Updated policy brief: Future directions in hepatitis C treatment - closing in on a cure for the vast majority
Professor Gregory Dore
Policy Brief 1
- Hepatitis C is a viral infection that is curable with pegylated interferon and ribavirin (PEG-IFN/RBV) in around 60% of people, but has considerable side effects and requires relatively prolonged treatment duration (24-48 weeks).
- The initial direct-acting antiviral (DAA) agents - HCV protease inhibitors, telaprevir and boceprevir, were recently listed on the Australian PBS for treatment of chronic hepatitis C genotype 1.
- When combined with PEG-IFN/RBV in triple therapy regimens these initial DAA agents improve cure rates (by 20-25%), and shorten treatment duration from 48 to 24 weeks for around half of patients.
- Although increasing cure rates, there are several concerns with these initial two DAA agents: not effective against genotype 2/3; additional toxicity (e.g. rash, anaemia); problematic dosing (three times per day with food); and complex monitoring schedules and stopping rules.
- Several other DAA agents in development appear to be as potent (and possibly more potent), have reduced toxicity, and better dosing schedules (some are once daily), and should become available in 3-4 years.
- Several studies of combination DAA treatment (without PEG-IFN/RBV) have been extremely encouraging in demonstrating cure of hepatitis C in 90%.
The first available IFN-free DAA regimen is likely to be sofosbuvir (Nucleotide analogue) and ribavirin with a treatment cure (called a sustained virological response - SVR) of 90% for genotype 2 and 60% for genotype 3.
- The future of hepatitis C treatment with DAA therapy is extremely promising - with the potential to cure the vast majority of people commenced on therapy. The challenge now and into the future is to increase access to treatment as currently only one to two per cent of Australians with chronic hepatitis C commence treatment each year.
- As people who inject drugs are the group at greatest risk of hepatitis C, further research and specifically developed treatment programs will be crucial.
What is the issue?
Hepatitis C is somewhat unusual among chronic diseases generally and chronic liver disease specifically – it is eminently curable. Around 60% of people commenced on current standard of care (PEG-IFN/RBV) will be cured of their chronic hepatitis C infection, with most people also having reversal of underlying liver damage. However, current treatment remains problematic due to the considerable side effects, the requirement for contraception during and for six months following treatment (due to RBV causing foetal malformation), the relatively prolonged treatment duration (24-48 weeks), and the restrictive settings in which most treatment is provided (tertiary clinics in large hospitals). As such, only 1-2% of people with chronic hepatitis C are commenced on treatment each year in Australia.
The landscape of hepatitis C treatment will alter enormously over the coming decade following the development of direct acting antiviral (DAA) agents that enhance treatment efficacy (that is more people will be cured of their hepatitis C). The duration of therapy will be shortened with treatment demonstrated to be curative without interferon-based therapy. As new treatments become available, there will be a need to evaluate them among current injecting drug users, the group at greatest risk of hepatitis C infection who have to date been excluded from clinical trials developing these agents. It will also be crucial to improve access through specifically developed treatment programs.
What is the evidence?
Over the last 12 months several major milestones have been reached in the clinical development of DAA therapy for chronic HCV infection. The initial HCV protease inhibitors, telaprevir and boceprevir, have been approved in Australia for use in combination with PEG-IFN/RBV for people with HCV genotype 1 who have never previously been treated for hepatitis C (treatment naïve) and people previously treated for hepatitis C (treatment experienced).
In treatment naïve populations, telaprevir or boceprevir when added to PEG-IFN/RBV improved the chance of a treatment cure (called a sustained virological response - SVR) from 40-45% to 65-75% and enabled the length of treatment to be shortened from 48 weeks to 24-28 weeks for around half of patients. In treatment experienced populations, telaprevir and boceprevir both provided considerably enhanced but variable SVR when combined with PEG-IFN/RBV (from 30% to 85%).
Although telaprevir and boceprevir are now listed on the Pharmaceutical Benefits Scheme, several concerns remain regarding these two agents, including:
- Problematic dosing schedule of three times per day with a meal (fatty for telaprevir), and large pill burden (boceprevir, 12 pills per day; telaprevir, 6 pills per day);
- Low level of treatment response (efficacy) in patients who had a minimal reduction in the level of the virus when treated with PEG-IFN/RBV in the past, particularly those with advanced fibrosis (15-20% SVR);
- The potential for drug resistance;
- Increased side effects – in particular rash (telapravir) and anaemia (bocepravir and telapravir);
- Potential for a large number of drug interactions due to the way that telapravir and bocepravir are broken down in the liver (they impact on the cytochrome P450 (CYP) 3A4 pathways);
- The strategies for administering telapravir and bocepravir in particular vary (they have different “start” and “stop” rules) and can be confusing for both patients and doctors.
- Telaprevir and boceprevir are only approved for HCV genotype 1.
There are several important pathways for future DAA clinical development, with many studies recently releasing promising findings. Some of the major areas for development will include:
- Shortened PEG-IFN/RBV/DAA therapy durations: a phase III study demonstrated 90% SVR rate for people with HCV genotype 1 (treatment naïve) treated with PEG/RBV and sofosbuvir (nucleotide analogue) with total treatment duration of only 12 weeks.
- IFN-free DAA regimens: There are several promising regimens in development. Sofosbuvir and ribavirin should be licensed by the US Food and Drug Administration in late 2013 for HCV genotype 2 (12 weeks) and HCV genotype 3 (16 weeks), based on SVR rates of around 90% for genotype 2 and 60% for genotype 3. Subsequent regimens will combine at least 2 DAA agents, possibly without the need for ribavirin, and possibly with activity against all HCV genotypes.
- Over the next five to ten years there will be major improvements in hepatitis C therapy, with simplified, short duration, probably once daily single combination pill dosing. Side effects and pill-burden (the number of tablets the person needs to take each day) will also reduce.
Preliminary evidence that IFN-free regimens are curative and the development of other promising once-daily agents shines a bright light on the way forward.
What resources are useful?
Dore GJ. The changing therapeutic landscape for hepatitis C. MJA 2012; 196: 629-632.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878-87.
Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013; 368: 1867-77.
The Treatment Action Group in New York produces excellent community-based reports on hepatitis C treatment developments in their Pipeline Report series. See the chapter titled ‘Hepatitis C drug development goes from pony ride to rocket launch’ by Swan and Kaplan in the most recent report - HIV, Hepatitis C Virus (HCV), and Tuberculosis (TB) Drugs, Diagnostics, Vaccines, and Preventive Technologies in Development(Clayden et al. 2012) Go to the website for Pipeline Reports and updates