Elbasvir/Grazoprevir (Zepatier) Combination Pill for HCV a Welcome New Option -- With a Few Buts

As expected, there's a new option for HCV therapy, the combination pill elbasvir/grazoprevir (EBR/GZR, brand name Zepatier, more on this below), and it's indicated for genotypes 1 and 4. For those mechanistically inclined, elbasvir is an NS5A inhibitor (like ledipasvir), and grazoprevir is a protease inhibitor (like simeprevir).

This is the second one-pill, once a day option for HCV, and unlike the first (ledipasvir/sofosbuvir, or LDV/SOF), it can be used in patients with end-stage renal disease on hemodialysis -- an advantage that granted the regimen a "breakthrough therapy" designation, speeding FDA approval.

In addition, the list price is substantially lower -- $54,000 for 12 weeks of EBR/GBR, vs $94,000 for LDV/SOF. Of course the actual price paid by government and private payers is heavily negotiated, so how the two will compare remains to be seen. And some providers are treating their low viral load genotype 1 patients with just 8 weeks of LDV/SOF therapy, bringing the price much closer to $54,000 (at least in those cases).

But why the lower price? After all, cure rates are outstanding (94-97% for genotype 1), side effect rates low, and you can't get simpler than one pill a day.

Seems to me there are two major reasons:

  1. They're not the first. LDV/SOF has been available for over a year, and providers are incredibly comfortable with it. Plus, you can barely take a walk down the street, turn on the radio in your car, or flip on the TV without encountering a direct-to-patient advertisement for LDV/SOF. This lower price will be an important strategy for convincing providers, patients, and payers that EBR/GZP is an option.
  2. It's not quite as convenient as LDV/SOF. A patient starting HCV with EBR/GZP is somewhat less likely to be taking just one pill a day for 12 weeks than if treated with LDV/SOF.

The reason for this slightly greater complexity is that one of the predictors of treatment failure in studies of EBR/GZP was the pre-treatment presence of certain NS5A polymorphisms -- which are similar to resistance mutations:

SVR12 in HCV Genotype 1a-Infected Subjects Without or With Baseline NS5A Polymorphisms

Providers will need to do a pre-treatment test for these polymorphisms. Based on these results and the treatment history, here are the treatment recommendations for the EBR/GZP regimen:

Dosage Regimens and Durations for Zepatier in Patients With Genotype 1 or 4 HCV With or Without Cirrhosis

And how common are the polymorphisms? Per the package insert, "The prevalence of polymorphisms at any of these positions in genotype 1a-infected subjects was 11% (62/561) overall, and 12% (37/309) specifically for subjects in the U.S. across Phase 2 and Phase 3 clinical trials ..."

Furthermore, as noted above, some of the regimens will also need to be extended to 16 weeks, and the prescribing information recommends LFT monitoring during treatment for all patients. Drug-drug interactions are also more common than with LDV/SOF.

These issues notwithstanding, EBR/GZR is a simpler treatment than the "PrOD" regimen (paritaprevir, ritonavir, ombitasvir, and dasabuvir) -- and for the record less expensive than that one, too.

Not only that, the brand name (Zepatier!) offers a nice French souffle to our existing Italian baked pasta with cheese (Harvoni!).

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