New Hep C Recs Target Unique Populations

Updated guidelines from the American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) for the treatment of hepatitis C have identified preferred regimens for patients with decompensated cirrhosis and for other unique populations, such as those with renal impairment.

The recommendations have been divided into a list of variables, including genotype, status of liver function, prior treatment and eligibility for ribavirin (RBV). As with all of the recommendations, bullet point listings are accompanied by a grading of the evidence followed by a detailed analysis of the data on which the recommendation is based.
In a change from the conventional way of preparing clinical recommendations, the guidelines appear on the joint AASLD/IDSA website, www.hcvguidelines.com. The goal is to make current data “accessible to all who are treating HCV,” said Hugo E. Vargas, MD, professor of medicine at Mayo Clinic, in Scottsdale, Ariz.
Speaking at the 2015 annual meeting of the AASLD, Dr. Vargas said the rapid and constant reviews with immediate posting to the website ensure that recommendations remain current with the “dynamic” changes that have been occurring in this area of medicine.
Consistent With Near-Universal Treatment
Treating hepatitis C virus (HCV) even in patients with severe decompensated cirrhosis is consistent with the position by AASLD/IDSA that essentially everyone infected with HCV should now be considered a candidate for therapy. The major exception is a patient with a life expectancy too short to benefit from HCV treatment. According to Dr. Vargas, one goal of these guidelines is to “minimize barriers” to the benefits of a sustained virologic response (SVR).
Ensuring that all HCV patients obtain access to care “has been a very difficult nut to crack,” Dr. Vargas said. Providing joint AASLD/IDSA recommendations that consolidate and explain the quality of the evidence has been one step toward promoting treatment.
Decompensated Cirrhosis
The guidelines for decompensated cirrhosis recommend direct-acting antiviral agents for patients with HCV genotypes 1, 2, 3 and 4. For HCV genotypes 1 and 4, the strongest evidence (class I, level A) supports 12 weeks of 90 mg of ledipasvir (LED) plus 400 mg of sofosbuvir (SOF; Harvoni, Gilead) and RBV, according to the updated recommendations. Slightly weaker evidence supports 60 mg of daclatasvir (DAC; Daklinza, Bristol-Myers Squibb) plus 400 mg of SOF and RBV (class I, level B).

For HCV genotype 1 and 4 patients with decompensated cirrhosis who are ineligible for RBV, the two societies recommend two regimens, but with lower-quality evidence (both class II, level C). One is 60 mg of DAC plus 400 mg of SOF for 24 weeks. The other is 90 mg of LED plus 400 mg of SOF for 24 weeks. Hepatocellular carcinoma is not considered a contraindication for the treatment of any HCV genotype in patients with decompensated cirrhosis under the new guidance.
In genotype 2 or 3 HCV patients with decompensated cirrhosis, 60 mg of DAC plus 400 mg of SOF and RBV for 12 weeks (class II, level B) was the only regimen specifically recommended, although the document discusses several alternatives, particularly for those who are not eligible for RBV.
For treating HCV in patients with cirrhosis, the guidelines identify appropriate therapy, but they also specify that these patients “should be referred to a medical practitioner with expertise, ideally in a liver transplant center.” Yet, the new recommendations alert clinicians that advanced liver disease is no longer a contraindication for treatment.
With the recommended therapies, SVR rates in the presence of decompensated cirrhosis have been high, typically exceeding 85% for most of the HCV genotypes even when decompensation is severe. Also important, SVR has been accompanied by improved liver function, whether measured with Model for End-Stage Liver Disease scores or improvement in Child-Turcotte-Pugh class.
The potential for serious adverse events may be why the guidelines recommend referring HCV patients with decompensated cirrhosis to experienced practitioners. In one study, 5% of such patients died over the course of follow-up (Gastroenterology 2015;149:649-659). Although none of the deaths was attributed to antiviral therapy, HCV treatment often is considered in the context of liver transplant, suggesting that complex decisions may be required for stabilizing patients and weighing the benefit–risk ratio of different regimens, particularly those that include RBV.
Addressing Renal Impairment
On the basis of recent trials, the two societies also identified preferred therapies in HCV patients with severe renal impairment, defined as a creatinine clearance of less than 30 mL per minute, or end-stage renal disease. In patients with HCV genotype 1a, 1b or 4 infection, the preferred direct-acting antiviral regimen is the combination of 50 mg of elbasvir and 100 mg of grazoprevir (Zepatier, Merck) for 12 weeks (class IIb, level B). The alternative, 150 mg of ritonavir-boosted paritaprevir (PAR/r) plus 25 mg of ombitasvir (OMB) and 250 mg of twice-daily dasabuvir (Viekira Pak, AbbVie) for 12 weeks, received the same grading even if the dosing regimen is more complicated.
For genotypes 2, 3, 5 or 6, interferon-based regimens remain an option (class IIb, level B). For HCV patients with mild or moderate renal impairment (>30 mL per minute) the guidelines cite class I, grade A evidence showing that dose adjustments are not necessary for DAC, SOF, simeprevir (Olysio, Janssen), or fixed-dose combinations of LED-SOF or PAR/r-OMB with DAC.
The Future of Guidelines?
The advantage of the website posting of the recommendations is that it is informed by data almost immediately after they become available. According to Dr. Vargas, the rotating members on the AASLD/IDSA joint panels monitor the progress of clinical trials in order to be prepared to act on the results even in advance of publication. The AASLD/IDSA joint website was initiated two years ago, but it appears to be well received. Dr. Vargas reported that by the time of the AASLD meeting in November, the website had more than 1.5 million views and 250,000 unique visitors.
“There is actually a mobile app that allows you to view this guideline on the go, on the fly, so you can still find the information when you do not have access to a desktop,” Dr. Vargas said. He said plans to expand the capabilities of the website include a section designed to educate patients about treatment options.
Several experts agree that a Web-based platform is an appropriate approach for keeping clinical practice current with available data.
“Given the rapidly changing arena of HCV therapeutics, I believe this is currently the only way to provide guidance to those caring for patients. The timeline of evidence-based guideline development is such that they would be outdated before they were published,” commented Norah Terrault, MD, MPH, director of the Viral Hepatitis Center at the University of California, San Francisco Medical Center.
“At some point in the future, when the number of new drugs approved slows down, then published guidelines using the PICO model, as AASLD has done recently for hepatitis B virus, would be appropriate, but at the present time the Web-based format is the best means of aiding physicians treating HCV,” Dr. Terrault added.
Paul Y. Kwo, MD, medical director of liver transplantation at Indiana University School of Medicine, in Indianapolis, seconded the underlying premise of the AASLD/IDSA guidelines that the vast majority of patients with HCV are candidates for treatment, and these guidelines help clinicians select an appropriate therapy. He also agreed that a method of rapidly communicating evolving standards of therapy is appropriately addressed with Web-based dissemination.
“Given the rapid advances that have occurred in the past three years, a guideline that is a living document is far more useful for those who care for HCV patients,” Dr. Kwo observed. “It allows clinicians to keep abreast of the latest updates and approvals for treatment of HCV, as well as to explore treatment options for patients who they previously would not have considered treating or who have comorbidities that they have not previously encountered.”