Black box warnings for ‘lifesaving’ hepatitis C drugs highlight systematic misinformation

You may have seen the news a few weeks ago that the FDA is now requiring a “black box warning” on drug labels for certain antiviral hepatitis C medications known as direct-acting antivirals.

As Roy Poses, MD, noted on the blog Health Care Renewal, the drugs have been reported to reactivate dormant hepatitis B infections, a side effect that has so far resulted in the deaths of two patients and the need for a liver transplant in a third. Those are only the cases we know about because they’ve been reported in medical journals or to the FDA—there are almost certainly others.

This follows another label change from last year, when the FDA warned about these drugs’ previously unknown potential to cause severe, possibly deadly heart rhythm abnormalities in patients taking the drug amiodarone.

That’s two label changes in two years—an indication that dangerous side effects are not being caught in the clinical testing process for drugs that are often unquestionably touted as a “cure,” “game-changer” or “breakthrough.”

While the Wall Street Journal, U.S. News and World Report, UPI and NBC News all wrote news stories about the black box warning, none of these outlets–nor any other major news sites, from what we saw online–went a layer deeper in their reporting to scrutinize reasons why a black box warning occurred after these drug were approved.

Instead, the story is quickly fading from the news cycle, and reports of a few deaths “likely won’t dent sales much” as one drug industry news source put it.

That’s due in part from reassuring–yet misleading–statements from the FDA and others, exemplified by this statement from Dr. John Farley, the deputy director of FDA’s Office of Antimicrobial Products: “I think it is important to recognize that these hepatitis C drugs are lifesaving medications.”

But do we know if these drugs are ‘lifesaving’ or not?

That’s misleading because we don’t actually know if these drugs are lifesaving or always cure hepatitis long-term.

That’s because the buzz generated around these drugs–including claims that they’re “life-saving”–were based on a handful of short-term studies (typically just three months) that measured the drugs’ abilities to reduce viral load, or the amount of virus in the bloodstream, to very low levels. This reduction is known as a “sustained virologic response” (SVR).

But SVR isn’t a guarantee of a longer life free of cirrhosis or liver cancer, although drug manufacturers like Gilead define it that way in the fine print of their direct-to-consumer advertising.

In reality, SVR is what’s known as a surrogate outcome, as Poses points out—and as we’ve documented time and again in our reviews of news stories and news releases about these drugs over the year.

We have yet to see a story on a clinical trial showing that the drugs helped anyone live longer or even that they reduced rates of complications like cirrhosis or liver cancer.

Here are some excerpts from our past reviews:

In Early Test, New Hepatitis C Drug Shows Promise

“Considering that this was a phase 1 study designed primarily to collect information about drug safety, we think it’s unfortunate that the story chose to emphasize a secondary test result—reduction in viral load—and downplay potential safety issues.”

Achillion, Gilead drug cocktail cures hepatitis C in six weeks

“The story says the drug ‘eradicated signs of the virus,’ but there is nothing about who the patients were, how sick they were, or how many there were. It may be easier to eradicate the virus in individuals whose disease is not very advanced.”

Merck Receives FDA Approval of ZEPATIER™ (elbasvir and grazoprevir) for the Treatment of Chronic Hepatitis C Virus Genotype 1 or 4 Infection in Adults Following Priority Review

“…the trial looked at the reduction in viral load, not the prevention of specific conditions like cirrhosis, an outcome that is supposed to be prevented by the use of these drugs. Patients care most about conditions that affect them and not how many virus particles are in their blood, so this was an important omission.”

FDA approves Epclusa for treatment of chronic Hepatitis C virus infection

“The FDA also missed an opportunity to inform readers about limitations of these studies and gaps in our knowledge related to these medications. For example, these were short-term studies, and so we don’t yet know whether these patients will have fewer cases of liver cancer, liver failure, or need for liver transplants down the line. That’s an educated inference based on the drug’s ability to eradicate the virus — but not proven.”

And is hepatitis C infection even particularly fatal?

Granted, despite these limitations and potentially deadly side effects, these drugs will be lifesaving for some people who take them.

Then again, some experts have observed that “[Hepatitis C] is an indolent infection, and most adults with this infection will never develop negative health effects during their lifetime.”

How can your life be “saved” from a condition that never would have caused you any negative health effects?

The drugs don’t seem to have been lifesaving for patients who had a serious, possibly deadly interaction with another medication they were taking.

And they definitely weren’t lifesaving for those people who experienced deadly reactivation of their hepatitis B infections—quite the opposite in fact.

We don’t know how many of those people there are—or how many might experience other serious harms—because the existing studies specifically excluded the sicker people most likely to suffer such reactions.

My point is not to diminish the potential value of these drugs but to emphasize that we don’t know how valuable they may or may not be, and “lifesaving” is never as simple as it may seem, especially when drugs carry potentially deadly side effects and are targeted at an infection that may never cause a problem.

Or as gastroenterologist Michael Kirsch explained on the blog KevinMD, “TV or print ads about HCV treatment suggest that you ‘talk with your doctor to see if the drug is right for you.’ When you do so, ask for the evidence that the treatment will allow you to live longer or live better.  Clearing your body of HCV sounds like a triumph and is marketed as such, but this might not change your life at all.”

Why does this matter?

This matters because policymakers, physicians, and patients have to make decisions about these drugs in the treatment of hepatitis C. And it’s hard to make good decisions based on information that systematically overstates benefits and downplays or ignores limitations and harms.

Claims of “cure,” “breakthrough,” etc, engender a false certainty when they aren’t accompanied by sober analysis of potential downsides. And that, in turn, can lead individuals to make choices that aren’t consistent with their priorities and beliefs. Or it could lead society to squander resources on a drug that doesn’t deliver the promised benefits.

Dr. Poses and our reviewers aren’t the only ones raising questions about the evidence on hepatitis C drugs.

• Last year, a BMJ piece by Ronald Koretz, Kenny Lin, John Ioannidis and Jeanne Lenzer asked, “Is widespread screening for hepatitis C justified?“ Their key message: “Physicians should resist screening until we have strong evidence that antiviral therapy is clinically effective and the benefits outweigh the harms”
• A paper in JAMA Internal Medicine raised questions about the value of a new hepatitis C drug for the most patients. The authors noted: “Many people with HCV infection have no evident liver dysfunction. For such patients, the decision about whether and when to initiate treatment should involve careful consideration of the balance of risks and benefits and shared decision-making with experienced clinicians.”

We might see more such skepticism if media messages encouraged critical thinking about the tradeoffs involved with these drugs and emphasized how much we’ve yet to learn about them.