re-exposure."

Patients may be more receptive to these messages after cure of their hepatitis C than they were before, Martin says. "It's an opportunity for a fresh start. They are free of the virus, and they are more optimistic about the future."

Knowing the best ways to intervene at this point may decrease the chances your patients will return to you in a worse condition than when you last saw them.

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