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Ms Joyeta Das, MPharm, Dip Clin Pharm, IPresc
Lead Pharmacist, Hepatology
Imperial College Healthcare NHS Trust
London, UK
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 hepatitis C virus (HCV) and more than 350,000 people are estimated to die from hepatitis C-related liver disease each year.
The hepatitis C virus is a small, enveloped, single-stranded RNA virus and a member of the flaviviridae family.2 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 (see Table 1).
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 hepatitis C 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.
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 accidently 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.
Standard treatment
The goal of HCV treatment is to eradicate the virus and prevent the development of cirrhosis and its complications.
There is currently no vaccine available for hepatitis C, although several are in development. Since the discovery of the virus in 1989 the development of HCV therapy has progressed significantly, with the introduction of interferon (IFN) monotherapy and the current standard of care treatment with pegylated interferon (PegIFN) and ribavirin. Figure 1 summarises the evolution of HCV therapy and response rates. Response rates are measured by virological response. Several types of virological response can occur, labelled according to their timing relative to treatment. The most important is the sustained virological response (SVR), defined as the absence of HCV-RNA 24 weeks following discontinuation of therapy; this is generally regarded as a virological cure.
Undetectable virus at the end of either 24 weeks or 48 weeks of treatment is referred to as an end-of-treatment response (ETR). An ETR does not predict accurately that an SVR will be achieved, but is necessary for it to occur. A rapid virological response is defined as undetectable HCV-RNA at Week 4 of treatment, and predicts a high likelihood of achieving an SVR. An early virological response (EVR) is defined as a more than 2 log reduction or complete absence of serum HCV-RNA at Week 12 of therapy, compared with baseline level. Failure to achieve an EVR is the most accurate predictor of not achieving an SVR.
The goal of treatment is to prevent complications and death from HCV infection. Therefore the primary aim of treatment is to eradicate the virus. This is signified by a patient achieving an SVR, which is indicated by the absence of HCV-RNA in the patient’s serum six months after treatment is completed. This is generally considered to indicate a permanent resolution of infection, although relapse may occur in approximately 5% of people after five years.
Interferon
Interferons are proteins which act via species-specific surface target cell receptors. They interfere with several stages of the viral life cycle, although the actual mechanism is unknown.
Pegylated interferons
Limitation in the effectiveness of IFN-alpha has been attributed to its rapid systemic clearance and short plasma elimination half-life. Pegylated subcutaneous formulations of IFN-alpha have been developed, which are produced by the addition of polyethylene glycol moieties. These molecules protect the IFN protein from enzymatic degradation, reducing systemic clearance. Pegylation thus changes the pharmacokinetics and pharmacodynamics of IFN-alpha, and the improved drug concentrations and sustained exposure is clinically advantageous. It also permits more convenient once-weekly dosing. There are currently two licensed pegylated interferons, peginterferon alpha-2a (Pegasys) and peginterferon alpha-2b (ViraferonPeg). The doses of these two preparations differ.
The recommended dose of peginterferon alpha-2a is 180mcg once a week, administered subcutaneously for 16, 24 or 48 weeks, depending on HCV genotype, baseline viral load and response to treatment. The recommended dose of peginterferon alpha-2b is 1.5mcg/kg once a week, administered subcutaneously for 24 or 48 weeks, again depending on HCV genotype, viral load at the start of treatment and response to treatment.
Ribavirin
Ribavirin is a guanosine nucleoside analogue. The agent only has modest activity against hepatitis C but it increases the activity of IFN when the two agents are used in combination. The drug exerts its action after intracellular phosphorylation. Ribavirin may also induce mutations in the HCV genome, affecting HCV replication. Two forms of ribavirin are available, Copegus and Rebetol. Each product is licensed for use only in combination with a specific interferon product and therefore it is considered good practice to use the brand of ribavirin that corresponds with the prescribed brand of peginterferon; however, this is not essential.
The recommended dose of ribavirin ranges from 800 to 1,400mcg, depending on body weight. The dose of Copegus also varies according to the genotype being treated.
Choice of brand
The only head-to-head study comparing the two brands of peginterferon is the IDEAL study. The findings from the study demonstrated that SVR rates were not significantly different between the two brands; however, end of treatment response was higher in the peginterferon alpha-2a arm and relapses were less frequent in the peginterferon alpha-2b arm.
Duration of therapy
The recommended duration of treatment is 24 weeks or 48 weeks depending on a combination of factors, which include HCV genotype, the viral load at the start of treatment and whether a patient has an RVR to treatment.
If HCV-RNA levels are re-checked six months after completion of treatment and found to be detectable, then the disease has relapsed and the patient should be considered for re-treatment. Table 2 summarises treatment durations; patients re-treated with peginterferon alpha, and in whom HCV-RNA is still detectable at Week 12, are unlikely to have an SVR after 48 weeks of therapy.
Adverse effects
Almost all patients treated with peginterferon and ribavirin experience one or more adverse events during the course of therapy. Adverse effects during the course of therapy are a major reason why patients decline or stop therapy altogether. Common adverse effects associated with interferon are influenza-like symptoms; chills, fever, malaise, muscle ache, headaches, poor appetite, weight loss, increased need for sleep, psychological effects (irritability, anxiety, depression), hair loss, thrombocytopenia and leucopaenia are all common. The major side effects associated with ribavirin are haemolytic anaemia and myalgia. During treatment patients should be appropriately monitored for the side effects and full blood counts taken.
Another consideration for patients before starting treatment is the likelihood of pregnancy. It is recommended that patients and their spouses do not become pregnant either during therapy or during the six months after completion of treatment. This is due to the teratogenicity of ribavirin.
Dose reduction
The development of side effects frequently necessitates dose reduction and discontinuation of therapy. The dose of peginterferon and/or ribavirin may be reduced due to haematological side effects. It is important to note that any dose reduction will limit the chance of achieving SVR so a full dose of both should be maintained for as long as possible. Full details of dose reductions can be found in the manufacturer’s summary of product characteristics.
Management of adverse effects
Flu-like symptoms are experienced by almost all patients, can be managed with paracetamol and tend to resolve as treatment progresses. However, some patients do experience these symptoms throughout treatment. In addition, supportive therapies such as anti-depressants, erythropoietin and granulocyte colony-stimulating factor have beenshown to reduce the incidence of depression, anaemia and neutropenia, and to enhance adherence to therapy, but have not yet been shown to improve the SVR rate and are an added expense.
New developments
Standard treatment with pegylated interferon and ribavirin has limited success. The best treatment response is seen in patients with HCV genotypes 2 and 3, in whom SVR rates of approximately 80% can be achieved. Patients with HCV genotype 1 remain the most difficult to treat, with SVR rates of less than 50%. In addition to being ineffective in some patients, peginterferon and ribavirin are difficult to tolerate, and many patients treated with these drugs discontinue therapy due to adverse events. There has therefore been considerable pressure for the development of new drugs in this area.
Since current standard-of-care treatment stimulates the immune response rather than targeting the virus directly, the development of new drugs for hepatitis C has focused on targeting the virus. New therapies that act directly at various points in the viral life cycle are in development. This group is referred to as direct-acting antiviral (DAA) agents.
Two that have been approved by the FDA are boceprevir and telaprevir. Both are protease inhibitors, which interfere with the ability of the HCV to replicate by inhibiting a key viral enzyme, NS3A/4B serine protease.
Proteases play a crucial role in HCV’s ability to reproduce itself. Once HCV gains entry into a liver cell, it releases instructions to build up new protein structures. These new structures will be made using a mixture of the virus’s components and those of the host cell. It is during this phase that the virus passes its genetic information on. This extended and unravelled chain is called a polypeptide. The next stage is for this chain to divide into individual HCV proteins at highly specific locations. The virus can only begin to reprotuce itself after all the indvidiaul 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.
Boceprevir in combination with pegylated interferon plus ribavirin produced higher SVR rates than standard therapy alone in the SPRINT-2 and RESPOND-2 studies. The likelihood of SVR for genotype 1, treatment-naïve patients approached 70% with boceprevir combination therapy, versus 40% with standard treatment alone. For genotype 1 prior non-responders, SVR rates were around 59–66% with boceprevir plus pegylated interferon and ribavirin, compared to 21% with standard therapy.
The ADVANCE and REALIZE studies showed that combining telaprevir with pegylated interferon and ribavirin produced higher 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.8 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.9 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 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.
The advent of these new agents will revolutionise hepatitis C treatment. Compared to current standard therapy, both new agents significantly increase a patient’s chance of achieving SVR However, issues to consider with the arrival of these new agents are: how best to use these drugs to avoid the development of resistance, the importance of adherence, the cost, side effects and whether HCV protease inhibitors should now be considered the comparison standard-of-care when conducting clinical trials of new agents.
These new drugs are only the beginning as there are many more currently in preclinical and clinical development. The hope is to eventually use several drugs in combination, avoiding the need for interferon-based regimens while staying off drug resistance.
References
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