This article reviews the efficacy and health economic evidence relating to protease inhibitors, such as telaprevir, used in the management of hepatitis C
Steven Simoens PhD
Research Centre for Pharmaceutical Care and Pharmaco-economics,
Katholieke Universiteit Leuven,
Belgium
Protease inhibitors are used to prevent or treat viral infections such as human immunodeficiency virus (HIV) and hepatitis C. For example, new protease inhibitors, such as telaprevir and boceprevir, eliminate the hepatitis C virus in 70–80% of patients as compared with 40–50% with current standard therapy of pegylated interferon-α in combination with ribavirin. HIV and hepatitis C are not only leading causes of morbidity and mortality in the world, but also impose an economic burden on society in terms of healthcare costs and productivity loss.
For example, HIV and hepatitis C are estimated to affect 33 million and 170 million individuals, respectively. Hepatitis C virus (HCV) infection may lead to chronic liver disease, liver transplantation and hepatocellular carcinoma, is associated with shorter life expectancy, and impairs quality of life. A Belgian study calculated the following three-year healthcare costs according to hepatitis C stage: €18,993 for mild disease; €19,687 for moderate disease or compensated cirrhosis without varices; €29,759 for decompensated cirrhosis; €35,987 for hepatocellular carcinoma; and €65,120 (costs over two years only) for liver transplantation.(1)
Hepatitis: the disease
Hepatitis is a general term for inflammation of the liver and can be caused by several factors, including viruses such as hepatitis A, B, C, D and E. Hepatitis C was discovered in the 1980s, when it became apparent that there was a new virus (not hepatitis A or B) causing liver damage. It was known as non-A non-B hepatitis until it was properly identified in 1989.
Globally, an estimated 170 million people (3% of the global population) are infected with HCV and more than 350,000 people are estimated to die from HCV-related liver disease each year.(2)
HCV is a small, enveloped, single-stranded RNA virus and a member of the flaviviridae family.(3) Six different genotypes of the virus have been identified. Different genotypes predominate in different parts of the world.
Transmission
HCV is a blood-borne virus transmitted parenterally, commonly via intravenous/intranasal drug use and the sharing of needles. It was also spread through blood transfusion prior to the introduction of screening in 1991. There is also a small risk of HCV infection associated with tattooing, electrolysis, body piercing, acupuncture, sexual contact and vertical transmission from mother to baby.
Disease progression
Hepatitis C infection can be categorised into two stages: firstly, an acute stage following an initial infection; secondly, a chronic stage. The acute stage refers to the first six months of infection and does not necessarily mean that there are any noticeable symptoms. Approximately 20% of those infected with HCV will clear the virus naturally from their body and experience no long-term effects from the infection. However, for the remaining 80% a long-term infection will develop.
The progression of HCV is variable and each person has a different response to the virus. Not every individual will go on to develop serious complications and the severity of liver damage varies. Cirrhosis will develop in approximately 20% of patients over a period of 20–50 years; this can further progress to end-stage liver disease requiring liver transplant, or death, or result in hepatocellular carcinoma. Older age at infection, concomitant alcohol abuse, concurrent hepatitis B virus or HIV infection may be factors which can increase the rate of progression.(3)
Symptoms
The range and degree of symptoms also vary significantly. For some people symptoms are severe enough to affect their quality of life significantly and consistently, while other people experience none at all. Sometimes they will be vaguely noticeable, but for many people they come and go and the severity varies. Symptoms associated with hepatitis C include fatigue, muscle ache, loss of appetite or nausea, which are unspecific and, in many cases, mild or absent. Consequently, hepatitis C is often diagnosed accidentally and remains under-diagnosed due to the lack of specific symptoms.
Diagnosis
The diagnosis of HCV involves two blood tests initially.
Anti-HCV tests are the first tests performed to detect the presence of antibodies to the virus, indicating exposure to HCV. This test does not indicate if the individual has an active viral infection, only that they have been exposed to the virus in the past, and is usually reported as positive or negative. It can take up to 12 weeks for antibodies to develop following exposure, therefore the timing of testing is critical. If the result is positive it does not necessarily mean that the individual is currently infected. Up to 20% of people spontaneously clear the virus yet they still have hepatitis C antibodies. There is a chance that they could have been infected with hepatitis C in the past but are no longer infected.
If the antibody test is positive, the next test is to check if the virus is still present by having a qualitative polymerase chain reaction (PCR) test. The PCR test determines whether there is active hepatitis C virus replication in the blood. A positive detectable PCR result means that the immune system did not clear the infection during the acute phase of infection and has progressed to the chronic phase. Following diagnosis, HCV genotyping is helpful for predicting the likelihood of response to, and duration of, treatment; it is generally ordered before treatment is started. Patients infected with genotypes 2 or 3 have a better chance of responding to treatment than those infected with other genotypes.
A liver biopsy is generally recommended; however, it is not considered mandatory. A biopsy is useful for staging the severity of disease. It also helps to guide decisions on when to start treatment, and long term prognosis.
New proteases
Proteases play a crucial role in the ability of HCV to reproduce itself. Once HCV gains entry into a liver cell, it releases instructions to build up new protein structures. These new structures will comprise a mixture of viral components and those of the host cell. It is during this phase that the viral genetic information is transmitted. The polypeptide chain divides into individual HCV proteins at highly specific locations. The virus can only begin to reproduce once all the individual HCV proteins have been cut from the polypeptide chain. It is the function of a protease to trigger this separation. A protease inhibitor tries to stop this separation happening by interfering with the function of the protease.
Boceprevir and telaprevir have been approved for use in combination with pegylated interferon plus ribivarin in both naïve and non-responder patients infected with HCV genotype 1.
Clinical trials
The ADVANCE and REALIZE studies showed that combining telaprevir with pegylated interferon and ribavirin produced higher sustained virologic response (SVR) rates then standard therapy alone. Telaprevir triple therapy boosted SVR rates to 69–75% in treatment-naïve patients, versus 44% with standard treatment alone.(4) For genotype 1 prior non-responders, SVR rates were 83–88% with telaprevir plus pegylated interferon and ribavirin, compared to 24% with standard therapy alone.(5) For bocepravir, the standard dose is 800mg orally three times a day with food. There will be a four-week lead-in period of pegylated interferon plus ribavirin before boceprevir is added to the regimen and triple therapy will be continued for the remainder of the course (either 28 weeks or 48 weeks).
For telaprevir the standard oral dose is 750mg, three times daily with food. Telapravir should be taken for the first 12 weeks in combination with pegylated interferon plus ribavirin, followed by pegylated interferon and ribavirin alone through 24 or 48 weeks using a response-guided strategy based on early response. For both protease inhibitors, measurement of HCV-RNA levels during treatment is very important.
Economic evaluation
Health economic evaluation is a tool that assesses the cost-effectiveness of a medicine as compared with an alternative. Evidence derived from economic evaluations is used to inform pharmaceutical reimbursement (and/or pricing) decisions in many countries. The requirement for economic evaluation fits within an overall trend towards evidence-based decision making in healthcare.
The results of an economic evaluation can be expressed in the form of an incremental cost-effectiveness ratio (ICER). This ratio relates the difference in costs between a medicine and the comparator to the difference in outcomes. The ICER is then compared with a threshold value, which reflects the maximum cost per unit of outcome that a healthcare payer is willing to pay for a medicine. This means that a medicine with an ICER below the threshold value is likely to be accepted by a health care payer, and a medicine with a ratio exceeding the threshold value is likely to be refused.
Telaprevir and boceprevir
New protease inhibitors have significantly improved sustained virological response rates in both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C as compared with peg-interferon (a-2a or a-2b) in combination with ribavirin. In the absence of head-to-head clinical trials, an indirect comparison of telaprevir with boceprevir showed that the probability that telaprevir is more effective in terms of sustained virological response rate than boceprevir is 0.93 in treatment-naïve patients and 0.98 in treatment-experienced patients.(6)
A US economic evaluation compared three strategies in treatment-naïve patients with genotype 1 chronic hepatitis C: a) telaprevir in combination with pegylated interferon and ribavirin; b) boceprevir in combination with pegylated interferon and ribavirin; and c) pegylated interferon and ribavirin.(7)
Depending on the sustained virological response rate, the cost-effectiveness of boceprevir in combination with pegylated interferon and ribavirin was US$11,433–27,261 per quality-adjusted life year gained as compared with pegylated interferon and ribavirin. Similarly, the cost-effectiveness of telaprevir in combination with pegylated interferon and ribavirin was US$21,985-53,190 per quality-adjusted life year gained as compared with pegylated interferon and ribavirin.
Treatment with telaprevir may have a positive impact on work productivity. A US study showed that work productivity of treatment-naïve patients with genotype 1 chronic hepatitis C fell during the first 12 weeks of treatment with telaprevir.(8) However, work productivity returned sooner to pre-treatment levels in patients treated with telaprevir than in patients treated with pegylated interferon a-2a in combination with ribavirin.
In 2012, the National Institute for Health and Clinical Excellence (NICE) in the UK recommended telaprevir in combination with peginterferon-a and ribavirin as an option for the treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease who were previously untreated or in whom previous treatment had failed.(9)
For the previously untreated population, the manufacturer’s model estimated that telaprevir plus peginterferon-2a and ribavirin provides an incremental health gain of 0.84 quality-adjusted life years (QALYs) compared with PEG2a/R alone, at an incremental cost of £11,430, resulting in an ICER of £13,553 per QALY gained. For the previously treated population, the manufacturer’s model estimated that telaprevir plus peginterferon-2a and ribavirin provides an incremental health gain of 1.17 QALYs compared with peginterferon-2a and ribavirin alone, at an incremental cost of £10,195, resulting in an ICER of £8688 per QALY gained.(9)
An economic evaluation carried out by the National Centre for Pharmacoeconomics in Ireland(10) considered telaprevir a highly cost-effective therapy when added to peginterferon–ribavirin for the treatment of patients infected with genotype 1 hepatitis C virus in the Irish healthcare setting.
Conclusions
The advent of new protease inhibitors has revolutionised hepatitis C treatment. Compared with current standard therapy, telaprevir significantly increases a patient’s chance of achieving SVR. Data support the efficacy and cost-effectiveness of telaprevir in treatment-naïve patients with genotype 1 chronic hepatitis C.
References
- Wong JB. Hepatitis C: cost of illness and considerations for the economic evaluation of antiviral therapies. Pharmacoeconomics 2006;24(7):661–72.
- World Health Organization. Viral hepatitis. http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_15-en.pdf, published 25 March 2010.
- Dusheiko G. Hepatitis C. Medicine 2007; 35: 43–48. Medicine 2007;35: 43–49.
- Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: 2417–28.
- Jacobson I, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405–16.
- Diels J, Cure S, Gavart S. The comparative efficacy of telaprevir versus boceprevir in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus infection: a mixed treatment comparison analysis. 2011 Nov 5; Madrid 2011.
- Chan K et al. Potential costs associated with new direct-acting antivirals (DAAs) therapy for untreated Chronic Hepatitis C genotype 1 infection in the Veterans Health Administration. 2011 Nov 5; Madrid 2011.
- Thal G et al. Work productivity among genotype 1 hepatitis C virus (HCV) treatment-naïve patients receiving telaprevir-based treatment regimens: results from Advance and Illuminate studies. 2011 May 23; Baltimore 2011
- National Institute for Health and Clinical Excellence. Telaprevir for the treatment of genotype 1 chronic hepatitis C. Guidance T252. http://www.nice.org.uk/guidance/TA252.
- National Centre for Pharmacoeconomics. Economic evaluation of Telaprevir (Incivo®) as add-on therapy to pegylated interferon and ribavirin for the treatment of patients infected with Hepatitis C Genotype 1. www.ncpe.ie/drugs/telapravir/
