More than 6,000 veterans with HCV have been treated at the VA in the past two years with the triple therapy of boceprevir or telaprevir plus ribavirin and interferon. In addition, hundreds of veterans have started only in the past few months on the next generation direct-acting antivirals. VA public health officials report impressive results: The cure rates for first generation DAAs were more than 50% — and could be even better with the new treatments.
By Annette M. Boyle
WASHINGTON — Since 2011, a parade of new drugs has changed nearly everything about treatment for chronic hepatitis C viral infection — who can be treated, the length of therapy, the common side effects, the mode of administration and, most significantly, the cure rate. With even more treatment options with different mechanisms of action on the horizon, the pace of change is unlikely to slow anytime soon.
Recognizing the need for timely, accurate information about the therapies available and recommendations for their use, the Infectious Diseases Society of America (IDSA), the American Association for the Study of Liver Disease (AASLD) and the International Antiviral Society-USA (IAS-USA) recently launched HCVguidelines.org. The site has current guidance for clinicians about diagnosis, treatment and unique patient populations. Updates for the site will include new sections on management and monitoring patients. The online resource provides close to real-time information about the methodology underlying the recommendations and links to the supporting research.1
The Veterans Administration National Viral Hepatitis Treatment Guidelines Workgroup also will release updated treatment guidelines this spring, according to a VA spokesperson. The largest provider of HCV care in the country, the VA cares for more than 5% of all HCV patients in the United States. The new guidelines will reflect the real-world experience gained from treating thousands of HCV patients with the first-generation direct-acting antivirals (DAAs), boceprevir and telaprevir, as well as emerging results from the second-generation DAAs, sofosbuvir and simeprevir, which gained Food and Drug Administration (FDA) approval late last year.
In the past two years, the VA treated more than 6,000 veterans with the triple therapy of boceprevir or telaprevir, plus ribavirin and interferon. In the past few months, “hundreds of veterans have been started on the recently FDA-approved next-generation DAAs,” according to the VA Office of Public Health, “and the rate of uptake is considerably higher than for the first-generation DAAs.” All four medications are on the VA National Formulary.
So far, the results have been impressive. “The cure rates for the first-generation DAAs in VA patients were over 50%, compared to only 20% for older treatments. We expect those rates to be even higher with these new treatments,” VA spokesperson Ndidi Mojay told U.S. Medicine.
Increased willingness to undergo HCV treatment might come down to two factors: less reluctance to recommend treatment on the part of healthcare providers and more interest in the shorter, oral therapies on the part of patients. Both traditional (pre-2011) treatments and the triple therapies developed with the first-generation DAAs relied on interferon (PEG) and ribavirin (RBV).
“The problem up to now has been that interferon has low cure rates and is horribly toxic,” David Ross, MD, PhD, director of the HIV, HCV and public pathogens programs at the VA told U.S. Medicine last fall. “Ribavirin is no walk in the park, either. Patients suffer severe anemia and rash; some have to have blood transfusions or take growth factor to combat anemia.”
Relatively few patients completed the full 48-week course of traditional treatment. The protease inhibitors boceprevir and telaprevir added in the triple therapies reduced the number of weeks of treatment required but increased the complexity of the therapy by adding as many as 18 pills that had to be taken at set intervals in the day and requiring response-guided therapy (RGT) to determine whether to continue treatment.
“These new medications (sofosbuvir and simeprevir) have far fewer side effects than previous treatments, have shortened treatment duration for most patients with HCV, and clinical trial data have shown them to be much more efficacious,” according to the VA Office of Public Health. “Over the next five years, it is very likely that ‘standard treatment,’ the combination of interferon and ribavirin, will no longer be necessary, except under rare circumstances.”
Already, the new AASLD/IDSA guidance recommends interferon-free therapies as the preferred treatment for treatment-naive patients and those who have relapsed with genotypes 2, 3, 5 and 6 and as alternative treatments for IFN-ineligible patients with genotypes 1 and 4. All the preferred and alternative regimens call for combinations of sofosbuvir and ribavirin with or without simeprevir and interferon.
In a major change, the guidelines specifically note that “although regimens of PEG/RBV plus telaprevir or boceprevir for 24 to 48 weeks using RGT are also FDA approved, they are markedly inferior to the preferred and alternative regimens. These regimens are associated with their higher rates of serious adverse events (e.g., anemia and rash), longer treatment duration, high pill burden, numerous drug-drug interactions, frequency of dosing, intensity of monitoring for continuation and stopping of therapy and the requirement to be taken with food or with high-fat meals.”
Interferon-free therapies should soon emerge from the pipeline for previously treated patients, as well. Research released at The Liver Meeting 2014 and published in the New England Journal of Medicine in April showed sustained virologic response (SVR) rates of 95% to 100% in patients treated with ABT-450/r, ombitasvir and dasabuvir with ribavirin who had experienced a relapse or had partial or null response to prior treatment. ABT-450/r is a NS3/4A protease inhibitor with added ritonavir to inhibit its metabolism. Ombitaxvir is an HCV NS5A inhibitor and dasabuvir in a NS5B RNA polymerase inhibitor.2
In research also published earlier this year, researchers found that a combination of sofosbuvir and daclatasvir, which is not yet FDA approved, achieved undetectable viral levels in 98% of both previously untreated patients and those who had not responded to triple therapy. The results were consistent across genotypes 1, 2 and 3. A study published in April showed similar response rates with a combination of the NS5A inhibitor ledipasvir and sofsbuvirfor in both treatment naïve and previously treated patients. 3, 4, 5
Improved therapeutic options and recommendations for broader screening could increase substantially the number of veterans receiving treatment for HCV. In 2012, the national Centers for Disease Control and Prevention (CDC) recommended a one-time HCV test for everyone born between 1945 and 1965, regardless of risk factors.
An analysis of VA records shows that about two-thirds of baby boomers who receive care through the VA have been screened for HCV, and nearly 10% have the virus, compared to 1% to 2% of veterans born before or after the cutoff dates. Systemwide screening of this cohort could add 51,000 veterans with HCV to the nearly 170,000 already identified, according to research results presented at The Liver Meeting 2013 by Lisa Backus, MD, PhD, deputy chief consultant in the VA’s public health group. 6
“Given the rapidly shifting landscape of hepatitis treatment, VA is responding by focusing on system redesign to restructure the way that viral hepatitis care is delivered to 1) address treatment limiting medical and mental health co-morbidities, and 2) increase access to high quality HCV care for the expanding population of veterans who can now be successfully treated,” the VA Office of Public Health noted.
Active and untreated mental health and substance use disorders as well as comorbidities such as human immunodeficiency virus (HIV), renal impairment and cirrhosis can make treatment more challenging. As part of the restructuring to better treat HCV patients, the VA is making efforts to connect these patients with patient care teams and specialists that can address these concerns, so that they may become eligible for and more likely to succeed in treatment.
The VA’s telehealth and Specialty Care Access Network-Extension for Community Healthcare Outcomes (SCAN ECHO) are crucial components of VA plans to provide access to growing numbers of HCV-infected veterans who seek treatment. The SCAN ECHO project helps healthcare providers in smaller VA clinics manage patients requiring complex care by connecting them to specialists at VA academic medical centers.
1 AASLD/IDSA. Recommendations for Testing, Managing, and Treating Hepatitis C. Revised March 12, 2014. Hcvguidelines.org.
2 Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin. N Engl J Med 2014; online April 10, 2014.
3 Sulkowski MS, et al. Daclatasvir Plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection. N Engl J Med 2014; 370: 211-221.
4 Kowdley KV, et al. Ledipasvir and Sofosbuvir for 8 or 12 weeks in Chronic HCV without Cirrhosis. N Engl J Med 2014; online April 11, 2014.
5 Afdhal N, et al. Ledipasivir and Sofosbuvir for Untreated HCV Genotype 1 Infection. N Engl J Med 2014; online April 12, 2014.
6 L Backus, PS Belperio, TP Loomis, et al. Hepatitis C Virus Screening and Prevalence among US Veterans in Department of Veterans Affairs Care in 2012. 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2013). Washington, DC, Nov. 1-5, 2013. Abstract 21.