Special populations: treatment of people with acute HCV infection

Acute HCV infection refers to the 6-month period after infection acquisition, though definitions vary95 and the distinction between acute and early chronic infection is somewhat arbitrary. In Australia, it is estimated that approximately 8500–9000 new infections occur each year.1,3 While in some cases acute HCV infection may develop after discrete exposure (eg, a needlestick injury in a health care worker), detection of acute HCV infection is often hampered by its asymptomatic or non-specific presentation, lack of specific diagnostic tests and the inherent difficulties in identifying and following individuals at highest risk of transmitting and acquiring HCV, including PWID. Another high-risk group for HCV transmission is HIV-positive MSM, in whom sexual or permucosal transmission has become increasingly common.81,96,97 Risk factors for sexual transmission include, but are not limited to, traumatic sexual practices, recreational non-injecting drug use, group sex and the presence of a coexistent sexually transmitted infection.98 Acute HCV infection is characterised by the appearance of HCV RNA in blood within 2–14 days of exposure, elevation of liver-associated enzyme levels (particularly ALT), and development of HCV antibodies within 30–60 days of exposure. Up to 80% of acute HCV infections are asymptomatic, making detection and estimation of duration of infection difficult if seroconversion cannot be documented. Clinical features suggestive of acute infection include significant elevation of ALT level or an acute illness manifest by jaundice. However, only 15%–30% of those infected develop a symptomatic illness, and elevation of ALT level is non-specific. Acute infection should be suspected if the clinical signs and symptoms are compatible with acute hepatitis C — such as serum ALT level > 10 × ULN and jaundice in the absence of a history of chronic liver disease or other causes of acute hepatitis, and/or if a likely recent source of transmission is identifiable. The preferred criteria for diagnosis of acute HCV infection are: i) positive anti-HCV IgG and a documented negative anti-HCV IgG in breast enhancement the previous 12 months; or ii) positive serum HCV RNA test and a documented negative serum HCV RNA test and negative antiHCV IgG in the previous 12 months. Alternative, less stringent criteria are the presence of positive serum HCV RNA regardless of anti-HCV IgG and with: i) an acute rise in ALT level > 10 × ULN; or ii) an acute rise in ALT level > 5 × ULN, with documented normal ALT level within the past 12 months; or iii) in individuals with a previously high ALT level, an acute rise to 3.5 times the baseline ALT level; and in the absence of serological evidence of HAV or HBV infection or other causes of acute hepatitis. Documentation of seroconversion is difficult in the absence of routine serological testing, but monitoring of at-risk populations, including PWID99 and HIV-positive MSM, may be beneficial. There is no single definitive laboratory test to distinguish acute from chronic HCV infection.

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Special populations: treatment of HCV in people with renal impairment

Hepatitis C is associated with intrinsic renal disease, including cryoglobulinaemia and glomerulonephritis.101 People with renal impairment should be investigated to determine the underlying cause and managed appropriately. Those with severe acute vasculitic manifestations may require immunosup- pressive therapy, including anti-CD20 antibody therapy and/or plasma exchange. In addition, the prevalence of anti-HCV antibodies is higher in patients requiring haemodialysis compared with the general population. Management of HCV in individuals with renal impairment is complicated by renal clearance of drugs including sofosbuvir and ribavirin, as well as the complications and treatment of the intrinsic renal disease, including drug–drug interactions. 102,103 People with moderate–severe renal impairment (eGFR < 50 mL/min/1.73 m 2 ) should be referred to specialist centres for consideration of antiviral therapy.

People with mild–moderate renal impairment (eGFR, 30–80 mL/min/1.73 m 2)

For people with mild to moderate renal impairment (eGFR, 30–80 mL/min/1.73 m 2 ), no dose adjustment is required for sofosbuvir, ledipasvir, paritaprevir– ritonavir, ombitasvir, dasabuvir, daclatasvir, elbasvir or grazoprevir. Ribavirin is renally excreted and can- not be removed by dialysis. Ribavirin accumulates in the setting of renal impairment with creatinine clearance < 50 mL/min and can cause severe anaemia.104 The product information recommends that ribavirin should not be used in individuals with an eGFR < 50 mL/min/1.73 m 2 . In specialist centres, ribavirin-containing regimens may be considered for those with an eGFR < 50 mL/min/1.73 m 2 . In this setting, ribavirin therapy should be started at a low dose, with close monitoring of haemoglobin levels. Recommended ribavirin dose according to eGFR is: > 50 mL/min/1.73 m 2 , no dose adjustment; 30–50 mL/min/1.73 m 2 , alternating doses of 200 m and 400 mg every other day; < 30 mL/min/1.73 m 2 , 200 mg daily; haemodialysis, 200 mg pre-dialysis.

People with severe renal impairment (eGFR < 30 mL/min/1.73 m 2 or haemodialysis)

Drugs that are primarily metabolised by the liver can be used in people with severe renal impairment and in those receiving haemodialysis; drugs excreted by the kidneys should be avoided or the dose regimen modified. Sofosbuvir is renally excreted and there are limited safety data on its use in people with severe renal impairment. Pharmacokinetic studies of a single 400 mg dose of sofosbuvir resulted in an increased area under the curve of 171% for sofosbuvir and 451% for its inactive metabolite (GS-331007), which is excreted exclusively by the kidneys, in people with an eGFR < 30 mL/min/1.73 m2. Sofosbuvir is not recommended in people with an eGFR < 30 mL/min/1.73 m2. As noted above, severe renal impairment necessitates a significant dose reduction for ribavirin. Ribavirin should only be used in this setting under the supervision of a specialist with experience in treating HCV infection in people with severe renal impairment.

Elbasvir and grazoprevir are cleared by hepatic metabolism and can be used in people with severe renal impairment. The efficacy of this regimen in people with chronic kidney disease (eGFR < 30 mL/min/1.73 m2, with or without haemodialysis requirements) was evaluated in a large Phase III randomised study,45 in which 224 people with chronic Gt 1 HCV infection were randomly assigned to immediate or deferred therapy with elbasvir and grazoprevir. The deferred treatment arm provided a placebo comparator to the immediate treatment arm. Ribavirin was not used, despite 52% of the cohort being infected with Gt 1a HCV. In the immediate treatment arm, the SVR rate was 94.3% in the full analysis set. The SVR rate was 99.1% in a modified analysis set that excluded patients who discontinued treatment for reasons that were not related to virological failure. Adverse events were frequent in this population with significant comorbidities, but were comparable between the immediate and deferred treatment groups (76% v 84%). People with Gt 1a or Gt 1b HCV, as well as those with Gt 4 HCV infection, who have severe renal impairment (eGFR < 30 mL/min/1.73 m2) or end-stage renal disease, including patients receiving dialysis, should be treated with elbasvir plus grazoprevir without ribavirin.45

Paritaprevir–ritonavir, ombitasvir and dasabuvir are all cleared by hepatic metabolism and can be used in individuals with severe renal disease. The efficacy of this regimen was demonstrated in the RUBY-I study, a small, open-label, Phase IIIb study that enrolled 20 patients with Gt 1 HCV and no cirrhosis with an eGFR < 30 mL/min/1.73 m2 (including patients receiving haemodialysis).105 All patients had a baseline haemoglobin level > 100 g/L. People with Gt 1a HCV infection (n = 13) were treated with PrOD plus ribavirin (200 mg daily for patients not on haemodialysis; 200 mg 4 hours before dialysis for patients on haemodialysis), and people with Gt 1b HCV infection (n = 7) were treated with PrOD alone. Of 19 patients with post-treatment data, 18 (95%) achieved SVR. Overall, treatment was well tolerated, but ribavirin dose interruption was required for management of anaemia in most patients receiving ribavirin 200 mg daily. More recent data from the RUBY-II study suggest that ribavirin is not necessary in people with Gt 1a HCV and severe renal impairment who are treated with PrOD. In 13 patients treated for 12 weeks with PrOD and no ribavirin, the SVR rate was 100%.40

Daclatasvir is also hepatically cleared,106 but is used in combination with sofosbuvir and therefore cannot be recommended.

Clearance of pegIFN is reduced and overall exposure increased in proportion to the degree of renal dysfunction. Haemodialysis has little effect on clearance. In patients with an eGFR < 30 mL/min/1.73 m2 or receiving haemodialysis, the dose of peginterferon alfa-2a should be reduced to 135 mg weekly and further reduced to 90 mg weekly if adverse events occur.

The treatment of HCV continues to evolve. A number of sofosbuvir-free and ribavirin-free regimens are in clinical development for the treatment of people with moderate to severe renal impairment. For people with Gt 2, 3 or 6 HCV infection, therapy should be deferred pending the availability of these regimens. 

 

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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 9.4) 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 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 + ledipasvir ± ribavirin for 12 or 24 weeksB1
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB1
The first-line treatment regimen for chronic Gt 3 HCV infection and decompensated liver disease is (see Table 7):
• sofosbuvir + daclatasvir + ribavirin for 24 weeksB1
A first-line treatment regimen for chronic Gt 2, 4–6 HCV infection in the setting of decompensated liver disease is (see Table 7):
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks
C2
A first-line treatment regimen for chronic Gt 4 or 6 HCV infection in the setting of decompensated liver disease is (see Table 7):
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksC2
The combination of paritaprevir–ritonavir, ombitasvir and dasabuvir should NOT BE USED in people with decompensated liver disease.A1
PegIFN should NOT BE USED in people with decompensated liver disease.A1
Notes: None of the currently available DAAs in Australia include a specific indication for the treatment of decompensated HCV liver disease. Recommended or preferred treatment regimens may not be eligible for prescription on the PBS, reflecting the dynamic nature of this area (see Table 7).

 

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Treatment of HCV after liver transplantation

Chronic hepatitis C is the leading indication for adult liver transplantation in Australia, accounting for about 40% of transplants.77 Recurrence of hepatitis C after liver transplantation is universal and is a major clinical problem. Recurrent HCV pursues a more aggressive course after transplantation, with up to 80% of patients developing chronic hepatitis and 30% of patients progressing to cirrhosis within 5 years.78 Furthermore, in the setting of immunosuppression, 2%–5% of patients develop FCH within 6 months of transplantation.79 FCH is associated with very high-level viraemia, which is directly cytotoxic, causing rapid progression to jaundice, liver failure and death. Mortality rates of 80% are reported. Finally, although recurrent HCV infection is a major cause of allograft dysfunction after transplantation, it is not the only cause, and discrimination from other causes, including acute cellular rejection, biliary and vascular complications and drug hepatotoxicity, is challenging.

Treatment with DAAs offers the opportunity to clear HCV either before transplantation (preventing recurrence) or after transplantation (treating recurrence). Where possible, treatment should be initiated early after transplantation to prevent fibrosis progression; however, treatment is also indicated in people with established recurrence, including cirrhosis. People with FCH should be identified and treated immediately to prevent rapid progression to allograft failure.

Preventing recurrent HCV after transplantation: treatment of people on the transplant waiting list

Some people, such as those with HCC or very advanced liver failure, require liver transplantation regardless of whether hepatitis C is present or not, and receiving treatment while on the waiting list is unlikely to impact the timing or outcome of liver transplantation. A decision as to whether to treat a patient on the waiting list, or wait until after transplantation, should be made on a case-by-case basis by a liver transplant physician. Treatment regimen and duration should be chosen according to recommendations for treatment of compensated cirrhosis (for patients with HCC) or decompensated cirrhosis (see sections on treatment for chronic hep C and special populations: treatment of decompensated liver disease). 

If a decision is made to treat a person while awaiting liver transplantation, a period of at least 30 days with undetectable HCV RNA during treatment is associated with a very low risk of recurrence of HCV after transplantation.69 People treated for ³ 12 weeks, with a period of undetectable serum HCV RNA of ³ 8 weeks, can have antiviral treatment stopped at transplantation. For people treated for < 12 weeks before transplant, treatment should continue after transplantation until a total treatment duration of 12 weeks has been achieved. The development of severe acute kidney injury may lead to an interruption of dosing if the person is taking a sofosbuvir-containing regimen. Potential drug–drug interactions in the post-transplant setting should be considered.

Treatment of HCV and compensated liver disease after transplantation

Recommendations for the treatment of HCV after liver transplantation are based on clinical trial data where available. We have tried to avoid extrapolation from studies performed in non-liver transplant patients, given the complexity associated with post-transplant immunosuppression. Therefore, treatment recommendations may differ from those for the non-transplant population, and may differ from the treatment regimens currently eligible for prescription under the PBS (Table 8). None of the currently available DAAs in Australia include a specific indication for treating HCV after liver transplantation. 

Clinical trial data are limited. The safety and efficacy of sofosbuvir plus velpatasvir has not been formally evaluated in the post-transplant setting but should be safe and effective. The role of ribavirin combined with sofosbuvir plus velpatasvir in the post-transplant setting is not clear, but should be considered. In the SOLAR-1 study, treatment with sofosbuvir plus ledipasvir plus 1000/1200 mg of ribavirin daily for 12 or 24 weeks was studied in 162 post-transplant patients with HCV Gt 1 (31% with Child–Pugh A cirrhosis).67 SVR was observed in 96%–98% (157/162) and there was no significant difference between 12 and 24 weeks of treatment. Similar SVR results were found for the combination of sofosbuvir and daclatasvir plus ribavirin for 12 weeks in patients with HCV Gt 1 and post-transplant HCV recurrence in the ALLY-1 study.80 This regimen was also effective in 10 of 11 patients (91%) with Gt 3 and is the only currently available regimen suitable for people with Gt 3 HCV. It is therefore recommended for post-transplant patients with HCV Gt 3. Treatment was well tolerated in these studies and there were no clinically significant drug–drug interactions between sofosbuvir plus ledipasvir or sofosbuvir plus daclatasvir and calcineurin inhibitors or mTOR inhibitors.

The combination of PrOD and ribavirin for 24 weeks’ duration was evaluated for the treatment of post-transplant Gt 1 HCV recurrence in 34 individuals with no or minimal fibrosis in an open-label, prospective, multicentre study.81 All those enrolled had received their transplant more than 12 months previously. SVR was achieved in 97%. The majority of patients received 600–800 mg of ribavirin daily. Treatment was well tolerated, and no one developed allograft rejection. This regimen is associated with drug–drug interactions that require dose modification of calcineurin inhibitors; use in combination with mTOR inhibitors is not recommended.

There are limited data on treatment of post-transplant patients with HCV Gt 2, 4, 5 or 6. Until such data are available, we recommend treatment with sofosbuvir plus ledipasvir plus ribavirin for 12 weeks for people with Gt 4 or 6, or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks for those with Gt 2–6.

Treatment of HCV and decompensated liver disease after transplantation

The treatment of decompensated liver disease due to recurrent HCV after liver transplantation has been evaluated in a multicentre, prospective study in which 52 patients with Gt 1 or 4 HCV were treated with sofosbuvir plus ledipasvir plus ribavirin for 12 versus 24 weeks (SOLAR-1).67 The ribavirin starting dose was 600 mg; increased dosing on-treatment was rare. SVR was observed in 85%–88% of patients (45/52) with Child–Pugh B cirrhosis and 60%–75% (6/9) with Child–Pugh C cirrhosis. Response rates were similar with 12 and 24 weeks of treatment. No study has examined a ribavirin-free regimen in post-transplant patients. There are no prospective clinical trial data that specifically evaluate treatment of post-transplant HCV in people with decompensated cirrhosis and HCV Gt 2, 3, 5 or 6. Until such data are available, we recommend treatment with sofosbuvir plus an NS5A inhibitor (velpatasvir or daclatasvir) plus ribavirin 600 mg daily for 12 weeks, or sofosbuvir plus daclatasvir for 24 weeks if ribavirin is not tolerated (Table 8).

Treatment of fibrosing cholestatic hepatitis C

Diagnosis of FCH should be made according to established criteria.82 Treatment with DAAs results in rapid clinical improvement and high rates of SVR (Table 8). Clinical trial data evaluating the efficacy of DAAs are limited, but available data are encouraging.67,83 In the absence of prospective clinical trials, we recommend people with FCH be treated with regimens recommended for people after liver transplantation, according to whether liver disease is compensated or decompensated (Table 8).

 

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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 + 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 + daclatasvir ± ribavirin for 12 or 24 weeksB2
Gt 4, 6 HCV:
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksB2
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB2
Preferred treatment options for chronic HCV infection and decompensated liver disease after transplantation include (see Table 8 ):
Gt 1 HCV:
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksA1
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB1
Gt 2 HCV:
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB2
Gt 3 HCV:
• sofosbuvir + daclatasvir + ribavirin for 24 weeksB2
Gt 4, 6 HCV:
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksB2
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB2
Preferred treatment options for FCH after transplantation include (see Table 8):
Gt 1, 4, 6 HCV:
• sofosbuvir + ledipasvir ± ribavirin for 12 or 24 weeksB1
Gt 1–6 HCV:
• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeksB1
Treatment with sofosbuvir + ledipasvir, sofosbuvir + daclatasvir or sofosbuvir + ribavirin does not require dose adjustment of calcineurin inhibitors or mTOR inhibitorsA2
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).
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