Pre-treatment assessment for patients with chronic HCV infection

Key Practice Points

• Prior to treatment patients should be assessed for cirrhosis using clinical examination, laboratory tests and a non-invasive assessment of liver pathology (see below); treatment can be initiated in primary care for patients without evidence of cirrhosis
• Liver elastography is the gold-standard method to determine cirrhosis status. However, access to liver elastography is limited therefore the ratio of aspartate aminotransferase (AST) levels to platelet concentration (APRI) is a pragmatic alternative method of assessment for cirrhosis.
• Test patients for HIV and chronic hepatitis B infection
• Assess potential medicine interactions before prescribing glecaprevir + pibrentasvir. Medicines frequently prescribed in primary care which are contraindicated in combination with glecaprevir + pibrentasvir include statins, some antiepileptic medicines, dabigatran, rivaroxaban and combined oral contraceptives.
• Warn patients not to take St John’s wort while taking glecaprevir + pibrentasvir as it may decrease the effectiveness of treatment
• Discuss with a gastroenterologist or refer to secondary care patients:
• Who have previously been unsuccessfully treated with other hepatitis C medicines; longer treatment courses may be necessary
• With evidence of cirrhosis, which can include:
  • Clinical signs or symptoms, i.e. jaundice, abdominal pain and ascites, peripheral oedema
  • Laboratory findings, e.g. decreased serum albumin, elevated serum bilirubin, high INR (> 1.3), low platelet count
  • Liver elastography results suggestive of severe fibrosis or cirrhosis (see below)
  • An APRI score ≥ 1.0
• With uncertain results from investigations for liver pathology
• With eGFR < 30 mL/min/1.73 m²
• With hepatitis B or HIV co-infection

Deciding whether treatment can be initiated in primary care

Patients with hepatitis C require pre-treatment assessment to establish if they can be safely treated in primary care with glecaprevir + pibrentasvir, similar to the pre-treatment assessment previously recommended for patients initiating Viekira Pak regimens. Pre-treatment assessment is necessary to identify patients with cirrhosis, as these patients will need long-term follow-up for complications including hepatocellular carcinoma (liver cancer) and oesophageal varices.¹ Patients with cirrhosis should be referred to secondary care for further assessment in order to exclude the presence of hepatic decompensation. Patients with decompensated cirrhosis cannot be treated with glecaprevir + pibrentasvir because of the risk of toxicity. They can, however, receive treatment with ledipasvir + sofosbuvir (Harvoni) + ribavirin in secondary care.

Laboratory tests and investigations recommended prior to starting treatment include:^{* 1, 2}

• Liver elastography or APRI
• Full blood count
• Liver function tests
• Renal function
• Hepatitis B and HIV
• Pregnancy test for women of reproductive age

For further information on the diagnosis and management of hepatitis B, see: www.bpac.org.nz/2018/hepb.aspx

^* For patients with an existing long-term infection, an HCV RNA assay or HCV core antigen assay should also be performed if one has not been done in the last five years to confirm ongoing infection.² Spontaneous clearance of HCV can occur during the acute stage of infection but is rare during chronic infection.¹

Assess patients for the presence of cirrhosis

Excluding the presence of cirrhosis is required prior to prescribing glecaprevir + pibrentasvir in primary care, as this medicine is contraindicated in patients with severe, i.e. decompensated, cirrhosis.^{4, 5} In addition, patients with cirrhosis will require long-term monitoring for the development of hepatocellular carcinoma after treatment with glecaprevir + pibrentasvir has finished, and this assessment must take place prior to initiating HCV medicines as treatment affects the reliability of non-invasive assessments.⁶ Referral to secondary care or discussion with a gastroenterologist is recommended for patients with cirrhosis.

A combination of clinical examination, laboratory tests and liver imaging (Table 1) is used to determine the presence and severity of any liver disease.^{2, 8}

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Table 1: Risk factors for cirrhosis based on clinical examination and patient history.^{1, 8–13}

Assessing liver disease stage with an APRI score

Patients with HCV infection can be assessed for the likelihood of cirrhosis by calculating an AST to platelet ratio index (APRI) score

An APRI score of < 1.0 has a negative predictive value of approximately 94% to exclude cirrhosis in patients with hepatitis C.¹⁷ A recent clinical trial investigated the safety of using an APRI score of ≤ 1.0 to rule out cirrhosis in over 200 patients prior to prescribing glecaprevir + pibrentasvir and reported that <1% of patients discontinued treatment due to adverse effects.¹⁸

An APRI score of:^{8, 19}

• < 1.0 indicates that the patient is unlikely to have cirrhosis and clinicians in primary care can be confident that treatment can be initiated in the community
• ≥ 1.0 indicates that the patient may have cirrhosis and should be referred for liver elastography to confirm cirrhosis status prior to starting treatment. If the liver elastography result is < 12.5 kPa then the patient can still be treated in primary care.

For example, a female patient with a low platelet count of 120 × 10⁹/L and a mildly elevated AST value of 50 U/L (reference range 10–35 U/L) ¹³, has an APRI score of:

 APRI = AST as % of upper limit of normal/platelet count

• = (50/35) × 100 / 120
• = 1.43 × 100 / 120
• = 1.19

An APRI calculator is freely available from: www.hepatitisc.uw.edu/page/clinical-calculators/apri

The APRI score cannot be used to assess the likelihood of cirrhosis in patients with acute hepatitis as they often have elevated AST levels.¹²

Commercially available testing panels, e.g. Fibrotest and Fibrosure, can also be used to assess serum fibrosis markers if imaging is not available. These tests are not, however, publicly funded and are not available at many laboratories in New Zealand.

Liver elastography

Liver elastography performed by Fibroscan or shear wave ultrasound can be used to detect fibrosis or cirrhosis in patients with HCV infection. It is strongly recommended that this investigation be conducted in all patients with hepatitis C, wherever possible, before treatment with glecaprevir + pibrentasvir is initiated. However, access to liver elastography is variable, therefore it is accepted that calculating an APRI score is a pragmatic alternative. Both liver elastography measurements and APRI scores will give falsely low results after successful treatment; even patients with cirrhosis may have normal liver stiffness measurements following successful treatment, due to rapid resolution of liver inflammation associated with HCV infection.^6,7

In situations where the patient’s HCV infection is known to be recent, e.g. in a patient with recent onset injectable drug use and previously negative serology, liver elastography is not necessary.¹⁴

Either a Fibroscan machine or an ultrasound machine capable of “shear wave” assessments is used to perform liver elastography.^{2, 15} Elastography testing takes approximately ten minutes, with results available immediately. The availability of liver elastography varies throughout the country; clinicians are advised to contact a local radiology service to determine if this type of imaging is available in their DHB and how patients can be referred for assessment.

Elastography measures the velocity of a low-frequency wave which correlates with the degree of liver stiffness which is increased in patients with fibrosis.⁸ Liver biopsy is typically reserved for patients where either elastography is unsuccessful (see below) or there is uncertainty regarding the cause of cirrhosis detected with imaging.^{8, 12} A standard liver ultrasound is inappropriate for liver assessment in patients with HCV infection.

Liver elastography results will report a liver stiffness measurement (LSM) in kilopascals (kPa). A cut-off of 12.5 kPa is recommended to detect cirrhosis; patients with liver elastography measurements of:¹⁶

• < 12.5 kPa are unlikely to have cirrhosis and can be treated in primary care with glecaprevir + pibrentasvir (Table 2)
• ≥ 12.5 kPa are likely to have cirrhosis and the patient should be referred to secondary care or discussed with a gastroenterologist prior to prescribing glecaprevir + pibrentasvir

The reliability of elastography is decreased or the scan may be unsuccessful if performed immediately after a meal or in patients with:¹²

• Obesity
• Ascites/peritoneal dialysis
• Heart failure
• A narrow intercostal space (where a smaller paediatric probe may be indicated)

For the small number of patients where liver elastography is unsuccessful, clinical examination and blood tests are used (see below) to determine if cirrhosis is present; discussion with a gastroenterologist may be necessary.²

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Table 2: Treating or referring on the basis of liver assessments^{2, 14}

Non-hepatic assessment prior to initiating treatment in primary care

Patients with cryoglobulinaemia can now be treated in primary care

Long-term HCV infection can cause complications, including cryoglobulinaemia, leading to systemic vasculitis due to deposition of immune complexes in small blood vessels. Approximately 30% of patients with HCV infection will have circulating cryoglobulins, with approximately 10% of these patients developing systemic vasculitis.²⁰ The most common manifestation is a purpuric skin rash in the lower limbs, most evident in cold weather.³ Renal impairment from glomerulonephritis and abdominal pain from enteric vasculitis are less common.³ Testing for cryoglobulinaemia can begin with rheumatoid factor, and if positive, followed by testing for serum cryoglobulins.³

Previously, patients with hepatitis C and cryoglobulinaemia in New Zealand were recommended to undergo treatment with Harvoni in secondary care.² These patients can now be treated in primary care with glecaprevir + pibrentasvir.

Patients with severe renal impairment should be referred to secondary care or discussed with a gastroenterologist

Glecaprevir + pibrentasvir is the preferred treatment for patients with severe renal impairment (< 30 mL/min/1.73m²).⁸ In clinical trials, no accumulation of either glecaprevir or pibrentasvir was observed in patients with chronic kidney disease (CKD) stage 4 or 5 (an eGFR < 30 mL/min/1.73 m²); hence, the same dosing is recommended in these patients. Most patients with CKD stage 4 or 5 will already be managed in secondary care. If not, then discussion with a gastroenterologist is recommended prior to commencing glecaprevir + pibrentasvir as patients with CKD have higher rates of adverse effects than patients without renal impairment.^{8, 21}

Are patients co-infected with hepatitis B or HIV?

Referral to secondary care is strongly recommended for all patients with HCV who are co-infected with either hepatitis B or HIV. In patients with HCV-HBV co-infection, treatment for HCV may cause reactivation of hepatitis B viral activity and careful monitoring is required.^{8, 12} In patients with HIV-HCV co-infection, serious drug-drug interactions may occur between glecaprevir + pibrentasvir and several of the commonly prescribed antiretroviral medicines.

Ensure that patients’ vaccinations against hepatitis A and B are up to date to reduce the progression of any liver disease.²² Hepatitis B vaccination is funded for patients with chronic HCV infection. Hepatitis A vaccination is recommended but not funded. Pneumococcal vaccination is recommended but not funded for individuals with chronic liver disease.²³

For further information on the diagnosis and management of patients with hepatitis B, see: www.bpac.org.nz/2018/hepb.aspx

Defer treatment in patients who are pregnant or breastfeeding

The safety of glecaprevir + pibrentasvir in pregnancy or breastfeeding has not been studied. Deferring treatment until after pregnancy is recommended.²⁴ Mothers can be reassured that the risk of transmission of HCV to their child is low, as approximately only 6% of infants born to mothers with HCV become infected.²⁵

For women who are breastfeeding, clinicians can discuss with them the benefits and risks of deferring treatment with glecaprevir + pibrentasvir until breastfeeding has ceased, or stopping breastfeeding early to initiate treatment.

Defer treatment in children aged under 18 years

Glecaprevir + pibrentasvir is not currently approved for use in children aged under 18 years. A clinical trial has been undertaken evaluating the safety and efficacy of glecaprevir + pibrentasvir in patients of this age, with the results presented at a conference in late 2018.²⁶ On the basis of these clinical trial results, glecaprevir + pibrentasvir may be approved for use in children in the future.

Check potential medicine interactions prior to prescription

A number of significant interactions are possible between glecaprevir + pibrentasvir and other commonly prescribed medicines, including statins, some antiepileptic medicines, and anticoagulants (Table 3).

Contraceptives containing ethinylestradiol or oestrogen are contraindicated during treatment with glecaprevir + pibrentasvir, as studies have found some patients experience increased ALT levels when these medicines are taken with glecaprevir + pibrentasvir.²⁷ Female patients using combined oral contraceptives or the combined hormonal contraceptive ring should be prescribed an alternative form of contraception during treatment.

St John’s wort can reduce antiviral efficacy so should be avoided.²⁷

Prior to prescribing, check for potential medicine interactions with an online tool:

• The University of Liverpool hepatitis medicines interactions checker provides detailed information on potential interactions: www.hep-druginteractions.org/checker
• The NZF interactions checker: www.nzf.org.nz

In patients where a potential interaction with glecaprevir + pibrentasvir has been identified, consider if the current regimen can be temporarily withdrawn, replaced with another medicine or the dose reduced. For example, patients using statins could withdraw from these medicines while taking glecaprevir + pibrentasvir and reinitiate the statin after treatment has finished. Subsidised anticoagulant medicines are either contraindicated (dabigatran) or should be used with caution (warfarin and rivaroxaban) in patients taking glecaprevir + pirbentasvir. Increased monitoring of INR or increased attention to the possibility of bleeding are recommended in patients taking warfarin or rivaroxaban; consider discussion with a gastroenterologist or cardiologist.²⁷ Discussion with a gastroenterologist is recommended if patients have medicine interactions which cannot be avoided.

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Table 3: Examples of medicines which are contraindicated or should be used with caution in patients taking glecaprevir + pibrentasvir^*:^{5, 27}

^* This table is not a complete list of medicine interactions; further information is available from: www.hep-druginteractions.org/checker and medicine data sheets