An estimated 1% of the world population is affected by hepatitis C virus (HCV) infection, and approximately 399,000 of the 71 million infected people die each year from HCV-related cirrhosis and liver cancer.1
Most current guidelines on treatment of chronic HCV recommend 12 weeks of treatment with direct-acting antivirals (DAAs),2,3 because of the high rates of sustained virologic response (SVR) achieved with this treatment regimen. However, emerging research suggests that short-duration regimens, lasting 8 weeks or less, may be equally effective in inducing SVR in many patients.4,5 A recent review and meta-analysis of 4 real-world cohorts found that an 8-week treatment with ledipasvir/sofosbuvir has an overall effectiveness of 97.9% in people with HCV, with favorable characteristics.6
The high cost of DAA-based regimens remains an ethical issue and an obstacle to treatment accessibility.7 Shorter treatment regimens may offer substantial cost savings, improved treatment adherence, and a reduced rate of side effects. However, potential limitations of these regimens, such as higher relapse rates and development of viral resistance, need to be investigated further.7
In an email interview with Infectious Disease Advisor, Eleanor Wilson, MD, MHS, assistant professor at the Institute of Human Virology, University of Maryland School of Medicine in Baltimore, and Thomas R. O’Brien, MD, MPH, senior investigator at the Division of Cancer Epidemiology and Genetics, National Cancer Institute in Bethesda, Maryland, discussed the advantages and limitations of short-duration regimens for chronic HCV.
Infectious Disease Advisor: How much clinical evidence is available that demonstrates the effectiveness of short-duration regimens for treatment of chronic HCV?
Eleanor Wilson, MD, MHS: In our recent opinion piece,7 we summarized the 20 clinical trial study arms that looked at various drug combinations in short-course treatment with varying response rates. From these data and from subsequent analyses as well as modeling, we know that there are some predictors of improved response to short-duration treatment such as viral (HCV genotype and viral load) and host factors (age, sex, genetic polymorphisms, and fibrosis stage).
The SODAPI study8 was the first to select treatment groups based on these factors and apply a test to determine whether patients had an adequate early viral response before deciding whether they receive full or short-course treatment — it showed a tremendous response to extremely short (3 week) treatment. However, this was a small study in a homogeneous population with access to sophisticated laboratory testing not available as routine standard of care, so it remains to be seen whether it could work in a population with different polymorphisms and HCV subgenotypes. Larger studies are definitely needed before anyone could recommend short-course treatment.
Infectious Disease Advisor: What are some of the potential implications/benefits of treating chronic HCV with short-duration regimens lasting 8 weeks or less?
Dr Wilson: Shorter treatment durations would have several advantages — studies of adherence during hepatitis C clinical trials have shown that treatment adherence is higher during the first month of treatment, declines slightly over the second month, and then falls further over the third month. Therefore, if treatment could be limited to 4 to 6 weeks, patients are more likely to take it correctly. While combination direct-acting antiviral-based regimens are overwhelmingly safe, they are associated with some side effects. Shorter treatment durations would limit some of these side effects, like fatigue and headache, which may interfere with a patient’s quality of life.
Furthermore, DAA-based regimens are associated with significant drug interactions, so patients often have to limit the amount of antacids or other medications (particularly cardiac medications like statins or antiarrhythmics) that might interact with HCV treatment; therefore, shorter durations lead to less disruption. Finally, cost can’t be ignored — while many systems price the full regimen regardless of length, others have a per bottle cost. If treatment durations can be reduced, more patients could be treated with the same amount of drug.
Infectious Disease Advisor: What types of studies still need to be conducted before short-duration regimens for HCV can be recommended?
Dr Wilson: Larger studies in real-world populations are definitely needed. So far, most of the studies have been sponsored by or done in collaboration with individual pharmaceutical companies, so the tested treatment combinations have involved only one manufacturer. The exception is the SODAPI study,8 which combined drugs from several different companies and showed that it is possible to cure HCV with ultrashort treatment durations if you can pick the best-in-class DAAs and favorable patient characteristics. Future studies with powerful combinations of drugs need to be done to show whether shorter treatment durations can be applied to more heterogeneous populations and those with less favorable baseline characteristics (HCV subgenotype 1a, advanced fibrosis and cirrhosis, HIV co-infection, etc.).
Infectious Disease Advisor: Can you describe how a clinical algorithm mentioned in your recent opinion article7 could help clinicians in the selection of patients, or patient populations, suitable for short-duration treatment for chronic HCV infection?
Thomas R. O’Brien, MD, MPH: Clinical prediction models are tools that can improve medical decision making and individualize care by estimating an individual’s probability of a clinical outcome based on relevant variables. The statistical methods to construct and validate such models are well developed, and this approach has been employed successfully for other clinical outcomes. For example, Mitchell Gail, my colleague at the National Cancer Institute, has created a publicly available “Breast Cancer Risk Assessment Tool” that serves as the basis for guidelines from the American Society of Clinical Oncology regarding which patients are most likely to benefit from tamoxifen or raloxifene for prevention of breast cancer.
We need much more data to develop such models for hepatitis C, but we envision that we might include information on commonly measured demographic and clinical variables (such as age, sex, race, presence of cirrhosis, pretreatment HCV RNA level, viral genotype, as well as the patient’s IFNL4 genotype). The model would provide each patient with the probability of treatment success for a range of potential regimens and duration of treatment. These results might be provided as part of the testing for IFNL4 genotype result or through an online instrument such as has been implemented for the Gail model.
Infectious Disease Advisor: In clinical trials to date, which DAAs have shown the most promise in short-duration treatment regimens?
Dr O’Brien: I don’t think we have the data yet to compare specific regimens, and that might not be the right question. In a study among Chinese patients,8 George Lau and his colleagues demonstrated that HCV infection can be cured with only 3 weeks of treatment. They used several different regimens (all based on 3 direct DAA agents) in that study, but all patients were infected with HCV genotype 1b, which is generally considered easy to treat, and none carried the least favorable IFNL4 genotype. It is possible that the genetics of the virus and the patient will be important for very short duration treatment.
Infectious Disease Advisor: What are some of the limitations of short-duration DAA regimens for treatment of chronic HCV?
Dr O’Brien: At this point, we have quite a bit of information on treating selected patients with ledipasvir/sofosbuvir for 8 weeks and, although the cure rates for that treatment are quite high (~95% of adherent patients), many physicians opt to treat for 12 weeks. Some reasons for that conservative approach are insurer unwillingness to pay for retreatment, concerns about potential selection of difficult-to-treat, resistant viral strains, and lack of a clear strategy for individuals who fail initial treatment. We will need to resolve those issues if patients are to be treated for even less than 8 weeks.
- World Health Organization (WHO). Hepatitis C fact sheet http://www.who.int/mediacentre/factsheets/fs164/en/. Updated July 2017. Accessed September 27, 2017.
- AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62:932-954.
- Polish Group of Experts for HCV, Halota W, Flisiak R, et al. Recommendations for the treatment of hepatitis C in 2017. Clin Exp Hepatol. 2017;3:47-55.
- Kowdley KV, Gordon SC, Reddy KR, et al. for the ION-3 investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370:1879-1888.
- Terrault NA, Zeuzem S, Di Bisceglie AM, et al. Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology 2016;151:1131-1140.
- Kowdley KV, Sundaram V, Jeon CY, et al. Eight weeks of ledipasvir/sofosbuvir is effective for selected patients with genotype 1 hepatitis C virus infection. Hepatology 2017;65:1094-1103.
- Emmanuel B, Wilson EM, O’Brien TR, Kottilil S, Lau G. Shortening the duration of therapy for chronic hepatitis C infection. Lancet Gastroenterol Hepatol. 2017;2:832-836.
- Lau G, Benhamou Y, Chen G, et al. Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. Lancet Gastroenterol Hepatol. 2016;1:97-104.