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Abbreviations

ALTalanine aminotransferase
ARFIacoustic radiation force impulse
APRIaspartate aminotransferase to platelet ratio index
ARTantiretroviral treatment
ASTaspartate aminotransferase
DAAdirect-acting antiviral
eGFRestimated glomerular filtration rate
ELFEnhanced Liver Fibrosis
FCHfibrosing cholestatic hepatitis
GRADEGrading of Recommendations Assessment, Development and Evaluation
Gtgenotype
HAVhepatitis A virus
HBVhepatitis B virus
HCChepatocellular carcinoma
HCVhepatitis C virus
HIVhuman immunodeficiency virus
IFNinterferon
INRinternational normalised ratio
LFTliver function test
MSMmen who have sex with men
MELDModel for End-Stage Liver Disease
mTORmammalian target of rapamycin
PBACPharmaceutical Benefits Advisory Committee
PBSPharmaceutical Benefits Scheme
PCRpolymerase chain reaction
pegIFNpeginterferon-alfa
PrODparitaprevir (ritonavir-boosted), ombitasvir and dasabuvir
PWIDpeople who inject drugs
RAVresistance-associated variant
HSDHighly Specialised Drugs
SVRsustained virological response at least 12 weeks after treatment (cure)
TGATherapeutic Goods Administration
ULNupper limit of normal

Acknowledgements

The Consensus Statement was prepared by an expert panel representing the Gastroenterological Society of Australia (Australian Liver Association), the Australasian Society for Infectious Diseases, the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine, the Australasian Hepatology Association, Hepatitis Australia and the Royal Australian College of General Practitioners.

Steering committee: Alexander J Thompson (chair), Fran Bramwell, Wendy Cheng, Krispin Hajkowicz, William Kemp, Gail Matthews, Lucy McDonald, Stuart Roberts, William Sievert, Alison Stewart, Simone Strasser, Caroline Tallis, Helen Tyrrell, Alan Wigg.

Working parties: Peter Angus, Narin Bak, David Baker, Annie Balcombe, Sally Bell, Wendy Cheng, Paul Clark, Mark Danta, Josh Davis, Anouk Dev, Greg Dore, Mark Douglas, Joe Doyle, Geoff Farrell, Jacob George, Paul Gow, Winita Hardikar, Margaret Hellard, Jessica Howell, David Iser, Miriam Levy, Andrew Lloyd, John Lubel, Graeme Macdonald, Gerry MacQuillan, Kevin Marriott, Susan Mason, Geoff McCaughan, Stephen Pianko, David Pieper, Elizabeth Powell, Joe Sasadeusz, David Siebert, Kasha Singh, Steven Tong, Deborah Warneke-Arnold, Martin Weltman, Amany Zekry.

Adherence to treatment

Adherence to treatment is important, and managing any condition or circumstance that may affect adherence to treatment is recommended before commencing DAA therapy for HCV. People with stable psychiatric conditions and/or stable injecting drug use are candidates for DAA treatment. People with no cirrhosis may continue to drink alcohol at low risk levels during treatment (no more than two standard drinks on any day28). Complete abstinence from alcohol is recommended for people with cirrhosis or people with alcohol dependence. People with high-risk alcohol use should be considered for management for alcohol dependence before DAA therapy.

The Australasian Hepatology Association (AHA) has recently released the AHA consensus guidelines for the provision of adherence support to patients with hepatitis C on direct acting antivirals.29 The guidelines consist of 24 consensus recommendations that promote a patient-centred approach, asserting that all patients are at risk of medication non-adherence. “Treatment readiness” is a pivotal concept that influences subsequent adherent behaviour. The AHA guidelines recommend supporting DAA adherence through implementing interventions focused on the patient, such as identifying memory triggers and hooks; and linguistic advice for health professionals, including using non-confrontational and non-judgemental language. See the AHA website (www.hepatologyassociation.com.au) for further information.30

Consensus recommendations for treatment of HCV in the setting of HIV coinfection

Consensus recommendationsGrade
People with HCV–HIV coinfection should be cared for by a clinician who is experienced in managing both viral infections.B1
All people living with HCV should be tested for HIV.A1
All HCV-negative people living with HIV should be tested for HCV annually if they have risk factors for HCV exposure.A1
HIV should be controlled before HCV treatment.B1
ART should not be switched for people who are on a stable regimen, unless an unavoidable and unmanageable drug–drug interaction is identified.B1
The treatment regimens for chronic HCV infection in people living with HIV should be the same as those used for HCV mono-infection, because DAA regimens for the treatment of HCV are just as effective in the setting of HIV coinfection. However, cirrhosis and advanced fibrosis should be excluded by transient elastography or other imaging modality before use of an 8-week regimen of sofosbuvir–ledipasvir in people with Gt 1 HCV infection.B1
A careful assessment of potential drug–drug interactions between DAAs and ART and drugs prescribed to manage HIV-related complications and comorbidities should be performed and used to guide the selection of an appropriate DAA regimen for HCV.A1
HIV-positive individuals who achieve SVR after DAA therapy and who remain at risk of reinfection with HCV should continue to be screened with annual HCV RNA PCR and 3–6-monthly liver function test monitoring.C2

Consensus recommendations for HCV treatment after liver transplantation

Consensus recommendationsGrade
People with post-transplant HCV infection should be treated as soon as possible, as they are at risk of severe complications.A1
Optimal timing of initiation of treatment has not been established. For people with newly transplanted livers, initiation of treatment at 3–6 months after transplantation is recommended.B1
Preferred treatment options for chronic HCV infection and compensated liver disease after transplantation include (see Table 8):
Gt 1 HCV:
• sofosbuvir + velpatasvir ± ribavirin for 12 weeksB1
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksA1
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB1
• paritaprevir–ritonavir, ombitasvir, dasabuvir ± ribavirin for 24 weeksB1
Gt 2, 3 HCV:
• sofosbuvir + velpatasvir ± ribavirin for 12 weeksB2
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB2
Gt 4, 6 HCV:
• sofosbuvir + velpatasvir ± ribavirin for 12 weeksB2
Preferred treatment options for chronic HCV infection and decompensated liver disease or fibrosing cholestatic hepatitis after transplantation include (see Table 8):

Gt 1 HCV:
• sofosbuvir + velpatasvir + ribavirin for 12 weeksB1
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksA1
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB1
Gt 2 HCV:
• sofosbuvir + velpatasvir + ribavirin for 12 weeksB2
Gt 3 HCV:
• sofosbuvir + daclatasvir + ribavirin for 24 weeksB2
Gt 4, 6 HCV:
• sofosbuvir + velpatasvir + ribavirin for 12 weeksB2
Treatment with sofosbuvir + velpatasvir, sofosbuvir + ledipasvir, sofosbuvir + daclatasvir or ribavirin does not require dose adjustment of calcineurin inhibitors or mTOR inhibitors.A2
Treatment with paritaprevir–ritonavir, ombitasvir, and dasabuvir requires dose modification of calcineurin inhibitors; use in combination with mTOR inhibitors is not recommended.A2
Notes: None of the currently available DAAs in Australia include a specific indication for the treatment of HCV infection after transplantation. Recommended or preferred treatment regimens may not be eligible for prescription on the PBS, reflecting the dynamic nature of this area (see Table 8).
 

Consensus recommendations for models of care

Consensus recommendationsGrade
HCV treatment uptake in Australia must be substantially increased in order to limit HCV-related liver disease and deaths and to reduce ongoing transmission of HCV. This will require new models of care.A1
Tertiary care centres must continue to have a major role in managing people with HCV who have cirrhosis or complex care needs.A1
GP-led HCV care should be a major driver of increased HCV treatment uptake. GPs who are experienced in the treatment of HCV can prescribe HCV medicines. GPs who are not experienced in the treatment of HCV should provide treatment in consultation with an experienced specialist.B2
For GPs, “experienced” should include all practitioners who have previously been accredited as prescribers for HCV medicines, as well as interested GPs who have participated in a formal education session and completed treatment in consultation with an experienced specialist for at least 10 people living with HCV infection.B2
Hepatology advanced practice nurses linked to specialist care centres are a safe and effective way of increasing HCV treatment capacity in a range of health care environments and should have a critical role in the expansion of treatment uptake.B1
Authorised nurse practitioners experienced in the treatment of chronic HCV can prescribe HCV medicines, and this will increase timely, affordable and equitable access to treatment in Australia.B2
Specific models of care for high-prevalence but under-served populations (PWID, including those attending primary health care services and opioid substitution treatment centres; prisoners; people with mental health disorders; rural and remote populations; Aboriginal and Torres Strait Islander people; and migrant communities) must be developed to reduce barriers to treatment and increase HCV treatment uptake.B1
surgery

Consensus recommendations for on-treatment monitoring

Consensus recommendationsGrade
On-treatment monitoring for medication adherence, side effects and hepatic function should be performed.A1
Routine on-treatment HCV PCR testing is not required as it is unlikely to change management. Quantitative HCV PCR testing should be considered if there are concerns about DAA adherence or viral resistance.B1
Qualitative HCV PCR testing at the end of treatment is reasonable to confirm an end-of-treatment response; however, given the high efficacy of DAA therapy, such monitoring is not mandated in all individuals.C2

Consensus recommendations for post-treatment follow-up

Consensus recommendationsGrade
HCV qualitative PCR should be performed 12 weeks after cessation of DAA therapy.A1
People with cirrhosis should continue in long-term variceal and HCC surveillance programs.A1
People with no cirrhosis who achieve SVR and normal liver function test results should be medically managed as individuals who have never had HCV infection.B1
People with persistently abnormal liver function test results after SVR should undergo further assessment and monitoring for alternative causes of liver disease.A1
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Consensus recommendations for pre-treatment assessment

Consensus recommendationsGrade
Assessment of comorbid conditions and liver disease cofactors should occur before commencing DAA therapy, and these conditions should be addressed before or concurrent with DAA therapy.A1
Assessment of HCV RNA level (quantitative PCR) and HCV genotype should occur before making decisions regarding HCV therapy.A1
Past HCV treatment experience should be documented, including regimen and response.A1
Detecting cirrhosis is essential to identify people requiring long-term management of chronic liver disease, and also determines treatment duration for a number of DAA regimens.A1
A non-invasive assessment of liver fibrosis is suitable for the majority of people.A1
People with cirrhosis should be screened for complications including:
> HCC (liver ultrasound)
> oesophageal varices (gastroscopy)
> osteoporosis (bone densitometry)
A1
All people with cirrhosis should be referred to, and managed in consultation with, a specialist familiar with the management of this condition.A1
Vaccination against HVA and HVB is recommended for all susceptible individuals with HCV infection.A1
All concomitant medications must be assessed for potential drug–drug interactions.A1
Men and women of childbearing potential should be cautioned to avoid pregnancy while receiving DAA treatment.B1
Men and women of childbearing potential should be cautioned to avoid pregnancy while receiving ribavirin-containing antiviral regimens, and for up to 6 months after stopping.Men and women of childbearing potential should be cautioned to avoid pregnancy while receiving ribavirin-containing antiviral regimens, and for up to 6 months after stopping.A1
Breastfeeding women should not be treated with DAAs.B1

Consensus recommendations for the treatment of chronic HCV

Consensus recommendationsGrade
All individuals with chronic HCV infection should be considered for antiviral therapy.A1
Choice of treatment regimen should be based on:
• HCV genotype and subtype
• the presence or absence of cirrhosis
• the presence or absence of liver decompensation
• prior treatment history
• the potential for drug–drug interactions
• comorbidities
A1
First-line treatment regimens for chronic Gt 1 HCV infection and compensated liver disease include (see Table 3):
• sofosbuvir + velpatasvir for 12 weeks
• sofosbuvir + ledipasvir for 8 or 12 or 24 weeks
• elbasvir + grazoprevir ± ribavirin for 12 or 16 weeks
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks
• paritaprevir–ritonavir + ombitasvir + dasabuvir ± ribavirin for 12 or 24 weeks
A1
The first-line treatment regimen for chronic Gt 2 HCV infection and compensated liver disease is (see Table 4):
• sofosbuvir + velpatasvir for 12 weeks
A1
First-line treatment regimens for chronic Gt 3 HCV infection and compensated liver disease include (see Table 4):
• sofosbuvir + velpatasvir ± ribavirin for 12 weeks
• sofosbuvir + daclatasvir for 12 weeks (no cirrhosis)
• sofosbuvir + daclatasvir ± ribavirin for 12 weeks (cirrhosis) or sofosbuvir + daclatasvir (cirrhosis) for 24 weeks
A1
First-line treatment regimens for chronic Gt 4 HCV infection and compensated liver disease include (see Table 5):
• sofosbuvir + velpatasvir for 12 weeks
• elbasvir + grazoprevir ± ribavirin for 12 or 16 weeks
A1
The current first-line treatment for chronic Gt 5/6 HCV infection and compensated liver disease is (see Table 5):
• sofosbuvir + velpatasvir for 12 weeks
A1
Dose reduction or dose interruption of DAA therapies is not recommended.A1
Dose reduction of ribavirin for the management of symptomatic anaemia according to the product information is appropriate and will not reduce the likelihood of SVR.A1
DAA therapies for HCV should not be used in combinations other than those that have demonstrated efficacy in prospective clinical trials.B1
People in whom first-line DAA therapy fails should be referred to a specialist centre for consideration of salvage therapy.B1

Consensus recommendations for treatment of decompensated liver disease

All individuals with decompensated liver disease must be assessed and managed in specialist centres. Typical clinical presentations of liver decompensation include variceal haemorrhage, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatopulmonary syndrome and jaundice. All predict a poor prognosis. Multiple scoring systems have been proposed to predict prognosis for people with chronic liver disease, the most well known being the Child–Pugh score (based on degree of ascites, encephalopathy, serum bilirubin level, albumin level and INR) and the MELD score (based on serum bilirubin level, creatinine level and INR) (Supplementary Table 2). These scoring systems have clinical utility for predicting short-term mortality and for prioritising individuals on liver transplant waiting lists. 

Liver transplantation provides excellent outcomes for patients with decompensated cirrhosis or early-stage HCC. People who are not referred until they have severe liver failure may not be suitable for transplantation, so early referral is advisable. Consider referring people to a transplant team if they have refractory ascites, an episode of spontaneous bacterial peritonitis or hepatorenal syndrome, recurrent or chronic hepatic encephalopathy, small HCCs or significant malnutrition. Additionally, people should be referred to a transplant team if they are eligible for liver transplantation and have a Child–Pugh score ³ B7 or MELD score ³ 13.

Contraindications to liver transplantation may include advanced HCC, extrahepatic malignancy, uncontrolled extrahepatic infection, active alcohol or substance misuse, significant coronary or cerebrovascular disease or inadequate social support. For more information about liver transplantation, see the DonateLife website.66

In people with decompensated liver disease, the goal of therapy is SVR, with the aim of improving liver function. The first regimen to be specifically listed on the PBS for treatment of decompensated liver disease is sofosbuvir plus velpatasvir plus ribavirin. The eligibility criteria for other DAA regimens that are PBS-listed for the treatment of HCV do not distinguish between people with compensated versus decompensated liver disease, with the exception of regimens that include a protease inhibitor (PrOD or elbasvir plus grazoprevir), which are contraindicated in the setting of hepatic decompensation (Child–Pugh score B or C). Therefore, people with decompensated liver disease are eligible to have the same treatment regimens prescribed under the PBS, according to HCV genotype and treatment history (Table 7). 

The efficacy of a number of DAA regimens in people with decompensated liver disease has been formally evaluated in recent clinical trials.67-73 Current data support the combination of sofosbuvir plus velpatasvir plus ribavirin for 12 weeks as a first-line treatment for patients with HCV and decompensated liver disease.74 

In the ASTRAL-4 study, 267 patients with Gt 1, 2, 3, 4 or 6 HCV and decompensated cirrhosis (90% Child–Pugh class B or C) were randomly assigned to treatment with sofosbuvir plus velpatasvir for 12 weeks, or sofosbuvir plus velpatasvir plus ribavirin (daily, according to body weight: < 75 kg, 1000 mg; ³ 75 kg, 1200 mg) for 12 weeks, or sofosbuvir plus velpatasvir for 24 weeks.74 SVR was 94% in people treated with sofosbuvir plus velpatasvir plus ribavirin for 12 weeks, versus 83% with sofosbuvir plus velpatasvir for 12 weeks, versus 86% with sofosbuvir plus velpatasvir for 24 weeks. Post-treatment virological relapse was observed in 2% of the 12-week group receiving sofosbuvir plus velpatasvir plus ribavirin, compared with 12% and 9%, respectively, in the groups that did not receive ribavirin. Although the ASTRAL-4 study was not powered to generate statistical significance, the data suggest that sofosbuvir plus velpatasvir plus ribavirin for 12 weeks is the optimal regimen for patients who will tolerate ribavirin. For patients in whom there is a concern about ribavirin intolerance, we recommend a starting dose of 600 mg daily, or treatment for 24 weeks without ribavirin. Note that important exclusion criteria for the ASTRAL-4 study included Child–Pugh score > C9, haemoglobin level < 100 g/L, platelet count £ 30 000/mm3, bilirubin level > 85.5 mmol/L and creatinine clearance < 50 mL/min. 

The combination of sofosbuvir plus ledipasvir plus ribavirin for 12 weeks is another first-line regimen for Gt 1 HCV.67,68 However, the combination of sofosbuvir plus ledipasvir plus ribavirin cannot currently be prescribed under the PBS. Early access programs suggest that treatment with sofosbuvir plus ledipasvir (no ribavirin) for 24 weeks has similar efficacy; this regimen is currently available under the PBS and can be recommended as a reasonable alternative (Table 7). 

Alternative regimens that have demonstrated efficacy for the treatment of Gt 1 HCV include the combination of sofosbuvir plus daclatasvir plus ribavirin for 12 weeks, or sofosbuvir plus daclatasvir (no ribavirin) for 24 weeks, both of which can also be prescribed under the PBS (Table 7). The rates of SVR observed using these regimens for Gt 1 HCV in the setting of Child–Pugh B cirrhosis were 85%–95%.68,71,75,76 Only small numbers of patients with Child–Pugh C scores have been included in studies to date; data suggest SVR may be lower (observed SVR, 56%–87%68,71,75,76) than in those with Child–Pugh B scores. Note that important exclusion criteria for the Phase II SOLAR-1/2 studies that evaluated ribavirin-containing regimens included a haemoglobin level < 100 g/L, platelet count < 20 m 109/L, bilirubin level > 170 mmol/L (with the exception of those with fibrosing cholestatic hepatitis [FCH]; see Section on Treatment of fibrosing cholestatic hepatitis C) and serum creatinine level > 2.5 x ULN. 

Patients with Gt 3 HCV and decompensated liver disease are harder to cure.72 The combination of sofosbuvir plus velpatasvir plus ribavirin is the only regimen to be prospectively evaluated in a Phase III study of patients with decompensated liver disease and should be first-line treatment. Again, we recommend that ribavirin dosing be started at 600 mg daily in this population, and incremented as tolerated. An alternative treatment regimen is sofosbuvir plus daclatasvir plus ribavirin for 24 weeks’ duration in this group (Table 7). If ribavirin is not tolerated, patients should be treated with sofosbuvir plus daclatasvir for 24 weeks. There are very limited clinical data available to support treatment recommendations for patients with Gt 2, 4–6 HCV infection and decompensated liver disease; recommendations in Table 7 represent expert opinion.

People with decompensated liver disease should not be treated with PrOD, elbasvir plus grazoprevir or pegIFN. These agents are contraindicated in people with decompensated liver disease, as there is a risk of causing further deterioration in liver function.

Early data based on short-term follow-up indicate that SVR may lead to improvement of liver function in some, but not all, people. The severity of baseline liver disease appears to determine the likelihood of clinical improvement. Three distinct groups are emerging: i) people with a MELD score < 15 and Child–Pugh score B; ii) those with a MELD score of 15–20 or Child–Pugh C cirrhosis; and iii) those with a MELD score > 20. 

People with a MELD score < 15 and Child–Pugh B cirrhosis are most likely to benefit from eradication of HCV and should start treatment immediately. In people with a MELD score of 15–20, or Child–Pugh C cirrhosis, liver function may improve with achievement of SVR, and some people may even be delisted for liver transplantation. However, predictive factors are yet to be determined and it must be noted that improvement in MELD score may result in prolonging the waiting time for transplantation in those who do not improve sufficiently to be delisted. Until predictive factors can be identified, it appears reasonable to treat and closely monitor the progress of patients on the liver transplant waiting list with MELD scores of 15–20. Longer term assessment of clinical outcomes after SVR in this population are needed to determine the impact on liver synthetic function, portal hypertension and HCC risk. People with a MELD score > 20 are unlikely to benefit sufficiently from SVR to be delisted.72,76 Antiviral therapy may be started with the intent of suppression and prevention of post-transplant HCV recurrence (see Section Preventing recurrent HCV after transplantation: treatment of people on the Transplant List). Alternatively, these individuals may be best served with HCV treatment after transplantation. DAA therapy after liver transplantation results in higher SVR rates than in the pre-transplant population with decompensated liver disease (see Section on Treatment of HCV and decompensated liver disease after transplantation), which minimises the risk of selecting for drug-resistant variants. Finally, among people who are not candidates for liver transplantation, it is reasonable to consider DAA therapy regardless of MELD score.

Consensus recommendationsGrade
Indications for assessment by a liver transplant centre include a Child–Pugh score ≥ B7, MELD score ≥ 13 or one of the following clinical events: refractory ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent or chronic hepatic encephalopathy, small HCC or severe malnutrition.A1
People with decompensated HCV cirrhosis, Child–Pugh score B and MELD score < 15 should be assessed by an expert hepatologist for consideration of treatment as soon as possible, as they are at risk of further decompensation and liver-related complications and death, which may be prevented by eradicating HCV.B2
People with decompensated HCV cirrhosis, Child–Pugh score B or C and MELD score > 15 (who are NOT liver transplant candidates) should be assessed by an expert hepatologist for consideration of treatment where there is an anticipated benefit from such treatment.B1
People with decompensated HCV cirrhosis, Child–Pugh score B or C and MELD score > 15 (who ARE liver transplant candidates) should be assessed by a liver transplant physician to consider the individual benefit and risks of treatment before transplantation.B2
When making treatment decisions, decompensated liver disease should be defined by a Child–Pugh score ≥ B7.A1
First-line treatment regimens for chronic Gt 1 HCV infection and decompensated liver disease include (see Table 7):
• sofosbuvir + velpatasvir + ribavirin for 12 weeks
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeks
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks
A1
A1
B1
First-line treatment regimen for chronic Gt 3 HCV infection and decompensated liver disease are (see Table 7):
• sofosbuvir + velpatasvir + ribavirin for 12 weeks
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks
A1
B1
First-line treatment regimens for chronic Gt 2, 4–6 HCV infection in the setting of decompensated liver disease are (see Table 7):
• sofosbuvir + velpatasvir + ribavirin for 12 weeks
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks
A1
C2
The following treatments should NOT BE USED in people with decompensated liver disease:
• paritaprevir–ritonavir, ombitasvir and dasabuvir
• elbasvir + grazoprevir
• pegIFN
A1

 

Consensus recommendations for treatment of HCV in people with renal impairment

Consensus recommendationsGrade
Renal function must be evaluated in all individuals before initiating antiviral therapy for HCV infection.A1
All people with chronic HCV infection and renal impairment (eGFR < 50 mL/min/1.73 m2) should be referred to a specialist for assessment and management of HCV as well as their renal disease.A1
In people with mild–moderate renal impairment (eGFR, 30–80 mL/min/1.73 m2), no dose adjustment is required for:
• sofosbuvir + velpatasvir
• sofosbuvir + ledipasvir
• sofosbuvir + daclatasvir
• paritaprevir–ritonavir + ombitasvir + dasabuvir
• elbasvir + grazoprevir
A1
Ribavirin should be used with caution in people with an eGFR < 50 mL/min/1.73 m2
treatment should be supervised by a specialist experienced in the treatment of HCV.
A1
In people with severe renal impairment (eGFR < 30 mL/min/1.73 m2 or haemodialysis):
• sofosbuvir cannot be recommended, pending further studiesB1
• elbasvir + grazoprevir can be used to treat Gt 1a, 1b and 4 HCVA1/B1
• paritaprevir–ritonavir + ombitasvir + dasabuvir can be used to treat Gt 1a HCVB1
• low-dose ribavirin should be used with close monitoring of haemoglobin levels (eg, ribavirin 200 mg daily for patients not on haemodialysis; ribavirin 200 mg pre-dialysis for patients on haemodialysis)B1
 

Consensus recommendations for treatment of HCV in the setting of HBV coinfection

Consensus recommendationsGrade
All patients with HCV infection undergoing DAA therapy should be screened for HBV infection with anti-HBc, HBsAg and anti-HBs testing.A1
Non-immune (HBsAg, anti-HBc and anti-HBs-negative) patients should be offered HBV vaccination.A1
HBsAg-positive patients
Patients with HCV infection who are HBsAg-positive should be managed by, or in conjunction with, a specialist experienced in the treatment of both conditions.
A1
Patients should be counselled regarding the risk of HBV reactivation and advised to immediately report any signs or symptoms indicative of serious liver disease.A1
All patients who are HBsAg-positive should undergo HBV DNA testing before commencing DAA therapy.A1
Anti-HBV therapy with tenofovir or entecavir should be commenced in all non-cirrhotic patients with an HBV DNA level > 2000 IU/mL and in all patients with underlying cirrhosis, regardless of HBV DNA level.A1

No

Non-cirrhotic patients with an HBV DNA level < 2000 IU/mL should be monitored for evidence of HBV reactivation. We recommend the following minimum requirements for monitoring:

§ALT — every 4 weeks until the end of treatment, and at SVR

§HBV DNA — every 12 weeks until SVR, plus if ALT level rises

§ If HBV DNA level remains < 2000 IU/mL at SVR, routine monitoring as per HBV guidelines can be reinstituted.

A1
A rise in HBV DNA level > 2000 IU/mL at any time during therapy and/or elevation in ALT level accompanied by any rise in HBV DNA level should prompt consideration of antiviral therapy and intensive monitoring.A1
Coinfected patients who are already receiving anti-HBV therapy and have suppressed HBV DNA levels do not appear to be at increased risk and can continue with routine clinical monitoring.A1
Anti-HBc-positive, HBsAg-negative patients
Patients who are anti-HBc-positive and HBsAg-negative have a low risk of HBV reactivation.
A2
Routine monitoring guidelines for patients treated with HCV DAAs should be followed, as recommended for people who are seronegative for HBV infection.B1
HBV reactivation should be considered in any patient who experiences an ALT flare during or after DAA treatment.
A1
 

Consensus recommendations for treatment of people with acute HCV infection

Consensus recommendationsGrade
There is no place for the use of post-exposure prophylaxis with antiviral therapy after HCV exposure.B1
A single HCV RNA level below the limit of detection should not be taken as an indication of clearance; at least two undetectable HCV RNA test results, a minimum of 1 month apart, are required before clearance can be confirmed.A1
If spontaneous clearance has not occurred by 6 months after presentation, a person can be considered to have chronic HCV infection and treated according to current DAA treatment guidelines.B1
The optimal timing and regimen for acute hepatitis C treatment is currently unclear due to a lack of data with IFN-free DAA therapies.B2
In the situation where a decision has been made to commence therapy early, within the first 6 months after infection, it is still recommended to hold treatment by monitoring HCV RNA for 12–16 weeks to determine that spontaneous clearance is unlikely.B1
If treatment with DAA-based therapy is considered in the first 6 months after HCV infection, treatment regimens in line with recommendations for chronic HCV infection should be used (note that the PBS criteria for treatment specify chronicity as a criterion for eligibility).B1
Following acute HCV infection, all individuals should undergo risk behaviour education and discussion regarding the possibility of reinfection risk after spontaneous or treatment-induced clearance.B1
Individuals with ongoing risk factors for HCV reinfection should be screened annually for HCV infection with HCV RNA (PCR).A1

Consider whether there is HBV or HIV coinfection or coexisting liver disease present

It is important to consider whether another liver disease is present as this increases the risk of cirrhosis being present, and will need ongoing management after viral eradication. Common comorbidities include excessive alcohol consumption, diabetes, obesity and non-alcoholic fatty liver disease.

Coinfection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) is more common in people with HCV infection than in the general population. It is therefore important to perform a targeted assessment in all patients, including calculation of body mass index and measurement of blood pressure, waist circumference, fasting glucose level and lipid levels, as well as HBV and HIV serology. All people with chronic HCV infection should be vaccinated against hepatitis A virus (HAV) and HBV if seronegative.

Testing for other causes of liver disease, including haemochromatosis, autoimmune hepatitis, primary biliary cholangitis, Wilson disease and alpha-1-antitrypsin deficiency, can be reserved for individuals whose liver function test results do not normalise once HCV infection has been cured, or in whom there is a high index of clinical suspicion. For people aged > 50 years in whom it is planned to use ribavirin-containing regimens, it is important to consider the complications of anaemia and screen for cardiovascular disease with directed history plus an electrocardiogram. For people with cardiovascular disease, a regimen that does not involve ribavirin may be most suitable. 

DAAs and drug resistance

Resistance-associated substitutions (RASs) have been identified in vitro for all of the DAAs approved for clinical use. NS3 and NS5A RASs may arise spontaneously due to the error-prone HCV RNA polymerase and therefore are present before DAA therapy. NS3 and NS5A RASs are selected during DAA therapy and enriched inpeople in whom treatment fails with NS3 and NS5A inhibitor-containing regimens, respectively. NS5B RASs have been reported but are very rare. For most regimens currently listed on the PBS, there is no clinical role for baseline HCV resistance testing in treatment-naivepeople or prior non-responders to either pegIFN-based therapy or protease inhibitor-based triple therapy, because such high SVR rates are achieved.

There is a theoretical role for NS5A RAS testing in people with Gt 1a HCV for whom treatment with the combination of elbasvir and grazoprevir for 12 weeks is planned (seeSection on Elbasvir plus grazoprevir).59 In these people, the presence of an RAS at amino acid position 28, 30, 31 or 93 in the NS5A protein is associated with lower rates of SVR. In this population, SVR can be increased by prolonging treatment duration to 16 weeks and combining treatment with ribavirin. However, the frequency of these RASs is very low in the Australian population (< 5%–10% using population sequencing),60 meaning that the clinical yield from testing is low. Furthermore, RAS testing is not widely available, nor is it currently reimbursed by the government. Given the low frequency of relevant NS5A RASs in the Australian population, we do not recommend routine resistance testing before treatment with elbasvir and grazoprevir.

Where available, resistance testing for NS3, NS5B and NS5A RASs should be considered after failure of combination DAA treatment, to guide salvage therapy. Resistance testing involves direct sequencing of the HCV genome and is available through specialised laboratories. As noted, this testing is not currently reimbursed by the government in Australia. HCV sequencing may also identify cases of reinfection. Patients in whom combination DAA therapy fails should be managed in specialist centres.

 

Direct-acting antiviral agents (DAAs)

DAA agents that target multiple steps in the HCV replication life cycle have been developed and are highly effective, safe and require a short treatment duration. Virtually all patients are suitable for DAA therapy, including those previously intolerant of or ineligible for IFN therapy. Multiple DAAs have been approved by the Therapeutic Goods Administration (TGA) in Australia, including the NS3 protease inhibitors paritaprevir (ritonavir-boosted) and grazoprevir; the NS5B nucleotide inhibitor sofosbuvir; the NS5B non-nucleotide inhibitor dasabuvir; and the NS5A inhibitors ledipasvir, ombitasvir, daclatasvir and elbasvir. Several IFN-free regimens combining these DAAs have been PBS-listed for the treatment of people with HCV infection, including people with compensated and decompensated liver disease.

There is one pan-genotypic DAA regimen listed on the PBS — sofosbuvir plus velpatasvir — which is the most recent regimen to become available, being listed on the PBS on 1 August 2017. The other DAA regimens are all genotype-specific, and each genotype will be considered individually here. The treatment for HCV will continue to evolve, and this consensus statement will be updated as new data emerge.

Drug–drug interactions

Drug–drug interactions are a potential issue for all IFN-free treatment regimens. Important drugs to consider for potential interactions with DAAs include proton pump inhibitors, statins, St John’s wort, antimicrobials, anti-epileptic agents, amiodarone, immunosuppressive agents including cyclophilin inhibitors and mammalian target of rapamycin (mTOR) inhibitors, and antiretroviral agents. Notably, the combination of sofosbuvir with a second DAA for the treatment of HCV is contraindicated with concomitant use of amiodarone due to the risk of severe symptomatic bradycardia. It is strongly recommended that concomitant medications be reviewed before starting treatment for any person, using the University of Liverpool’s Hepatitis Drug Interactions website (www.hep-druginteractions.org). We recommend working with an experienced pharmacist to confirm the safety of concomitant medications before starting DAA regimens. Patients should be advised to seek advice before starting any new medication during DAA therapy.

Evaluate for the presence of cirrhosis

Once a diagnosis of chronic HCV infection has been established, further investigation should be directed toward assessing for the presence or absence of cirrhosis. Although all people with chronic HCV infection are eligible for treatment, regardless of liver fibrosis stage, the presence of cirrhosis influences treatment duration and regimen (see section on treatment for chronic HCV), and a person’s cirrhosis status must be provided at the time of seeking PBS authority to write a prescription for the new HCV medicines. The presence of cirrhosis also identifies people who require lifelong surveillance for HCC and portal hypertension.

Clinical risk factors for cirrhosis include male sex, older age at infection, prolonged duration of HCV infection (> 20 years) and comorbidities including excessive alcohol consumption, diabetes, the metabolic syndrome and coinfection with HBV or HIV. Clues to the presence of advanced liver disease include peripheral stigmata of chronic liver disease (eg, leukonychia, spider naevi) and markers of portal hypertension, including splenomegaly and thrombocytopaenia. Low albumin levels, raised bilirubin levels and a raised international normalised ratio (INR) are markers of reduced liver functional reserve and decompensated liver disease. 

Formal evaluation for cirrhosis with a non-invasive test is recommended for all individuals with chronic HCV infection. Evaluation of liver fibrosis stage should be performed before commencing treatment. None of the non-invasive tests have been validated for diagnosing cirrhosis after SVR, and there is a risk of false negative results when performed after treatment. Transient elastography, or FibroScan (EchoSens, Paris), measures liver stiffness and is the most common method used for diagnosing cirrhosis. It has been extensively evaluated and validated in people with chronic HCV infection22 and outperforms serum biomarkers for detecting cirrhosis.23 FibroScan is available in most metropolitan centres. A liver stiffness of > 12.5 kPa measured using FibroScan is a reasonable threshold for identifying people with cirrhosis for treatment decision making.24,25 Alternative elastography methods for measuring liver stiffness include shear wave elastography and acoustic radiation force impulse (ARFI) technology. These techniques can be offered as an add-on to liver ultrasound using many machines, but have been less well validated for the assessment of fibrosis stage in the setting of chronic HCV infection, and the cut-offs for identification of cirrhosis are different.  

Serum biomarkers for liver fibrosis have also been developed, such as the APRI (aspartate aminotransferase [AST] to platelet ratio index), Hepascore, FibroGENE, Enhanced Liver Fibrosis (ELF) test and FibroTest. The APRI is a simple biochemical marker that can be calculated from routine blood test results.

Hepascore and the ELF test are alternative serum fibrosis markers that are available in Australia but not currently reimbursed. FibroGENE is a biomarker panel based on age, biochemical markers and IL28B genotype.26 FibroTest is not yet available in Australia. Serum biomarkers may be used to exclude the presence of cirrhosis in settings where other tools, such as transient elastography, are not accessible in a timely fashion. Supplementary Table 1 presents further information and key clinical thresholds for excluding the presence of cirrhosis in people using the serum biomarkers for liver fibrosis that are available in Australia.

It is important to remember that none of the methods for non-invasive assessment of liver fibrosis are perfectly accurate, and the results must be interpreted in the context of the pre-test probability based on other clinical information. For example, a 50-year-old obese man with a 30-year duration of HCV infection, a past history of heavy alcohol consumption, spider naevi evident on examination and a platelet count of 90 × 109/L is very likely to have cirrhosis, even if the liver stiffness measures 9.0 kPa using FibroScan. If there is concern about the accuracy of the liver fibrosis assessment, referral for further assessment for the presence of cirrhosis by a specialist with experience in assessing liver disease severity and managing patients with advanced liver disease is recommended. There is no routine role for liver biopsy. Liver biopsy is generally reserved for people in whom there is uncertainty about the underlying cause of liver disease, or where there is uncertainty about the liver fibrosis stage. Liver histology is not required for accessing antiviral therapy.

All individuals with cirrhosis should have a liver ultrasound to examine for features of portal hypertension (splenomegaly, reversal of portal vein flow) and to exclude HCC. Guidelines recommend gastroscopy for all people with cirrhosis to exclude the presence of clinically significant oesophageal varices before commencing therapy. Bone densitometry is recommended to screen for osteoporosis. Performance of these tests should not delay treatment for HCV infection, but may be scheduled simultaneously or after treatment.

In the setting of cirrhosis, it is also important to evaluate for markers of hepatic decompensation. Two key groups among those with cirrhosis are: i) people with Child–Pugh A cirrhosis who have a low albumin level (< 35 g/L) and/or platelets < 100 × 109 /L (NS3 protease inhibitors should be avoided in these people due to concerns about increased intrahepatic drug concentrations and secondary toxicity); and ii) people with true decompensated liver disease — this group should be considered a special population (see section on Special populations: treatment of decompensated liver disease). All individuals with decompensated liver disease should be assessed by a specialist with experience in managing chronic liver disease and, where appropriate, referred to a liver transplant centre. Indications for assessment by a liver transplant centre include Child–Pugh score ≥ B7, Model for End-Stage Liver Disease (MELD) score ≥ 13 or one of the following clinical events: refractory ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent or chronic hepatic encephalopathy, small HCC or severe malnutrition (Supplementary Table 227).

Due to the complexity of managing cirrhosis, it is recommended that these people are referred for assessment by a specialist who is an expert in the care of patients with chronic liver disease, and that they are treated in active collaboration with HCV treatment experts.