The dawn of a new era in the treatment of HCV infection: A view from the USA

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Abbreviations

AASLD‐IDSA

American Association for the Study of Liver Diseases‐Infectious Diseases Society of America

FDA

US Food and Drug Administration

FDC

fixed‐dose combination

GT

genotype

HCV

hepatitis C virus

IL28B

interleukin‐28B

NDA

new drug applications

NEJM

New England Journal of Medicine

PI

protease inhibitor

RBV

ribavirin

SVR

sustained virologic response.

It is rare for any of us to get a publication in the New England Journal of Medicine (NEJM); topics in our discipline do not typically merit international attention, and of course NEJM is an extremely competitive journal. It should not have escaped your attention, therefore, that in a brief period of a few months there were 10 original manuscripts and four accompanying editorials all devoted to a single topic in our field, that of new interferon‐free therapies for hepatitis C (HCV).1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 If nothing else, this exposure should testify to the importance of these breakthrough drugs, not just to the editors and reviewers for NEJM but also to physicians and patients in general. The lay press has been extremely busy writing stories about these drugs, their costs, and their access to patients—all factors that have garnered tremendous attention from the general public as well as from state and national governments around the world.

The purpose of this article is to give a brief snapshot of HCV therapy from the vantage point of US physicians. In coming months, Clinical Liver Disease will publish similar personal perspectives on the treatment of HCV in the new era from the viewpoint of providers in South America, Europe, and Asia.

Although we had an approved regimen for interferon‐free treatment of HCV by the end of 2013, it was limited to genotype (GT) 2 patients and had less efficacy in GT 1 and 3 patients, especially those with cirrhosis and prior treatment failures, and it required the addition of ribavirin (RBV) in everyone. Thus, there were numerous unanswered questions remaining this year in anticipation of the results of the first IFN‐free treatments for GT 1 patients: Would GT1a patients respond as well as those with GT1b? Would protease inhibitor (PI) resistance‐associated variants be treatable? Would cirrhosis remain a barrier to response? Would interleukin‐28B (IL28B) type matter? Would race matter? Would ribavirin be required in all regimens? Would a regimen without a nucleoside polymerase backbone be effective? Would the duration shorter than 12 weeks be effective? Would the drugs be safe and truly well tolerated? Would a fixed‐dose combination (FDC) pill be effective? And would results in the US population match those in a New Zealand population?15

The results from the phase 3 ION‐1, −2, and −3 studies combining ledipasvir and sofosbuvir from Gilead Sciences answered most of the questions.1, 2, 3 The ION‐1 and −2 studies clearly showed that SVR rates near 95% are obtainable, regardless of GT1 subtype, IL28B genotype, prior treatment failure, or race.1, 3 Secondly, all three trials showed that response with or without RBV was equal; therefore, RBV can be eliminated from the regimen, alleviating the only real adverse events in the trials, that of hemolytic anemia due to RBV. Thirdly, the therapy was effective as a once daily fixed dose combination (FDC) pill that is well tolerated with essentially no side effects. The ION‐3 trial further showed that an 8‐week regimen is as effective as 12 weeks in a treatment‐naïve noncirrhotic population.2 Presumably, this will be the regimen for many newly diagnosed patients in the coming years. Lastly, there were only a few cases for which SVRs dropped to 89% to 90%, namely those treatment failures with cirrhosis and those patients with preexisting Q80K mutations.1 The 24‐week treatment arm was nearly 100% effective in these cases and may then offer a salvage strategy for relapse cases.

The only unanswered question left was if a regimen that lacked a nucleoside backbone would be equally effective, especially in the difficult‐to‐treat populations. The three‐drug FDC studies from AbbVie using paritaprevir and ritonavir–ombitasvir and dasabuvir with or without ribavirin clearly showed that SVR rates of 95% or better could be achieved in virtually all patients using only a retonavir‐boosted NS3/4 PI, an NS5 inhibitor, and a nonnucleoside polymerase inhibitor with (for GT1a) or without (for GT1b) RBV.6, 7, 8, 9 This means that there is more than one way to skin a cat, and we will likely see other effective combinations without a nucleoside polymerase inhibitor backbone. Although the AbbVie regimen requires RBV for the GT1a population, the study results offered clarity regarding those with cirrhosis who clearly need a 24‐week regimen for maximal efficacy. This will likely allow for insurance approval of this regimen, when we prescribe a longer treatment for GT1a cirrhotic patients. In addition, the issues of drug cost that thus far have been controversial13 will obviously take a forefront once there are competing regimens that are equally effective and US Food and Drug Administration (FDA)‐approved.

The initial approvals of these two IFN‐free regimens will just be for GT1 patients because the new drug applications (NDA) submitted to the FDA only contained data on GT1 patients. However, other, less robust data exists for GT2 and 3 patients using daclatasvir plus sofosbuvir together without RBV, which obtained excellent SVR rates in a small number of patients.5 This may lead to extensive off‐label use of this combination in certain patients, once daclatasvir is approved, as witnessed with the use of simeprevir and sofosbuvir in the last 6 months since their approval. The barriers to treatment will likely fall once these new agents are approved; payers will have difficulty arguing that treatment should be limited to only patients with advanced disease, as they are now. There will be little justification for that argument when treatment is short, easy, well tolerated, and essentially effective for everyone regardless of the extent of liver disease.

The American Association for the Study of Liver Diseases‐Infectious Diseases Society of America guidelines regarding treatment populations have not fully supported this notion and recommend that we continue to treat HCV as a liver disease. Many experts have noted that this medical triumph would be wasted if only shared with those who have cirrhosis.12, 13 Thus far, US providers have generally had access to newly approved agents without restrictions as long as prescribed according to label. Hopefully, this year will be looked back on as the beginning of the end of the hepatitis C era. I hope that the morbidity and mortality that we have all seen due to this illness will become rare and we can welcome the ‘post‐hepatitis C era’.