In Canada and most other high-income countries today, standard treatment for people who have genotype 1 infection with hepatitis C virus (HCV) includes combinations of medicines called direct-acting antivirals (DAAs). These are medicines that are taken orally, every day, usually for 12 to 24 consecutive weeks. In large clinical trials, treatment with modern DAAs—such as Harvoni and Holkira Pak—has resulted in cure rates of 95% or greater. This is a tremendous advance compared to therapy that was in use over the past couple of decades—interferon and the broad-spectrum antiviral drug ribavirin. The combination of interferon, which had to be injected, and ribavirin was cumbersome, weaker and associated with many troublesome side effects.
Is shorter better?
Researchers have been testing short courses of therapy for HCV infection. In a phase II clinical trial of Harvoni (ledipasvir + sofosbuvir) and the experimental drug vedroprevir (also called GS-9451), just six consecutive weeks of this therapy resulted in 95% of participants (19 of 20) being cured. Note that none of the participants in this study had severe liver injury.
Caution with shorter courses of therapy
Now the same team of researchers at the U.S. National Institutes of Health (NIH) and elsewhere has tested triple DAA therapy—Harvoni and vedroprevir—in 50 HCV-infected volunteers who had severely or extremely scarred livers. This time researchers found that cure rates were relatively modest, around 76%. Taking many factors into account, researchers pointed the finger at liver scarring as an issue hindering recovery when short courses of HCV therapies are used. In this CATIE News bulletin, we explore this study as well as the issue of extensive scarring of the liver, called cirrhosis, and its impact on recovery from HCV infection.
Study details
Researchers enrolled 50 participants between April 2014 and June 2015. Their average profile at the time they entered the study was as follows:
- age – 58 years
- 66% men, 34% women
- body mass index (BMI—a relative measure of fatness) – 30, suggesting obesity
- HCV strain or genotype – most participants (74%) had genotype 1a
- liver injury – 22 participants had extensive scarring of the liver, or cirrhosis, graded as F4. The remaining participants had somewhat less severe scarring, graded as F3.
- 22% of participants had a high viral load – more than 6 million IU/ml
Prior to the present study, half of the participants had been treated with interferon and ribavirin but were not cured.
Participants took the following doses of medicines:
- Harvoni – one pill containing 90 mg of ledipasvir and 400 mg of sofosbuvir
- vedroprevir – 80 mg in one pill
Both pills were meant to be taken once daily for six weeks.
Results
Overall, 76% of participants were cured. That is, 76% of participants had HCV levels in their blood that were extremely low—less than 25 IU/ml (below a level at which it could be accurately counted) 12 weeks after the cessation of therapy. This result is written as SVR12.
There were no statistically significant differences in the rates of cure between participants who had been previously treated and those for whom this study was their first exposure to treatment.
Participants who were not cured experienced what researchers called “virologic relapse”; that is, their HCV initially became very low or, in some cases, less than 25 IU/ml. However, once their course of therapy ended, their viral load increased. All relapsed participants have either resumed therapy with Harvoni or are awaiting such therapy, taken for a longer course.
Side effects
In general, in uncomplicated cases of HCV infection, modern DAAs usually have a few side effects of mild to moderate intensity. Common side effects of this intensity in the present study were as follows:
- headache
- lack of energy
- nausea
- diarrhea
One participant developed severely elevated levels of blood sugar but this decreased over the course of the study.
No one left the study prematurely due to side effects and there were no deaths.
A note on inflammation and its effects in chronic HCV infection
In the struggle between the immune system and HCV-infected cells, the liver becomes inflamed. Gradually, healthy liver tissue is replaced with useless scar tissue in a process called fibrosis. As a result, the liver becomes increasingly dysfunctional. As scar tissue spreads, it can hinder the circulation of blood within this vital organ.
Canadian researcher Jordan Feld, MD, and colleagues (University of Toronto) have noted that as a result of these and other changes in the liver arising from chronic inflammation and injury linked to cirrhosis, the following issues may play a role when DAAs are unable to effect a cure:
- DAAs may not be broken down or converted into forms that are accessible to liver cells.
- The immune system within the liver may become dysfunctional.
- The concentration and penetration of DAAs within the liver is less-than-ideal because the flow of blood within the liver has been redirected as a result of the development of scarred tissue. Consequently, some parts of the liver may have very low (and ineffective) concentrations of DAAs. In theory, this may enable the easier development of strains of HCV that can resist the effect of DAAs.
All of these issues point to the need for longer courses of therapy for people who have extensive scarring in the liver (cirrhosis).
Furthermore, in the present study, there was no statistical connection between specific viral factors (such as high or low viral load, drug resistance mutations) or genetic factors in people that affected their immunological response to HCV. Therefore, the modest results seen in this study are very likely related to the degree of scarred liver tissue in participants. As mentioned earlier, a previous study by the same NIH team found about a 95% cure rate in HCV infection with the same regimen for the same duration of therapy in people without cirrhosis.
Although the present study was small and not randomized or placebo controlled, it was conducted by an experienced team of researchers and its general conclusion—people with widespread scarring of the liver very likely require longer courses of therapy—is likely correct.
Resources
- Harvoni – CATIE fact sheet
- Holkira Pak – CATIE fact sheet
- CATIE’s hepatitis C information
- Understanding cirrhosis of the liver: First steps for the newly diagnosed – Canadian Association of Hepatology Nurses (CAHN), CATIE
—Sean R. Hosein
REFERENCES:
- Kattakuzhy S, Wilson E, Sidharthan S, et al. Six-week combination directly acting anti-HCV therapy induces moderate rates of sustained virologic response in patients with advanced liver disease. Clinical Infectious Diseases. 2015; in press.
- Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015 Mar 21;385(9973):1107-13.
- Al Marzooqi SH, Feld JJ. Sorting out cirrhosis: mechanisms of non-response to hepatitis C therapy. Liver International. 2015 Aug;35(8):1923-33.
- Perelson AS, Guedj J. Modelling hepatitis C therapy—predicting effects of treatment. Nature reviews. Gastroenterology & Hepatology. 2015 Aug;12(8):437-45.