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
- 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
- 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
- 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
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
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
Table 1: Risk factors for cirrhosis based on clinical examination and patient history.1, 8–13
|Risk factors for cirrhosis include:
||Clinical features consistent with cirrhosis include:
||Clinical features consistent with decompensated cirrhosis include:
||Laboratory results consistent with cirrhosis are:
- Duration of HCV infection of > 10 years
- Male sex
- A history of excessive alcohol consumption or heavy cannabis use
- BMI ≥ 25 kg/m2
- Type 2 diabetes
- Other liver disease, e.g. non-alcoholic fatty liver disease
- HIV or HBV coinfection
- Signs of portal hypertension: splenomegaly or caput medusae (dilated superficial abdominal veins)
- Spider naevi
- Leukonychia (white spots on nails)
- Palmar erythema
- Peripheral oedema
- Abdominal pain or tenderness on palpation, with fever or chills, which could indicate spontaneous bacterial peritonitis
- Dyspnoea, digital clubbing or cyanosis; symptoms and signs of hepatopulmonary syndrome
- Variceal haemorrhage
- Low platelet count
- Decreased serum albumin
- Increased INR (> 1.3)
- Decreased platelet count (< 150 × 109/L)
- Elevated serum bilirubin, e.g. >20 micromol/L
- A liver stiffness measurement of > 12.5 KPa on liver elastography (Fibroscan)
- If a liver elastography scan is not possible, assess the possibility of cirrhosis with:
- An APRI ≥ 1.0 (cirrhosis cannot be excluded and referral to secondary care is recommended)
- A score of F3–F4 on Fibrotest or Fibrosure tests (see below)
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:
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 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
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
- 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
Table 2: Treating or referring on the basis of liver assessments2, 14
|Treatment in primary care is appropriate for patients with ALL of the following:
||Referral to or discussion with a gastroenterologist is appropriate for patients with ANY of the following:
- Clinical examination does not suggest cirrhosis
- No evidence of cirrhosis on non-invasive liver assessments:
- Liver stiffness measurement < 12.5 kPa on liver elastography
- Laboratory results, e.g. bilirubin, platelet count, INR and albumin, do not suggest cirrhosis
- Clinical examination consistent with cirrhosis
- APRI ≥ 1.0
- Liver stiffness measurement ≥ 12.5 kPa on liver elastography
- Laboratory results consistent with cirrhosis
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:
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.
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:
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.
Table 3: Examples of medicines which are contraindicated or should be used with caution in patients taking
glecaprevir + pibrentasvir*:5, 27
|Examples of medicines which are contraindicated
||Examples of medicines that should be used with caution
- Simvastatin, atorvastatin
- Antiepileptic medicines, including phenytoin, primidone, phenobarbital, carbamazepine
- Combined oral contraceptives and ethinylestradiol + etonogestrel contraceptive ring
- Rifabutin and rifampicin
- Many medicines for the treatment of HIV
- Other medicines for the treatment of HCV
- Opioid medicines: fentanyl, oxycodone
* This table is not a complete list of medicine interactions; further information is available
from: www.hep-druginteractions.org/checker and medicine data sheets
- American Association for the Study of Liver Diseases (AASLD), Infectious Diseases Society of America (IDSA). HCV guidance:
recommendations for testing, managing and treating and hepatitis C. 2018. Available from:
http://www.hcvguidelines.org (Accessed Jan, 2019).
- New Zealand Society of Gastroenterology. NZ Society of Gastroenterology HCV treatment guidelines. 2016. Available
https://nzsg.org.nz/assets/Uploads/NZSG-Hepatitis-C-Guidance-November-UPDATE.pdf (Accessed Jan, 2019).
- Cacoub P, Comarmond C, Domont F, et al. Cryoglobulinemia vasculitis. Am J Med 2015;128:950–5.
- European Association for Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C 2018. 2018. Available
- AbbVie Limited. Maviret. New Zealand Data Sheet. 2018. Available from:
http://www.medsafe.govt.nz/profs/datasheet/m/mavirettab.pdf (Accessed Jan, 2019).
- Bachofner JA, Valli PV, Kröger A, et al. Direct antiviral agent treatment of chronic hepatitis C results in rapid
regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio
index. Liver Int 2017;37:369–76. http://dx.doi.org/10.1111/liv.13256
- Vergniol J, Foucher J, Castéra L, et al. Changes of non-invasive markers and FibroScan values during HCV treatment.
J Viral Hepat 2009;16:132–40.
- Hepatitis C Virus Infection Consensus Statement Working Group. Australian recommendations for the management of hepatitis
C virus infection: a consensus statement. Melbourne: Gastroenterological Society of Australia 2018. Available from:
http://www.asid.net.au/documents/item/1208 (Accessed Jan, 2019).
- Garcia-Tsao G, Lim JK, Lim J, et al. Management and treatment of patients with cirrhosis and portal hypertension:
recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis
C Program. Am J Gastroenterol 2009;104:1802–29. http://dx.doi.org/10.1038/ajg.2009.191
- Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society practice guidelines: diagnosis and management
of hepatopulmonary syndrome and portopulmonary hypertension. Transplantation 2016;100:1440–52.
- Imai N, Kimura K. Images of the month: caput medusae. Am J Gastroenterol 2013;108:879.
- European Association for the Study of the Liver, Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH
Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol 2015;63:237–64.
- Kyle C (Ed). Sonic pathology handbook: a guide to the interpretation of pathology tests. New South Wales: Sonic Healthcare
2014. Available from: http://www.snp.com.au/ (Accessed Jan, 2019).
- Hepatitis C Implementation Advisory Group. Guidance to support the development of regional services to deliver identification
and treatment for people at risk of or with hepatitis C. Ministry of Health 2017. Available from:
http://www.health.govt.nz/our-work/diseases-and-conditions/hepatitis-c/training-and-education-resources-hepatitis-c (Accessed Jan, 2019).
- National Institutes for Health and Care Excellence (NICE). Cirrhosis in over 16s: assessment and management. 2016.
Available from: http://www.nice.org.uk/guidance/ng50 (Accessed Jan, 2019).
- Lim JK, Flamm SL, Singh S, et al. American Gastroenterological Association Institute guideline on the role of elastography
in the evaluation of liver fibrosis. Gastroenterology 2017;152:1536–43.
- Kelly ML, Riordan SM, Bopage R, et al. Capacity of non-invasive hepatic fibrosis algorithms to replace transient elastography
to exclude cirrhosis in people with hepatitis C virus infection: A multi-centre observational study. PLOS ONE 2018;13:e0192763.
- Fontana R, Lens S, McPherson S, et al. Poster abstract 653: Efficacy and safety of 8‐Weeks of glecaprevir/pibrentasvir
in treatment‐naïve adults with HCV genotype 1‐6 and aspartate aminotransferase to platelet ratio index (APRI) ≤1. Hepatology
- Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection:
a systematic review. Ann Intern Med 2013;158:807–20.
- Younossi Z, Park H, Henry L, et al. Extrahepatic manifestations of hepatitis C: a meta-analysis of prevalence, quality
of life, and economic burden. Gastroenterology 2016;150:1599–608.
- Gane E, Lawitz E, Pugatch D, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment.
N Engl J Med 2017;377:1448–55. http://dx.doi.org/10.1056/NEJMoa1704053
- Wilkins T, Akhtar M, Gititu E, et al. Diagnosis and management of hepatitis C. Am Fam Physician 2015;91:835–42.
- Ministry of Health. Immunisation Handbook 2017. Ministry of Health NZ 2018. Available from:
http://www.health.govt.nz/publication/immunisation-handbook-2017 (Accessed Jan, 2019).
- Society for Maternal-Fetal Medicine (SMFM), Hughes BL, Page CM, et al. Hepatitis C in pregnancy: screening, treatment,
and management. Am J Obstet Gynecol 2017;217:B2–12.
- Benova L, Mohamoud YA, Calvert C, et al. Vertical transmission of hepatitis C virus: systematic review and meta-analysis.
Clin Infect Dis 2014;59:765–73. http://dx.doi.org/10.1093/cid/ciu447
- Jonas MM, Squires R, Rhee S, et al. Poster abstract 2379: Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir
in pediatric patients with genotypes 1-6 chronic HCV infection: Part 1 of the Dora study. Hepatology 2018;68:1347A-1348A.
- University of Liverpool. HEP drug interactions. 2019. Available from:
http://www.hep-druginteractions.org/checker (Accessed Jan, 2019).