October 12th, 2014

Approval of Sofosbuvir/Ledipasvir Was Expected, but Still Is a Huge Advance

As expected, the FDA just approved the first single-pill treatment for hepatitis C genotype 1, a tablet containing 400 mg of sofosbuvir (SOF) and 90 mg of ledipasvir (LDV). For those not following this story closely, sofosbuvir is the pan-genotypic NRTI polymerase inhibitor approved last December to much rejoicing — and controversy about the price. Ledipasvir is the first HCV NS5A inhibitor, and is only available as part of this combination.

The brand name is “Harvoni”, which sounds a bit like an exotic offering on a menu that you need to ask your waiter to explain — “Ancho chile-rubbed Niman Ranch pork chop roasted in soy, ginger, and sesame, served with pan-sauted garlic kale, and garnished with corn and pinapple-harvoni salsa.”

But even though the approval was no surprise, and the brand name will (like all of them) take some getting used to, there’s no denying this is a huge step forward for HCV therapy. Let me list some of the reasons:

  • One pill a day. Can it get simpler than that? Full prescribing information here.
  • No interferon, no ribavirin. In clinical trials, all the latter added to the SOF/LDV combination was side effects. Ribavirin offered no additional efficacy even in cirrhotics.
  • For most patients, 12 weeks of therapy will have a 95%+ chance of cure.
  • For treatment-naive patients without cirrhosis who have a pretreatment HCV RNA level < 6 million copies/mL, just 8 weeks should do the trick.
  • For treatment-experienced patients who do have cirrhosis, 24 weeks is recommended, as “only” around 4 out 5 were cured with 12 weeks.
  • The rate of treatment discontinuation due to adverse effects in 3 different studies was 1%, 0%, and <1%, respectively. Think about that for a moment.

So yahoo. This is instantly a treatment of choice — and for now, the treatment of choice — for genotype 1 patients, and no doubt the HCV treatment guidelines will say as much when they’re revised. I’m not on the guidelines panel, just stating the obvious: The amount of supporting clinical trials data for SOF/LDV combination is vastly greater than the simeprevir-sofosbuvir treatment, which is already listed.

As with any new medical treatment, there are a few issues and questions to address with SOF/LDV — so let’s start with the elephant in the exam room, the cost.

The list price of this combination therapy for 12 weeks will be around $95,000, which means the ledipasvir component is priced around the same as 12 weeks of interferon/ribavirin — and substantially less than the current price of simeprevir. I’ve gone over before the various issues on the cost of HCV treatment — it totally depends on your perspective. It’s either incredible value for what your getting (a virtual guarantee of HCV cure, with no side effects!), or horribly too much ($95,000! That’s over $1100/pill!).

Regardless, SOF/LDV is already one-third cheaper and more effective than HCV treatment was last week with SIM/SOF, and will cost even less if the patient qualifies for 8 weeks of treatment. We’ll see how this all shakes out when the next interferon-free drug regimen gets approved later this year. I’m referring, of course, to the parataprevir/ritonavir/ombitasvir plus dasabuvir regimen, which is now so close to approval that all the drugs have real names. The guidelines committee will need to consider this one too when it’s approved.

A few more items of note:

  • There are remarkably few serious drug-drug interactions. Don’t use rifampin or the tricky anticonvulsants (phenytoin, carbamazepine, phenobarbital). And rosuvastatin levels go way up, avoid that statin. Further details in the package insert, linked above.
  • For patients with HIV co-infection, ledipasvir will increase tenofovir levels by around 30%, the same magnitude as ritonavir-boosted PIs and TDF/FTC/EVG/COBI. If you’re patient is on the former, the prescribing info advises to monitor closely; if on the latter, to switch. I’d recommend switching both, if possible, to a raltegravir, dolutegravir, or rilpivirine-based regimen until there are more safety data. A phase III study of SOF/LDV in HIV-coinfected subjects is fully enrolled.
  • No dosage change is required for those with mild-moderate renal impairment; for severe renal impairment or ESRD, no dose recommendation can be made.

Finally, did the FDA consider cost when they recommended 24 weeks of treatment for treatment-experienced patients with cirrhosis? Probably not, since an 80% cure would leave just 20% who would need a longer course. In support of the 24 week up front course of SOF/LDV, however, is that we don’t really have a proven approach to treatment failures yet (24 weeks of the same treatment with RBV? 24 weeks of SIM-SOF? Other?) Additionally, this is the group of patients who need HCV treatment most urgently.

Enjoy this video, I sure did.

5 Responses to “Approval of Sofosbuvir/Ledipasvir Was Expected, but Still Is a Huge Advance”

  1. Ben says:

    Excellent blog.
    Excellent clip.
    How much organic chicken would $95,000 buy?

  2. Joe says:

    This is most excellent.

  3. Martin says:

    Thanks for the update Paul. As always, your blog has a great mix of ID news / comment and humor.
    The update was great, but this time the clip was even better.
    Even my wife the vascular surgeon had a laugh with it while I don’t think she would have enjoyed the update as much.

    On a side note, how much are providers struggling with getting insurance approval for the newer treatments? I live in a small town and our GI guys are overwhelmed with consults (EGD/colonoscopies of course) and administration is reaching out to me exploring whether I could help with their Hep C, and I am a little afraid about how much time will approvals / paperwork take from me and my staff.
    Any comments, appreciated.


    • Paul Sax says:

      Best source is the hcv treatment guidelines, which will be updated soon to reflect this recent drug approval:


      The insurance approvals vary enormously from patient to patient — there are as many different plans and “tiers” out there as there are stars in the sky.


  4. Stephen Shafran says:

    my comment was distorted.

    I find it amazing that there is much fanfare about curing HCV for $800K without cure.

HIV Information: Author Paul Sax, M.D.

Paul E. Sax, MD

Contributing Editor

NEJM Journal Watch
Infectious Diseases

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