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Genotype 1 HCV–Infected Cirrhotic Patients: Still Hard to Treat?
Mark S. Sulkowski, MD - 6/27/2014
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After years of telling our patients that better HCV treatments are coming soon, we finally have access to potent, safe, oral direct-acting antivirals (DAAs) in our clinics and we expect more oral DAA regimens to be approved over the next 18 months. As clinicians, the ability to offer the opportunity for HCV cure to our patients with the greatest medical need—those with cirrhosis—is truly great news.
Patients with HCV-related cirrhosis have the greatest risk for the development of hepatic decompensation, hepatocellular carcinoma (HCC), and the need for transplantation. They are also at the greatest risk for liver-related death in the absence of liver transplantation. At the same time, we are increasingly confident that we can decrease the risk of these life-threatening outcomes in patients with compensated cirrhosis if their underlying HCV infection is cured, appropriate lifestyle modifications are adopted (eg, cessation of alcohol and reduction of caloric intake coupled with more exercise in obese patients), and medical interventions are provided (eg, serial liver imaging studies for HCC and endoscopic surveillance and/or treatment of esophageal varices). But the bottom line is this: Patients with compensated HCV-related cirrhosis need to be cured of their chronic HCV infection with some degree of urgency.
Poor Cure Rates, High Adverse Events With Previous Therapies
So, let’s set aside the decompensated patients and those with HCC for now and focus on compensated cirrhosis. In my practice, these patients tend to be older adults infected with HCV genotype 1 or 3 and are previous nonresponders to peginterferon/ribavirin or one of the first-generation protease inhibitors. Many are poor candidates for interferon-based treatments, as this drug simply does not work well for cirrhotics; this was demonstrated as far back as the IDEAL study evaluating peginterferon alfa-2a vs alfa-2b both with ribavirin (once an important question—my, how times have changed in the world of HCV therapeutics!). With peginterferon alfa plus ribavirin, the cure rate for genotype 1 HCV–infected patients with F3/F4 fibrosis or cirrhosis was low (24% with peginterferon alfa-2a and 21% to 30% with peginterferon alfa-2b across two dosing arm), and approximately one half that seen in patients with minimal fibrosis (44%). In later studies that added one of the first-generation HCV protease inhibitors to peginterferon/ribavirin, rates of HCV cure in cirrhotic patients with genotype 1 infection were higher, in the low 60% range, but not as high as those reported in patients without cirrhosis (approximately 80%).
However, when we drill down further to the most “difficult-to-treat” patients—those with genotype 1 infection, cirrhosis, and previous null response to peginterferon/ribavirin—the cure rate with telaprevir plus peginterferon/ribavirin was an abysmal 15%. Comparable data on boceprevir use in this population are limited. Two of 4 previous null responders with F3/F4 fibrosis who received boceprevir plus peginterferon/ribavirin in the PROVIDE study achieved SVR. To make matters worse, we commonly saw significant adverse effects in these patients, including anemia and infections, not to mention liver failure in some. Good riddance to that—boceprevir and telaprevir earned a “not recommended” designation in the 2014 AASLD/IDSA guidance, and I agree they should no longer be used in settings where the newer DAAs are now available.
The Current Era of HCV Therapies
Late 2013 saw the launch of the current era of HCV treatment with sofosbuvir, the first of a brand new class of antivirals, nucleotide analogue NS5B polymerase inhibitors, and simeprevir, a vastly improved HCV NS3/4A protease inhibitor with once-daily dosing and no discernible risk of anemia. After a couple years of administering epoetin alfa and blood transfusions to our boceprevir- and telaprevir-treated patients, I am grateful for that particular attribute. My clinic has been bustling with patients wanting treatment and, not surprisingly, many are treatment-experienced cirrhotic patients.
I would like to describe one such patient, a 55-year-old black man with genotype 1b HCV compensated cirrhosis (MELD score: 10) and previous null response to peginterferon/ribavirin (his HCV RNA level actually went up at Week 12 of peginterferon/ribavirin treatment). He is healthy otherwise and anxious to take treatment, even willing to take interferon if required.
Is an interferon-based regimen his best option? In the phase III NEUTRINO study, the SVR rate in treatment-naive, genotype 1 HCV–infected cirrhotic patients treated with sofosbuvir plus peginterferon/ribavirin was approximately 80%, a good response rate compared with the past regimens. Once again, noncirrhotic patients did better: In this group, more than 90% were cured. The NEUTRINO regimen was not tested in cirrhotic previous null responders like our case patient, but an FDA analysis estimated the likely SVR rate in such patients to be approximately 70%. A few years ago, if I could have gotten my hands on an HCV regimen that could cure 70% of black cirrhotic, null responders, I would have prescribed the regimen in a heartbeat. But, today, there are treatment regimens with a higher likelihood of success available for patients like this one, including the “off-label” combination of sofosbuvir plus simeprevir.
The Coming Wave of All-Oral DAA Therapy
The data are crystal clear: For previous null responders with cirrhosis and perhaps for treatment-naive cirrhotic patients too, the best chance for a potentially life-saving HCV cure is an oral combination regimen of potent DAAs. By the end of 2014, we expect the FDA approval of the first agents in a new class of HCV DAAs called NS5A inhibitors. These agents will be an important part of 2 potent, interferon-free, all-oral regimens: the once-daily, single tablet, fixed-dose combination of sofosbuvir/ledipasvir and a 3-drug regimen that includes a fixed-dose combination of a ritonavir-boosted HCV protease inhibitor (ABT-450) plus ombitasvir (an NS5A inhibitor) administered with dasabuvir (a nonnucleoside polymerase inhibitor). The New England Journal of Medicine has published results from a series of historic phase III studies, also presented at the 2014 EASL annual meeting, in which HCV cure rates were between 82% and 100% across treated and untreated genotype 1 HCV–infected cirrhotic patients receiving these novel regimens with or without ribavirin.
Some fine-tuning of therapy may still be needed in this group of patients. In the phase III ION-1 study of sofosbuvir/ledipasvir in untreated patients, there appeared to be some drop off in response rate among cirrhotic patients who did not receive additional ribavirin compared with those who did (94% vs 100%, respectively). In the phase III ION-2 study of the same regimen in previously treated patients, cirrhotic individuals appeared to benefit more from the 24-week regimens than from 12 weeks of therapy (100% vs 82% to 86%, respectively). And in the phase III TURQUOISE-II study of the 3-drug regimen plus ribavirin in cirrhotic patients, previous null responders with genotype 1a infection also appeared to do better with 24 weeks of therapy compared with 12 weeks (93% vs 80%, respectively). Overall, however, the development of these therapies remains a remarkable achievement, and we are really looking forward to these regimens as they will permanently transform how we think about this important disease.
What About Cirrhotic Patients Who Cannot Delay Therapy?
What about my patient? To recap, he’s a 55-year-old black cirrhotic null responder with HCV genotype 1b infection. Should I wait for these future treatment options in his case? After all, we have been waiting for new therapies since he first failed peginterferon/ribavirin in 2006. This is a long time to wait for treatment that can yield an HCV cure, while hoping that HCC is not found on the next liver ultrasound.
I opted to treat him in accordance with the AASLD/IDSA HCV guidance recommendation for genotype 1 patients with previous nonresponse to therapy. I prescribed a 12-week course of sofosbuvir and simeprevir, a potent once-daily regimen. Is this his best option? The final results of the phase II COSMOS study that evaluated this regimen were hard to beat for cirrhotic patients with genotype 1b HCV : All genotype 1b patients were cured, as were most cirrhotic null responders.
The response rates in this study for patients with genotype 1a infection were also quite good, although a number of patients with this subgenotype receiving the 12-week regimens did experience viral relapse, whereas those treated for 24 weeks did well: SVR rates in the 12-week arms were between 88% to 100% across arms vs 100% in both treatment arms for the 24-week regimens. Use of ribavirin did not appear to make a difference to SVR rates, but this is not definitive. I know that some of my colleagues are adding ribavirin to the regimen for patients with genotype 1a infection who are receiving sofosbuvir plus simeprevir, on the basis that other studies have demonstrated some benefit from this approach. While I understand the limitations of the COSMOS study—it is a small phase 2 trial—currently, it is the best option for HCV cure for this cirrhotic patient who has been waiting a long time for treatment. Achieving HCV cure will dramatically reduce the likelihood that he will develop HCC or liver failure and need a liver transplant, complications of HCV that are both expensive and, for at least 15,000 Americans each year, deadly.
I am interested to hear about your own current practice for treating cirrhotic patients. In light of the new data on all-oral regimens for genotype 1 HCV, what is your management approach? Please use the comments section below to provide your insights.
Topics: HCV - Treatment
Of Interest @ CCO
My Approach to Identifying Treatment Candidates and Maintaining Patients on Long-term HBV Therapy
Highlights From EASL 2014
Antiretroviral Therapy Update 2014