Pangenotypic regimens and the next generation hepatitis C virus therapy

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Abbreviations

AASLD

American Association for the Study of Liver Diseases

DAA

direct‐acting antiviral

FDC

fixed dose combination

GP

glecaprevir/pibrentasvir

MK3

grazoprevir/MK‐3682/NS5A inhibitor (elbasvir or Ruzasvir)

PEG

pegylated interferon

PI

protease inhibitor

RBV

ribavirin

SOF/VEL/VOX

sofosbuvir/velpatasvir/voxilaprevir

Three new antiviral therapies for viral hepatitis C are anticipated in the next several months: GP, glecaprevir (protease inhibitor [PI])/pibrentasvir (NS5A inhibitor); SOF/VEL/VOX, sofosbuvir (NS5B inhibitor)/velpatasvir (NS5A)/voxilaprevir (NS3); and MK3, grazoprevir (NS3) + MK‐3682 (NS5B) + NS5A inhibitor (elbasvir or Ruzasvir). Each is a pangenotypic all‐oral fixed dose combination (FDC) with high potency and efficacy against common NS3 and NS5A polymorphisms. Multiple safety and efficacy abstracts were presented at the 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in November 2016. In this article, I will address why we need new therapies as well as what is still unaddressed in the arsenal against hepatitis C.

Traditionally, several patient and viral characteristics conferred significant risk for treatment failure. In the era of pegylated interferon (PEG) and ribavirin (RBV) these included multiple facts such as gender, weight, age, treatment experience, cirrhosis status, viral load, and genotype. In addition, PEG/RBV was inappropriate for many patients, such as those with advanced cirrhosis or significant comorbidities. With the advent of all‐oral therapy, most of these baseline characteristics have disappeared or diminished to the point that we are now left with four primary Achilles heals: direct‐acting antiviral (DAA) failures, especially those exposed to NS5A inhibitors; genotype 3 with cirrhosis; decompensated cirrhosis; and lack of access to therapy. With the approval of the next wave of therapy, nearly each of these difficult subsets will again disappear.

DAA Failures

Although in phase 3 trials, less than 5% of patients treated with appropriate regimens of all‐oral DAAs experience virology failure; this still leaves a sizable number of individuals in need of a salvage therapy. This is most important for individuals who have been exposed to NS5A inhibitors because the treatment emergent resistance continues to replicate for months, and studies have shown that those with resistance experience lower cure rates on retreatment. All three combinations appear to have excellent efficacy in this population. Twelve weeks of GP achieved 96% sustained viral response twelve weeks after discontinuing therapy (SVR12) in 47 patients with prior failures including 25 (50%) who were NS5A experienced and 42 (84%) PI experienced.1 The POLARIS trials are the phase 3 studies of SOF/VEL/VOX. A total of 263 NS5A failures, 41% of which were cirrhotic, were treated for 12 weeks with SOF/VEL/VOX in POLARIS‐1, 96% of which achieved SVR12.2 DAA experienced (without prior NS5A exposure) patients were treated with either SOF/VEL/VOX or SOF/VEL for 12 weeks in POLARIS‐4. Forty‐six percent of patients had cirrhosis; 97% achieved SVR12 with the triple compared with 90% with the dual therapy.3 Integrated analysis of treatment‐naïve and treatment‐experienced patients treated with SOF/VEL/VOX in phase 2 studies found that the presence of NS3 or NS5A resistance‐associated substitutions had no impact on SVR12.4 C‐SURGE used MK3 with RBV for 16 weeks (N = 43) or MK3 for 24 weeks (N = 30) in NS5A failures and showed 100% efficacy.5

Genotype 3

The recently approved FDC SOF/VEL is a highly efficacious alternative for genotype 3 with a SVR12 rate of 95%. However, in ASTRAL 3, the efficacy was lower (88% versus 97%) for those with detectable NS5A variants (A30K, L31M, and Y93H).6

Luckily, these patients also have excellent options in the pipeline. SURVEYOR‐II Part 3 evaluated the efficacy and safety of GP in complicated genotype 3 patients. Twelve weeks of therapy achieved SVR in 91% (20/22) of treatment‐experienced patients without cirrhosis, and when extended to 16 weeks achieved 96% SVR12 (21/22). Treatment‐naive cirrhotic patients achieved SVR12 in 98% with 12 weeks of therapy and 96% of treatment‐experienced patients achieved SVR12 with 16 weeks of GP.7 POLARIS‐3 demonstrated 96% efficacy in treatment‐naive cirrhotic patients with only 8 weeks of the triple, which was equally efficacious to 12 weeks of SOF/VEL, also 96% SVR12.8 C‐ISLE demonstrated 100% efficacy using 12 to 16 weeks of EBR/GZR+SOF with or without RBV in treatment‐naive and treatment‐experienced G3 patients with cirrhosis.9

Access

Pricing is not set until the approval of an agent, but short, simple, safe therapy should expand the willing provider pool. Eight‐week duration therapy consistently showed high efficacy in most patients. Still, subsets will require longer duration treatment, making an algorithm that is “short” also contain the complexity of understanding the impact of cirrhosis, treatment experience, genotype or subgenotype, resistance‐associated substitution, and viral load, in addition to applying these rules to an individual regimen. Providers and patients must also be careful not to grow cavalier. The risk of missing cirrhosis not only impacts therapeutic efficacy but also fails to identify an individual with continued risk for liver‐related morbidity despite curing HCV.

The one remaining patient type that the pipeline will not influence is those with decompensated cirrhosis. Treatment of this group is already controversial because viral eradication does not lead to clinical improvement in all and may actually negatively impact access to liver transplant. Guidelines currently recommend only NS5A+SOF‐based therapy and advise against using PIs, because this class requires hepatic metabolism. In those who are actively listed for transplant, treatment after surgery also allows utilization of HCV‐positive donors. With more time and data, we will clarify which patients with advanced disease will most likely benefit from therapy. However, current PI‐based therapy is not advised in those with advanced cirrhosis (existing or prior decompensation) because of an increased risk for decompensation. The next generation PIs have not yet been studied in this population. In addition, treatment in those with hepatocellular carcinoma is controversial as a result of reports that tumor biology may be unfavorably changed with all‐oral therapy.

Overall, the pipeline of hepatitis C therapy will again redefine a “difficult” case, making viral eradication a reality for nearly every adherent patient with access to treatment.