By DENISE GRADY
JAN. 24, 2017
The New York Times
Drugs approved in recent years that can cure hepatitis C may have severe side effects, including liver failure, a new report suggests.
The number of adverse events appears relatively small, and the findings are not conclusive. But experts said the report was a warning that should not be ignored. It involves nine widely used antiviral drugs that were heralded as a huge advance because they greatly increased cure rates, seemingly with few side effects.
The report will be published online on Wednesday by the Institute for Safe Medication Practices, a nonprofit in Horsham, Pa., that studies drug safety. Its findings are based on the group’s analysis of the Food and Drug Administration’s database of reports from doctors around the world of adverse events that might be related to medications.
Dr. Robert S. Brown, the director of the Center for Liver Disease and Transplantation at NewYork-Presbyterian at Columbia and Weill Cornell, who was not involved in the study, said that there had been other, scattered accounts of problems with the new drugs and that they should be investigated further.
“We don’t want people to ignore it and lead to risks to patients,” he said. “We don’t want people to overreact and not treat patients who should be treated. A lot of doctors are unclear about it, and if doctors are unclear, patients are, too.”
Dr. Brown added that problems might arise from some doctors’ prescribing incorrectly, giving the drugs to patients with liver function too poor to tolerate them or benefit from them.
Hepatitis C is an enormous public health problem. Caused by a virus, it leads to chronic liver disease in most people who contract it, and some eventually develop cirrhosis and liver cancer.
In the United States, an estimated 2.7 million to 3.9 million people have chronic hepatitis C, at least 20,000 a year die from it and it is the leading cause of liver transplants, according to the Centers for Disease Control and Prevention.
Globally, the World Health Organization reports 130 million to 150 million current chronic cases, and 700,000 deaths per year.
The virus is blood-borne, and the most common source of infection is needle-sharing among people who use illicit drugs. In the United States before 1992, when a test became available to screen donated blood, many cases were caused by transfusions. In countries where the blood supply is not screened, transfusions still pose a risk. Needlestick injuries and other hospital accidents may also cause some cases.
There is no vaccine to prevent the infection, so treatments have long been eagerly sought.
The drugs covered in the new report include two blockbusters, Sovaldi and Harvoni, both made by Gilead Sciences and priced at $1,000 a pill, with billions of dollars in sales. Sovaldi was approved in 2013, and Harvoni in 2014. These drugs and other antivirals can cure the disease in 12 weeks in many patients.
Earlier drugs were less effective, had to be taken for much longer and had harsh side effects that left many patients unable to finish the course of therapy.
About 250,000 people took the newer drugs in 2015, the report said, at tremendous expense: $55,000 to $125,000 per patient. In those treated during the year ending June 30, 2016, the report identified 524 with liver failure, 165 of whom died. Of those with liver failure, 386 were from outside the United States. An additional 1,058 had severe liver injury, and in 761 the drugs appeared not to work.
But whether the drugs were to blame is not known. The problems were observed by doctors who suspected drugs were the cause, but that does not prove cause and effect. And details about the patients’ medical histories were not available.
A spokesman for Gilead, Mark Snyder, wrote in an email, “We closely assess both post-marketing safety reports as well as safety data from our clinical trials on an ongoing basis and have found no suggestion of a causal relationship between Sovaldi or Harvoni and liver failure.”
He added that Gilead’s drugs had been approved for people with severe liver disease from hepatitis C, and that some would inevitably suffer liver failure despite the best treatment.
The F.D.A. received a copy of the report, but declined to discuss it. A spokeswoman, Theresa Eisenman, wrote in an email, “The F.D.A. does not typically comment on specific studies, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”
For all types of drugs, the agency received nearly 300,000 new reports of adverse events during the second quarter of 2016, from the United States and other countries.
Most of the events were described by doctors and other health professionals. Because reporting is voluntary for doctors, researchers generally suspect that many problems go unreported and that the real number is higher.
In October, the F.D.A. identified the first major safety problem caused by the nine antiviral drugs. In 24 patients, the drugs wiped out hepatitis C — but also reactivated hepatitis B infections that had been dormant. Two of those patients died, and one needed a liver transplant. The agency said there were probably additional cases that had not been reported.
As a result, the agency required that a boxed warning, its most prominent advisory, be added to the labeling of the newer antivirals, telling doctors to screen and monitor for hepatitis B in all patients taking the drugs for hepatitis C. Infection with both viruses is not common, and how the reactivation occurs is not known. The problem was not detected during premarket testing of the drugs because patients who currently had hepatitis B or who had a history of it were not allowed into the studies.
With testing and the right treatment, Dr. Brown said, hepatitis B reactivation should be completely preventable.
The other cases of liver failure are a separate problem. He said it was important for doctors prescribing the newer drugs to test patients’ liver function thoroughly first, because liver disease can be deceptive, and people who look well may actually be on the brink of liver failure and therefore not candidates for the drugs.
Thomas J. Moore, a senior scientist at the Institute for Safe Medication Practices and an author of the report, said the study reflected a larger question about the drug approval process. Approval for the newer hepatitis C drugs was expedited because better treatments were so badly needed. But does the rush to market come at a price?
“Gosh, here is something that really qualifies as a breakthrough, and we have policies to get it into use as quickly as possible, which means we know less about it,” Mr. Moore said. “Benefits and side effects evolve over the long term, not over 12 weeks.”