Thursday, May 15, 2014

Reconsidering Whether to Treat Genotype 1 HCV Patients or Wait for All-Oral Therapy

Source - Clinical Thoughts @ Clinical Care Options

Post-EASL Update:
Reconsidering Whether to Treat Genotype 1 HCV Patients or Wait for All-Oral Therapy
Paul Y. Kwo, MD
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At the recent 2014 meeting of the European Association for the Study of Liver Disease (EASL) in London, extraordinary data were presented from large phase III trials involving the direct-acting antiviral (DAA) combinations of sofosbuvir plus ledipasvir and ABT-450/ritonavir plus ombitasvir and dasabuvir, each administered with and without ribavirin. Sustained virologic response (SVR) rates > 94% were reported with use of fixed-dose sofosbuvir/ledipasvir with or without ribavirin in genotype 1 treatment-naive patients and treatment-experienced patients (including protease inhibitor–exposed patients), including high SVR rates among the subsets of patients with cirrhosis. Similarly, the combination of fixed-dose ABT-450/ritonavir/ombitasvir with dasabuvir and ribavirin resulted in SVR rates > 95% in trials for treatment-naive and treatment-experienced patients, and > 90% in a trial for cirrhotic patients. In addition, small phase II studies demonstrated high SVR rates with the use of sofosbuvir/ledipasvir in HCV/HIV-coinfected patients, and with use of ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin in patients with recurrent HCV infection following orthotopic liver transplant. These high SVR rates were achieved without the addition of interferon, the backbone of hepatitis C therapy for the past 2 decades. These investigational therapies are expected to be approved by the FDA before the end of 2014. Clinicians will then be able to offer all-oral therapies for patients across all HCV genotypes with the expectation of high SVR rates.

In the United States, high SVR rates can currently be achieved in genotype 1 HCV–infected patients who are treatment naive and interferon eligible with the use of peginterferon, ribavirin, and sofosbuvir. This combination resulted in an overall SVR rate of 89% with a 12-week treatment course in the phase III NEUTRINO study. For patients who have been treated previously with peginterferon/ribavirin and those who are interferon ineligible, the combination of sofosbuvir and simeprevir with or without ribavirin has been recommended as a therapeutic option in the 2014 AASLD/IDSA treatment guidelines based on high SVR rates demonstrated in the phase II COSMOS study.

How I’m Currently Managing Genotype 1 Patients
In my practice, all genotype 1 patients are candidates for therapy at this time, although histologic disease severity strongly guides my treatment recommendations. For genotype 1 patients, we offer peginterferon, ribavirin, and sofosbuvir as first-line therapy, but we strongly encourage patients to consider waiting for the all-oral regimens that are likely only months away from FDA approval, particularly those individuals with mild disease (F0-F2) in whom deferral of therapy is unlikely to lead to adverse clinical outcomes. Given the phase III data that have been presented, I find that virtually all patients with milder disease wish to defer therapy in order to have the opportunity to achieve SVR without interferon. Moreover, patient monitoring is significantly less complicated without use of interferon, even with the shorter treatment courses currently recommended for genotype 1 patients. This approach also applies to patients with milder disease (F0-F2) who have previously failed treatment.

By contrast, patients with advanced fibrosis, including those with F3/F4 fibrosis, are given the option of receiving therapy now. These individuals require careful assessment of the degree of advanced fibrosis as they are at risk for decompensating and are also screened regularly for hepatocellular cancer. In a subanalysis of the phase III NEUTRINO study, high SVR rates were reported across all degrees of fibrosis following treatment with 12 weeks of sofosbuvir, peginterferon, and ribavirin, with patients having proven histologic cirrhosis by biopsy demonstrating an SVR rate of 78% whereas those with F3 fibrosis demonstrated an SVR rate of 89%. By historical standards, these are excellent SVR rates but are still numerically lower than rates reported from recent phase III all-oral therapy trials. After careful assessment, if I am confident that a patient’s fibrosis level is F3, I can tell them that they can safely defer therapy if they wish and that they will be followed closely, or they are offered peginterferon, ribavirin, and sofosbuvir or simeprevir with sofosbuvir, if available to them.

In my practice, patients with cirrhosis are all offered therapy. The phase II COSMOS study demonstrated high SVR rates with 12 weeks of sofosbuvir plus simeprevir with or without ribavirin in patients with F3/F4 fibrosis (94% to 100% in F3 fibrosis and 86% to 91% in F4) in both treatment-naive patients and null responders, and this is my preferred regimen in this population given the numerically higher SVR rates, regardless of whether the patient can tolerate interferon or not. In the COSMOS study, relapse was only seen in patients with genotype 1a HCV, of whom 2 of 3 relapsers had the Q80K polymorphism that is present in almost one half of genotype 1a individuals in North America and reduces susceptibility to simeprevir. Therefore, in genotype 1b patients, I recommend sofosbuvir plus simeprevir, and in patients with genotype 1a, I recommend sofosbuvir plus simeprevir with ribavirin. This option is particularly beneficial in patients with greater degrees of advanced fibrosis and portal hypertension, who are less likely to tolerate interferon, and in whom the CUPIC cohort study recently demonstrated that platelet count < 100,000/mm3 and albumin < 3.5 g/dL were associated with a significant risk of decompensation and/or severe infections.

There are of course circumstances that may necessitate immediate therapy initiation in patients with milder histologic disease, such as those who have significant extrahepatic manifestations of HCV infection (such as membranoproliferative glomerulonephritis). In addition, some patients do not wish to defer, regardless of disease severity. In my practice, these individuals are offered either peginterferon, ribavirin, and sofosbuvir or simeprevir plus sofosbuvir, if available to them. It is estimated that there are at least 500,000 individuals with advanced fibrosis in the United States, and it is this group that represents the highest priority for initiating therapy now. However, those with genotype 1 HCV will likely have FDA-approved all-oral therapies available to them by the end of 2014, with SVR rates that could not have been imagined 5 years ago.

Your Thoughts?
I’m interested to hear about your own approach to managing patients with genotype 1 HCV, given the recent data presented at EASL 2014 and in anticipation of further drug approvals in the coming year. Which patients are you currently advising to defer therapy, and which are you most concerned to treat now?

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Topics: HCV - Treatment

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