Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. Globally, an estimated 170 million people have chronic hepatitis C virus infection, with about 1.5 million new infections occurring per year. The World Health Organization (WHO) estimates that in 2019 approximately 290,000 people died because of hepatitis C – with cirrhosis and hepatocellular carcinoma being the primary cause of death in these cases.

HCV is a blood-borne virus with transmission typically occurring through the use of illicit injected drugs. Infection may also occur with sexual and perinatal transmission. During the 1970s and 1990s in Ireland, the administration of infected blood products resulted in almost 1,700 individuals contracting hepatitis C. By 2013, one in five chronically infected individuals had become cirrhotic, 2% had liver cancer, and 5% had died from liver disease.

While 20-30% of those exposed can clear the virus spontaneously, the majority of HCV infections lead to chronic infection. Replicative virions within hepatocytes result in chronic liver inflammation and fibrosis, which can progress to cirrhosis and hepatocellular carcinoma.

In 2016 the WHO announced the first Global Health Sector Strategy on Viral Hepatitis.¹ This was approved by all member states including Ireland. It set the year 2030 as a target for reduction of new HCV infections by 80% and mortality by 65%. 

Irish epidemiology

From 2004-2019, 15,729 cases of hepatitis C were notified in Ireland to the Health Protection Surveillance Centre (HPSC). There has been a significant decrease in recent years, with the highest number of notifications in 2007 (1,537). Of these, 67% were male, and 78% of cases had a history of current or previous use of injected drugs. 

The age at time of notification has also increased from 33.3 years in 2004 to 42.5 years in 2019. As most of these cases were identified through screening in high-risk settings, these trends may not accurately reflect the true incidence in Ireland. In Ireland, the HPSC estimates that between 20,000 and 40,000 people are currently infected with hepatitis C, and of those, approximately 10,000 have been diagnosed.²

Screening

A major barrier to the eradication of hepatitis C is the large proportion of patients who are unaware of their infection. The National Clinical Effectiveness Committee published guidelines in 2017 for hepatitis C screening.³ The same year, the European Union HCV collaborators concluded that because of its excellent healthcare infrastructure the EU could potentially eradicate hepatitis C, but that expansion of screening would be required to meet WHO targets. 

The 2017 guidelines break screening down into specific target populations. When screening for HCV, testing for other blood-borne viruses should be considered. This guideline is comprehensive, and available on the Department of Health website (www.gov.ie/en/collection/e4bb9d-hepatitis-c-screening/). Some of the key points are below. 

Birth cohort screening

Birth cohort screening is currently not carried out due to the significant cost and uncertain benefit, though this continues to remain under review. In July 2021, HIQA recommended the introduction of once-off testing in Ireland for people born between 1965 and 1985 and this is under consideration.⁴ Seroprevalence studies have been initiated in certain centres in Ireland to ascertain the true prevalence of HCV infection, with study outcomes awaited. 

Pregnant women

For pregnant women, HCV screening is recommended to be carried out in a standardised risk-based manner. Universal antenatal screening is not recommended as there are no interventions to reduce transmission to the infant and HCV treatment during pregnancy is not possible. 

Infants

Testing infants born to known hepatitis C-infected mothers allows them to be linked to care from an early age. Current guidelines recommend testing these infants for HCV-RNA at six weeks and six months of age. If both are negative, they should be tested for anti-HCV once they are over 18 months of age. If any of these are positive, they should be referred to the Rainbow Clinic, which is a multidisciplinary clinic for paediatric infectious diseases delivered in both the Children’s University Hospital, Temple Street and Our Lady’s Children’s Hospital, Crumlin.

If a woman who has had children is later found to have current or resolved hepatitis C infection, unless it is certain she was HCV-RNA negative at the time of their delivery, her children should be tested.

Household screening

While household transmission can occur, horizontal non-sexual transmission is considered to be low risk. In general, household screening is not recommended unless there are circumstances where transmission is more likely (eg. discarded needles, sharing of razors). If a household contact seeks testing for reassurance, this should be provided.

Screening in illicit drug users 

Screening should be offered to anyone who has ever injected illicit, unprescribed or performance-enhancing drugs. Regular retesting should be offered to those at ongoing risk of infection; it is a standard of care to screen all patients receiving opiate substitution therapy (OST) for HCV infection annually. Testing should also be offered to all those who use unprescribed drugs by a route other than injecting, if the possibility to acquire HCV exists through that route.  This includes intranasal drugs and the use of crack pipes. 

Screening in prisoners

All prisoners should be offered screening on entry. They should be screened yearly during imprisonment. All ex-prisoners are recommended to have one-off testing. 

Screening in marginalised groups

Homeless people are a marginalised group who have significant healthcare needs. Community-based support and dedicated resources may be required for screening and treatment in this population. Universal screening of people who are homeless is not currently recommended, though screening should be offered to those who have engaged in at-risk behaviours. 

One-off HCV screenings

One-off HCV screening should be offered to migrants from a country with an intermediate to high prevalence of hepatitis C (≥ 2%). It should also be offered to people who have received medical or dental treatment in these countries.

These National Screening Guidelines also state that anyone who has a tattoo may be considered for HCV screening. The risk is greatest in those whose tattoo was completed a number of decades ago, or in prison or in other circumstances where hygiene may not have been adequate. 

Screening in sexual partners  

The National Screening Guidelines do not recommend routine testing of heterosexual HIV-negative partners of people who have known hepatitis C; unless the contact is a user of illicit drugs or HIV-positive. If a sexual partner seeks testing for reassurance this should be facilitated. 

The guidance recommends that men who have sex with men should be offered testing annually as part of an overall STI screen and that HCV testing should be part of routine sexual health screening in commercial sex workers.

Other causes for screening 

Screening should also be offered to: 

• People who have had a kidney transplant or are on renal dialysis

• Recipients of blood or blood components in Ireland prior to October 1991 who have not yet been tested

• Recipients of anti-D immunoglobulin in Ireland between May 1,  1977 and the end of July 1979; and March 1, 1991 to February 1, 1994 who have not yet been tested

• Recipients of plasma-derived clotting factor concentrates in Ireland prior to 1992 who have not yet been tested

• Those who have received blood in countries that do not screen donor blood. 

Diagnosis and treatment

The diagnosis of hepatitis C is made by the detection of antibodies against HCV (anti-HCV), in combination with a positive HCV RNA viral load (PCR). Anti-HCV antibodies can be detected within three to six weeks after initial infection. False-negative results can occur in immunosuppressed patients, such as those with concurrent HIV infection. HCV-RNA PCR is carried out to determine active infection.

HCV genotype is also useful for guiding choice of antiviral treatment. Viral eradication or cure, termed ‘sustained virological response’ (SVR) is achieved following a negative HCV RNA taken three months after treatment completion. Once negative at this point, and without further behaviour that would put an individual at risk of re-infection, no further testing or surveillance is necessary. It is important to reassure the patient that there is no risk of spontaneous reactivation of the virus, once treatment is successful.

  There is little doubt that the advances in HCV treatment over the past 10 years have had a major impact. Hampered by low response rates and significant adverse effects of treatment, chronic HCV infection was once associated with major morbidity and mortality; now it is an easily curable disease in almost all cases. 

Many patients receive as little as one or three tablets a day for eight or 12 weeks to be cured, as opposed to weekly injections and tablets for one year, which was the previous norm. With these advances, HCV has decreased from a major cause of liver disease to a rarity, and led to dramatic reductions in HCV-related cirrhosis, liver cancer and mortality.

In 2014 the National HCV Treatment Programme (NHCTP) was established to oversee the treatment of HCV in Ireland. Novel direct-acting antiviral (DAA) regimes were initiated as gold standard HCV therapy. These regimes do not include interferon or ribavirin therapy, the previous standard of care for HCV, which were associated with severe complications such as anaemia, depression and significant fatigue. DAA regimens may cause mild symptoms such as headache, nausea, and fatigue, and discontinuation rates are less than 1%.

All patients with haemophilia who contracted HCV through contaminated blood products have been treated, leading to eradication in this community by the end of 2016. Since 2014, over 3,800 people have been successfully treated.

Disease staging

The use of transient elastography (Fibroscan) to accurately stage liver disease and guide treatment has increased dramatically, obviating the need for invasive liver biopsy. A Fibroscan score greater than 12kPa or liver biopsy demonstrating stage 3/4 fibrosis indicates advanced liver disease. Treatment with anti-HCV medication is tailored to the stage of liver disease at diagnosis, typically ranging from 8-12 weeks, with a longer duration of therapy for those with advanced liver disease.

Treatment regimens

Table 1 outlines recommended DAA therapies for patients without cirrhosis in the National Hepatitis C Treatment Programme Clinical Advisory Group, Community Treatment Guidelines 2020.⁵

Certain criteria may alter choice and duration of treatment, for example whether the patient is treatment-naïve versus previous HCV treatment. 

Eight-week treatment programmes have been implemented for patients in a prison setting and patients with a documented chaotic lifestyle which limits clinic attendances or compliance with treatment. The NHCTP and clinical advisory group have advised that eight-week treatment with glecaprevir/pibrentasvir should be first-line treatment in a prison setting.

Patients with decompensated cirrhosis (Child-Pugh B or C), HIV/HCV co-infection, renal failure, solid organ transplantation or on immunosuppressive medication should only be treated in specialised tertiary referral centres. It is important to note that protease inhibitor regimens are contraindicated in patients with decompensated cirrhosis; this includes glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir, as liver failure and death have been reported. Additionally, treatment regimens with sofosbuvir are cautioned in severe renal impairment (Crcl < 30ml/min). 

Drug interactions

The novel HCV treatment regimens have specific interactions with hepatic cytochrome P450 enzymes, as well as drug transporter proteins. A drug-drug interaction (DDI) could result in over- or underexposure of the DAA, leading to potential treatment failure or increased treatment side-effects. 

Common considerations include lipid-lowering drugs such as statins – a potential increase in statin concentration with certain DAAs may increase the risk of myopathy. Additionally, proton pump inhibitors can reduce the absorption of some DAAs necessitating dose modification or cessation of such agents. In specialist treatment centres, dedicated HCV pharmacist involvement is crucial to screen for any potential DDIs of concern prior to treatment. Helpful online tools also exist such as www.hep-druginteractions.org to guide treatment. 

In situations where co-administration has not been studied, the pharmacokinetics of each medication must be reviewed by the pharmacist to determine the potential for DDIs. Depending on the severity of the DDI, an adjustment to concurrent medications or increased monitoring may be required which is documented and discussed with the patient upon their treatment initiation clinic date. 

Of note, female patients are advised to avoid pregnancy during treatment and undertake appropriate contraceptive measures due to the limited information about their effects in pregnancy. 

Rapid reduction in hepatitis C viral load during initial treatment with DAA therapy for hepatitis C may lead to improvements in glucose metabolism in some patients with diabetes. Patients taking diabetes medication should be educated on the potential for symptomatic hypoglycaemia during and after DAA therapy while being monitored closely in the care setting. 

Additionally, there is a link between DAA therapy and a clinically significant reduction in warfarin dose response. Patients taking warfarin should be informed of this and international normalised ratio (INR) monitoring for sub-therapeutic anticoagulation is recommended during and after DAA treatment.

Treatment pathway

Prior to treatment initiation, patients are reviewed by the multidisciplinary team, including a nurse specialist, pharmacist, and physician. The aim is to provide a comprehensive rapid initial assessment to facilitate rapid access to treatment, to maintain engagement and increase compliance. 

In preparation for commencing DAA treatment the following steps must be undertaken:

• Registration to the National HCV Treatment Registry

• Baseline HCV-RNA level within six months of starting treatment

• Baseline labs (at week four [optional per community guidelines] and week 12): FBC, LFTs, and HCV RNA level

• Evaluation of liver staging: Fibroscan, serum markers of fibrosis if available

• Cirrhosis staging using Child-Pugh and MELD scores

• Pharmacist assessment for potential drug-drug interactions

• MDT review with determination of treatment type, duration, and follow-up plan.

Individuals starting DAA treatment are counselled on the importance of medication adherence for the entire duration of the 8-12 week course. Additionally, dosing, administration advice, potential side-effects and potential for DDIs are discussed. Advice is given to the patient regarding lifestyle measures to limit damage to the liver, and that immunity to re-infection is not guaranteed following treatment success. 

The structured visit gives the patient the opportunity to discuss their treatment plan, optimise their care and monitor their progress. Following successful therapy, a patient may be discharged from the clinic should they not have sustained significant liver damage prior to treatment initiation.

DAA treatment failure can occur in < 5% of cases, demonstrated by failure to achieve sustained virological response after exposure to two or more classes of DAA drugs. Resistance testing should be carried out at this point in treatment before commencing further anti-HCV therapy.

Additionally, HCV-infected patients should also be tested for human immunodeficiency virus (HIV) and hepatitis B virus (HBV), given the common modes of transmission and the association of these co-infections with more rapid disease progression. HBV reactivation can occur during treatment with a direct-acting antiviral (DAA) and has been rarely associated with liver failure and death. 

Lifestyle measures

Other causes of chronic liver disease, or those that affect the progression of liver disease, should be sought out and modified. Alcohol consumption and substance abuse should be assessed and quantified, with specific counselling given to minimise harm and encourage abstinence wherever possible. Disease progression is also affected by metabolic factors (increased BMI, diabetes) and healthy eating and regular exercise is promoted wherever possible. 

Additionally, those with hepatitis C should be counselled on ways to prevent the spread of the virus. These include use of waterproof dressings for cuts or grazes, not sharing personal items such as toothbrushes or razors, not donating blood, not sharing injecting equipment, and the use of condoms. 

Eradication of the virus will also require continued emphasis on public health programmes such as needle exchange. 

Other symptoms may also require lifestyle modification and management. These include fatigue (most common symptom), aches and pains, and depression. 

The Hepatitis C Partnership website www.hepcparntership.ie can provide information to people with HCV. 

Immunisations for patients with chronic liver disease

HBV and HAV vaccination should be encouraged for patients who are not immune.

All patients with chronic liver disease should receive the inactivated influenza vaccination yearly. The inactivated vaccines are generally well tolerated, with reactions seen in less than 5% of cases. There are no data about special safety concerns in patients with liver disease.

 All patients with chronic liver disease should receive one of the available Covid-19 vaccines, unless contraindicated for other reasons (eg. hypersensitivity to the vaccine). Chronic liver disease is a risk factor for adverse outcomes with Covid-19 infection, particularly those with cirrhosis.

For pneumococcal vaccination, the recommended vaccine to use is that of the 23-valent pneumococcal polysaccharide vaccine (PPSV23). 

Community treatment

Following the establishment of successful hospital-based treatment programmes, community-based services were established for suitable low risk patients. (This excludes those with cirrhosis, organ transplants, HIV and recurrent HCV infection). GPs must be registered to prescribe methadone to participate in the HCV community treatment programme (level 1 and 2). The National Hepatitis C Treatment Programme Community Treatment Guidelines 2020⁵ set out the procedures for collaboration between the prescribing GP, the community pharmacist, and other members of the multi-disciplinary team. For more information on aspects of the community programme see Forum Clinical Focus. Hepatitis C Community Treatment. 2021 Volume 15, No 1.

Current challenges

In Ireland, a significant number of individuals contract HCV through intravenous illicit drug use; this can naturally present difficulties as far as screening for HCV and ensuring engagement and compliance with care. Drug treatment centres providing OST have been targeted for screening patients at risk of HCV infection. HCV-positive non-cirrhotic patients may be offered DAA treatment in the community, removing the need for hospital attendance, with support from the specialist hospital hepatology/ID department. 

The National Hepatitis C Treatment Programme adopted an ambitious plan to make HCV a rare disease in Ireland by 2026, and to exceed the WHO target of elimination by 2030. In 2021, the main barriers to treatment remain the identification of cases in the community and bringing the treatment to the patient. 

A focus on the education of GPs, nurses, and pharmacists in primary care, as well as the provision of specialist liaison nurses working between hospitals and community sites to facilitate treatment looks to address these significant challenges.

Summary

The once life-threatening complications of chronic HCV infection such as cirrhosis, liver failure, and hepatocellular carcinoma are now rarely seen in clinical practice, highlighting the impact of highly effective and safe antiviral therapy. Learning from the success of HCV programmes around the world, the eradication of HCV in Ireland is an achievable goal, but will require an almost complete shift of care from the acute hospital into the community, where HCV infection persists for now.  

References

1. World Health Organization. (2016). Global health sector strategy on viral hepatitis 2016-2021. Towards ending viral hepatitis. World Health Organization. https://apps.who.int/iris/handle/10665/246177
2. Drug-related bloodborne viruses in Ireland 2018. Health Protection Surveillance Centre. https://www.hpsc.ie/a-z/hepatitis/hepatitisc/
3. Hepatitis C screening: National Clinical Guideline No. 15. 2017. Department of Health. https://www.gov.ie/en/collection/e4bb9d-hepatitis-c-screening/
4. Health technology assessment of birth cohort testing for hepatitis C. Health Information and Quality Authority. July 2021. https://www.hiqa.ie/reports-and-publications/health-technology-assessment/hta-birth-cohort-testing-hepatitis-c
5. National Hepatitis C Treatment Programme Clinical Advisory Group Community Treatment Guidelines. HSE 2020. Available at www.icgp.ie