Spotlight Series on Hepatitis C


Mystifying Cochrane Library Review on HCV Therapy Elicits Strong Response from IDSA

July 24, 2017

Paul E. Sax, M.D.

Paul E. Sax, M.D.

Last month, the Cochrane Review published a controversial paper on HCV therapy that left many ID doctors and hepatologists perplexed.

After reviewing 138 randomized clinical trials using directly acting, non-interferon based therapies, they came to the following conclusions:

  • The use of sustained virologic response ("SVR") -- or "cure", if you want to use plain English -- as a valid endpoint for predicting clinical outcomes is questionable.
  • There is currently insufficient evidence that treatment with DAA-based regimens improves clinical outcome.
  • The studies reviewed were at high risk of bias, so tended to overestimate benefits and minimize harm.
  • More randomized clinical trials are needed.

Anyone -- clinician, researcher, or patient -- who has experienced the miraculous advances in HCV therapy that started in 2014 could easily be scratching their heads at these conclusions.

The FDA might be surprised as well, since they have allowed SVR as an appropriate "surrogate" marker of the effectiveness of HCV therapy for some time.

Fortunately, we now have a focused, persuasive response by the IDSA, just published in Clinical Infectious Diseases.

I strongly encourage anyone who doubts the clinical benefits of curing HCV to read the full paper, but in essence the argument goes like this:

  1. The review was overly selective in the papers it included. Remember, many HCV trials could not include a control group since DAA therapies were so rapidly effective and well tolerated it would have been unethical. These non-controlled studies were not included in the review.
  2. HCV cure as an appropriate marker for treatment efficacy was established during the years of interferon-based therapy. Liver inflammation (as measured by biopsy or serial LFTs), fibrosis, portal hypertension, splenomegaly, even cirrhosis improved in those with SVR. And I would add that some surrogate markers are more intuitively obvious than others -- and you can't really get more obvious than curing the very infection that's causing the disease. HCV RNA is not an obscure, indirect tumor marker (oncology), or a change in lipids (cardiology). It's analogous to HIV RNA in HIV therapy, only better. And is there any plausible biologic reason why HCV cure with DAAs might be less effective in improving clinical outcomes than using interferon?
  3. The time horizon to see the full clinical benefit for HCV cure will take many years. We've only had these therapies widely available since 2015 -- hardly enough time to see reductions in the incidence of long-term complications such as cirrhosis or hepatocellular carcinoma. Note that we've already seen benefits in HCV transmission from treatment in a clinical cohort of MSM from Europe.
  4. Despite this short time period of DAA availability, clinical benefits have already been observed with HCV cure. These include resolution of vasculitis, spontaneous remission of non-Hodgkin lymphoma, and -- perhaps most remarkably -- stabilization or improvement in those with the most advanced forms of HCV liver disease.

I will note that this isn't the first time a "systematic review" of an Infectious Disease treatment under the Cochrane name ended up with a surprising conclusion.

Remember this one on HIV treatment with TDF/FTC/efavirenz? The one which stated there was insufficient evidence to support its use, despite numerous randomized clinical trials documenting its efficacy? And its widespread adoption in clinical guidelines?

It may be hard to find today, since it was later withdrawn.

Paul E. Sax, M.D., is director of the HIV Program and Division of Infectious Diseases at Brigham and Women's Hospital in Boston.

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This article was provided by NEJM Journal Watch. NEJM Journal Watch is a publication of the Massachusetts Medical Society.

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