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An update on new therapies for hepatitis C in Ireland

After infection with HCV, approximately 80 per cent of patients will remain chronically infected (as defined by detectable HCV RNA). Over time, chronic HCV infection will lead to fibrosis and cirrhosis in approximately 30 per cent of cases.

The clinical course of HCV-related cirrhosis is unpredictable. Patients with ‘early cirrhosis’ have an annual incidence of decompensation (defined as presence of one of the following clinical events: ascites, encephalopathy and variceal haemorrhage) and development of hepatocellular carcinoma (HCC) of 4.4 per cent and 2-to-5 per cent respectively, with a projected 10-year survival rate of >75 per cent.

In contrast, patients with ‘late cirrhosis’ and clinical evidence of liver failure or decompensation (including ascites, portal hypertensive gastrointestinal bleeding, severe bacterial infection or encephalopathy) have a poorer outlook, with survival rates of 81 per cent and 51 per cent at one and five years.

It is estimated there are approximately 500 HCV-infected patients with cirrhosis in Ireland currently.

Traditional HCV therapy

Over 25 years ago, IFN was identified as a potential therapeutic agent for the treatment of HCV, although initial clinical trials demonstrated disappointing cure rates. The addition of ribavirin (RBV) and the use of peg-IFN showed improved cure or sustained virological response (SVR) rates through the 1990s and early 2000s.

Since the early 2000s, the gold-standard treatment has been a dual drug regimen consisting of a weekly injection of peg-IFN plus daily oral RBV. This regimen has achieved SVR rates of 40-to-50 per cent in genotype 1 disease and 70-to-80 per cent in other genotypes.

Widespread treatment of patients with this regimen was limited due to side-effects of the medications and low SVR rates in patients with advanced fibrosis and prior treatment failure. Almost all patients treated with peg-IFN experience some side-effects including fatigue, flu-like symptoms, weight loss, seizures, peripheral neuropathy, bone marrow suppression and psychiatric symptoms.

The benefits of SVR in patients with cirrhosis are well documented, with a comprehensive meta-analysis reporting an 80 per cent relative risk reduction in all-cause morbidity and mortality following viral eradication in patients with advanced fibrosis. Hence, international treatment guidelines generally recommend antiviral therapy in this patient group. Unfortunately, using interferon-based regimens in patients with cirrhosis is not without significant risk to patients.

A recently-published French multi-centre study demonstrated high incidence of serious adverse events (40 per cent), death and severe complications (severe infection or hepatic decompensation) (6.4 per cent), in patients with compensated cirrhosis who were undergoing treatment with IFN-based therapy.

Changing landscape of HCV therapy

There are few areas in medicine which have seen such a significant change in recent years as HCV therapeutics. The identification of the virus in 1989, followed by the availability of a robust infectious cell-culture model in 2005, has permitted the development of several compounds known as ‘direct-acting antivirals’, or DAA. In contrast to peg-IFN and RBV, these DAA are specifically designed to target and inhibit the activity of key HCV proteins; the NS3/4A protease, the NS5A protein, and the NS5B RNA-dependent-RNA polymerase.

Initially designed to be used in combination with peg-IFN, combinations of DAA without IFN have achieved much higher cure rates (over 90 per cent in most cases) with far fewer toxicities and a much shorter duration of therapy. This is especially pertinent when compared to peg-IFN/RBV-based therapy, which needs six-to-12 months of therapy, has cure rates as low as 40 per cent in some genotypes, and, as mentioned above, came with a multitude of toxicities which often limited patients’ ability to continue with their medication.

Table 1: Currently available DAA Ireland

The DAA currently available in Ireland are listed in Table 1. There are several treatment options and combinations for patients, depending on HCV genotype, previous treatment history and presence or absence of cirrhosis, with most options available for treatment of GT1 infection. Many treatment combinations (especially in those with cirrhosis) still contain ribavirin.

Cost of HCV infection

There is clear evidence that active HCV infection has negative consequences for the individual and the health service. It has been shown to reduce patients’ quality of life and to have significant cost implications for the healthcare system.

A recent detailed analysis of the direct medical costs associated with the care of patients with HCV was performed in an Irish cohort (Table 2). This demonstrates an exponential rise in the cost of HCV care with the progression of liver disease. Successful treatment of HCV has been shown to improve health-related quality of life in Irish patients and in other cohorts, further strengthening the case for HCV treatment.

Table 2: Annual mean direct medical costs of chronic HCV care for patients with different stages of liver disease in Ireland

Over the past decade, approximately 20 per cent of liver transplants each year are performed due to HCV-related liver cirrhosis. Post-transplant HCV recurrence is universal and results in a significantly higher rate of graft loss and re-transplantation compared to other disease aetiologies (St Vincent’s University Hospital (SVUH) data).

In 2014, a dedicated HCC clinic was established in SVUH. There were 76 new cases referred to the clinic in 2014 and over 30 per cent of these cases occurred against a background of HCV cirrhosis (SVUH data). Given the clinical and economic burden caused by end-stage liver disease from HCV, there is a strong argument to target and treat those with the most severe liver disease to avoid the complications and costs of liver failure and cancer.

DAA therapy in Ireland

The early access programme (EAP) for the novel DAA began in Ireland in December 2014. Approximately 100 patients with decompensated cirrhosis or advanced liver disease (Child Pugh Score ≥7) were enrolled in the programme.

These patients are at highest risk of death, with a 35 per cent and 25 per cent risk of death over two years, respectively. It was felt by the Irish Hepatitis C Outcomes Research Network (ICORN) that given current fiscal constraints, targeting the “highest-risk” patients would have the greatest impact on patient mortality and need for liver transplantation among HCV-infected persons. A model similar to this has been adopted by other European countries including the UK, Sweden and France. Outcome data from the EAP is anticipated in the next few months. Following completion of the EAP, the HSE has committed to the treatment of all cirrhotic patients with IFN-free regimens. Currently, there are approximately 400 patients with liver cirrhosis registered with ICORN and treatment of this cohort is now underway.

It is unclear what groups of patients should be prioritised in the next year. It is likely that it will continue to be on the principle of greatest clinical need and patients will continue to be grouped according to the amount of fibrosis in their liver, and those with more advanced fibrosis targeted first. Performing liver biopsies to estimate fibrosis on all patients with HCV infection would be costly, invasive and impractical given the scarcity of hospital beds and drain on hospital resources.

Several non-invasive tests have been developed to estimate liver fibrosis, including the FibroScan (a measure of liver stiffness using elastography, a mechanism similar to ultrasound), APRI score (based on routine blood tests) and Fibrotest (a patented biomarker assay). Suggested cut-offs for each of these modalities for varying degrees of fibrosis are shown in Figure 1.

Figure 1: Suggested cut of values for the stages of fibrosis (F1 mild; F4 advanced) as estimated by FibroScan, Fibrotest and APRI score

Given that all treatment centres now have a FibroScan machine, we suggest that this should be the modality of choice to triage patients. Where a Fibroscan cannot be performed reliably due to the patient’s body habitus, the Fibrotest and APRI scores should be calculated. If both of these scores are in agreement, then the patient should be designated to the appropriate group. If, however, these scores disagree, it may be reasonable to carry out a liver biopsy for an accurate assessment of fibrosis.

Additional consideration should be given to the presence of factors that accelerate the progression of liver fibrosis in HCV individuals and special groups of patients. For example, patients with lower viral load and increased ALT levels have more rapid progression to cirrhosis. Additionally, the presence of one or more comorbidities, including diabetes mellitus, steatohepatitis or co-infection with either hepatitis B or HIV, is associated with more aggressive disease. Given the high rates of graft loss and higher mortality among liver transplant recipients, it would be reasonable to prioritise this group for DAA therapy.


Currently, there is no formalised general population screening programme for hepatitis C in Ireland. Protocols are in place for the screening of patients attending services such as drug treatment services, and for specific populations such as prisoners, but these programmes are not standardised across all services. The prevalence of HCV in the general population has not been determined, although there is information becoming available on the prevalence in different population groups.

This was evidenced by an opt-out screening study for blood-borne viruses which was undertaken in the emergency department of a large Dublin city centre hospital over a 20-week period in 2014. Of 5,299 patients screened, 287 patients were HCV-positive, with 44 new diagnoses. Of the patients previously known, approximately 60 per cent were linked with care. Another study that provided universal HCV screening in two large maternity hospitals in Dublin found that 0.7-to-0.9 per cent were anti-HCV positive. In Ireland, the cost-effectiveness of a population screening programme compared to alternative strategies has not been established.

Case discussion

The gentleman featured in this article has Child-Pugh Class A cirrhosis and currently meets criteria for IFN-free therapy in Ireland. There are four treatment options available for GT1a infection with cirrhosis; sofosbuvir/ledipasvir + ribavirin for 12 weeks; paritaprevir/ombitasvir/ritonavir + dasabuvir + ribavirin for 24 weeks; simeprevir+sofosbuvir for 12 weeks; or sofosbuvir + daclatasvir + ribavirin for 12 weeks. All of these regimens have about an 80-to-90 per cent chance of SVR. However, as this patient has previously failed therapy with boceprevir (a PI), he should not receive a PI-based regimen (ie, containing simeprevir or paritaprevir) again when other treatment options are available.

It will be the responsibility of the individual physician to discuss the pros and cons of each regimen with each patient, taking into consideration potential side-effects, drug-drug interactions and regimen cost.

Case report

A 56-year-old man has a history of chronic hepatitis C virus (HCV) infection for over 20 years, acquired from a distant history of intravenous drug use. He is infected with genotype 1a virus and was treated twice previously. In 2003, he received 48 weeks of pegylated interferon (peg-IFN) and ribavirin, which he partially responded to, but relapsed after completion of therapy. In 2011, he received another 48 weeks of treatment with the first-generation HCV protease inhibitor boceprevir, combined with IFN and ribavirin. Yet again he achieved viral suppression on therapy, but relapsed soon after completion.

He is overall clinically well, but suffers with ongoing fatigue. Clinical examination demonstrates no ascites or encephalopathy. Laboratory tests show platelets of 98,000, INR of 1.21, albumin of 30g/dl, bilirubin of 10umol/L, and AFP of 10ng/ml. He remains HCV PCR-positive, with a viral load of 46567IU/ml. He has a recent Fibroscan reading of 32kPa, consistent with cirrhosis.

How should he be treated? What are his chances of cure?

References available on request

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