July 28, 2015 marks World Hepatitis Day, a campaign to help raise awareness about prevention, testing, and treatment of hepatitis. This last year has been a time of rapid and exciting change for hepatitis C treatment in particular, with faster, simpler, and more effective courses available for curing the disease in some patients. Over the next year, additional treatment options for patient populations that remain more challenging to cure are expected to emerge.

The CCC provides free consultation to all U.S.-based healthcare providers on management of HIV and hepatitis B and C co-infection, as well as on potential exposures to hepatitis B and C. Through dedicated Veterans Health Administration (VHA) – U.S. Department of Veterans Affairs funding, the CCC also provides hepatitis B and C mono-infection consultation through the Hepline: this Hepline is only available for providers affiliated with VHA healthcare facilities.

In honor of World Hepatitis Day, the CCC is sharing a case from its CCC VHA Hepline.

Case Summary
The Clinician Consultation Center received an inquiry from an infectious disease specialist regarding a 50-year-old man with hepatitis C genotype 3a. On liver biopsy, the patient was found to have cirrhosis. He had no history of decompensated liver disease. The patient had a history of prior partial response to therapy with peginterferon and ribavirin; prior treatment was discontinued after six months. The clinician planned to re-treat the patient in the coming year and requested advice on the most efficacious regimen for genotype 3.

CCC Consultant Response
Background
Hepatitis C genotype 3 accounts for about 10% of hepatitis C infections in the U.S. Historically, genotype 3 was considered easier to treat than the more common genotype 1, due to better response rates to peginterferon-based therapies. For genotype 3 patients treated with peginterferon and ribavirin, rates of sustained virologic response (SVR, defined as an undetectable hepatitis C viral load 24 weeks after completion of treatment—essentially representing HCV eradication) were 65-80% versus 50% for genotype 1 using the same regimen (Zeuzem, 2004). However, in the current era of direct acting antivirals, SVR rates > 90% at 12 (not 24) weeks after treatment completion are the goal, and genotype 3 has proven more challenging to cure (especially for treatment-experienced, cirrhotic patients). This is concerning as patients with genotype 3 may have a faster progression of fibrosis and increased risk of hepatocellular carcinoma compared to other genotypes (Bochud, 2009).

As of July 2015, genotype 3 remains the one area where peginterferon continues to play a key role in therapy. For patients without advanced liver disease (defined as Metavir score < F3-F4) who cannot tolerate or do not want peginterferon, it is reasonable to delay therapy until shorter, better-tolerated regimens are available (see below). For patients with cirrhosis, however, the benefits of treatment may outweigh risks of treatment intolerance or failure. This decision should be made on a case-by-case basis.

Treatment Recommendations
Per AASLD/IDSA guidelines updated June 29, 2015 (available at hcvguidelines.org), the recommended regimen for patients with hepatitis C genotype 3 infection in whom prior peginterferon and ribavirin treatment has failed and who are peginterferon-eligible is 12 weeks of:

1. Retreatment with daily sofosbuvir (400 mg), plus
2. Weight-based ribavirin (1000 mg [75 kg]), plus
3. Weekly peginterferon

The recommended regimen for patients with genotype 3 infection in whom prior peginterferon and ribavirin treatment has failed who are not eligible to receive peginterferon is 24 weeks of:

1. Retreatment with daily sofosbuvir (400 mg), plus
2. Weight-based ribavirin (1000 mg [75 kg]).

A simeprevir-based regimen is only recommended for genotype 1 infection and should not be used in genotype 3 infection.

Evidence
These recommendations are based on findings from the randomized, open-label BOSON trial (Foster, 2015), where investigators enrolled 592 treatment-naive and treatment-experienced subjects with genotype 2 or 3 chronic HCV infection (with or without cirrhosis) to receive one of three treatment regimens: (1) sofosbuvir plus ribavirin for 16 weeks; (2) sofosbuvir plus ribavirin for 24 weeks; or (3) sofosbuvir plus ribavirin plus peginterferon alfa-2a for 12 weeks. Genotype 3 infection was present in 92% of subjects. The sustained virologic response 12 weeks after treatment in the BOSON trial in treatment-naive, GT3 subjects was:

• 77% in those who took a 16-week sofosbuvir plus ribavirin regimen
• 88% in those who took a 24-week sofosbuvir plus ribavirin regimen
• 95% in those who took a 12-week sofosbuvir plus ribavirin plus peginterferon regimen

For treatment-naive subjects with genotype 3 infection, superiority of the 12-week sofosbuvir plus ribavirin plus peginterferon regimen was maintained in subjects with or without cirrhosis (study summary).

For genotype 3 patients who can wait for peginterferon-free regimens, further options for therapy are expected by 2016. A new drug application for the pan-genotypic NS5A replication complex inhibitor daclatasvir was accepted for review by the FDA in March 2015. This submission was based on results of the phase 3 ALLY-3 trial (Nelson, 2014), which enrolled 152 subjects with genotype 3 infection (101 treatment-naive and 51 treatment experienced). All subjects received a 12-week course of oral daclatasvir (60 mg once daily) plus sofosbuvir (400 mg once daily). Sustained virologic response 12 weeks after treatment in the ALLY-3 trial was (study summary):

• 90% overall in treatment-naive subjects (97% for subjects without cirrhosis, 58% for subjects with cirrhosis)
• 86% overall in treatment-experienced subjects (94% for subjects without cirrhosis, 69% for subjects with cirrhosis)

Given that daclatasvir/sofosbuvir will be a shorter and generally better-tolerated regimen, some clinicians are choosing to delay therapy for their genotype 3 patients.

Conclusion
While hepatitis C treatment has progressed significantly over the past few years, we have not yet arrived at a pan-genotypic therapy that is equally effective in patients with advanced liver disease. Treatment options for cirrhotic, treatment-experienced genotype 3 patients remain somewhat limited. Peginterferon-based therapy continues to be a reasonable option for hepatitis C genotype 3 patients who can tolerate it.

References
1. American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and the International Antiviral Society-USA. Recommendations for testing, management, and treating hepatitis C.
2. PY Bochud, T Cai , K Overbeck, et al. Genotype 3 is associated with accelerated fibrosis progression in chronic hepatitis C. J Hepatol. 2009;51:655-66.
3. GR Foster, S Pianko, C Cooper, K Agarwal, et al. Sofosbuvir + peginterferon/ribavirin for 12 weeks vs sofosbuvir + ribavirin for 16 or 24 weeks in genotype 3 HCV infected patients and treatment-experienced cirrhotic patients with genotype 2 HCV: the BOSON study. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract L05.
4. DR Nelson, JN Cooper, JP Lalezari, et al. All-oral 12-week Combination Treatment with Daclatasvir (DCV) and Sofosbuvir (SOF) in Patients Infected with HCV Genotype (GT) 3: ALLY-3 Phase 3 Study. American Association for the Study of Liver Diseases (AASLD) Liver Meeting. Boston, November 7-12, 2014. Abstract LB-3.
5. S Zeuzem, R Hultcrantz, M Bourliere, et al. Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol. 2004; 40:993-9.

Because CCC consultations are based on information provided by the caller or clinician accessing the online consultation center, without the benefit of a direct evaluation or examination of the patient, consultations are intended to be used as a guide. They do not constitute medical advice and are not to serve as a substitute for medical judgment.