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  B7 or MELD score  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.[65]

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 was 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 (glecaprevir plus pibrentasvir, sofosbuvir plus velpatasvir plus voxilaprevir, or elbasvir plus grazoprevir), which are contraindicated in the setting of hepatic decompensation (Child–Pugh score B or C) (Table 5).

The efficacy of several DAA regimens in people with decompensated liver disease has been formally evaluated in clinical trials. [66-72]

Data from the ASTRAL-4 study 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.73 In this 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; ≥ 75 kg, 1200 mg) for 12 weeks, or sofosbuvir plus velpatasvir for 24 weeks.73 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. 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 µmol/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.[69,70] 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 available under the PBS and can be recommended as a reasonable alternative (Table 5).

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. The rates of SVR observed using these regimens for Gt 1 HCV in the setting of Child–Pugh B cirrhosis were 85%–95%.67,70,74,75 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% [67,70,74,75]) than in those with Child–Pugh B scores. 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 x 109/L, bilirubin level > 170 µmol/L (with the exception of those with fibrosing cholestatic hepatitis [FCH]; see Section 9.4) and serum creatinine level > 2.5 x ULN.

Prescriptions for sofosbuvir plus daclatasvir decreased dramatically after the introduction of sofosbuvir plus velpatasvir, which is a single-tablet regimen. It is expected that daclatasvir-containing regimens will be removed from the PBS later in 2020.

Patients with Gt 3 HCV and decompensated liver disease are harder to cure.71 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 in this population be started at 600 mg daily and incremented as tolerated. An alternative treatment regimen in this group is sofosbuvir plus daclatasvir plus ribavirin for 24 weeks’ duration. 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, 5 or 6 HCV infection and decompensated liver disease, which are based on expert opinion.

People with decompensated liver disease should not be treated with glecaprevir, voxilaprevir or elbasvir plus grazoprevir. 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 HCV cure 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.[71,75]Antiviral therapy may be started with the intent of suppression and prevention of post-transplant HCV recurrence (see Section 9.1). 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 9.3), 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.

Note that ribavirin can cause adverse events, including anaemia, rash, cough, dyspnoea, insomnia and anxiety. Anaemia is more common in patients with decompensated liver disease, and it is recommended that ribavirin be started at a low dose of 600 mg daily for these patients. Ribavirin is renally excreted, and dose adjustment is required according to eGFR (see Section 12). Patients with renal impairment have increased risk of anaemia during ribavirin therapy. Monitoring of haemoglobin levels is recommended every 2-4 weeks during ribavirin therapy in people with decompensated liver disease.

As ribavirin is teratogenic, both women and men should be counselled about the risks of pregnancy and advised that two forms of contraception are recommended while taking ribavirin and for 6 months after treatment.

Table 5. Recommended treatment protocols for hepatitis C virus (HCV) infection in people with decompensated liver disease

Regimen

HCV genotype

Duration

Sofosbuvir 400 mg, orally, daily

+

Velpatasvir 100 mg, orally, daily

+

Ribavirin 600 mg, orally, daily*

1–6

12 weeks

Sofosbuvir 400 mg, orally, daily

+

Ledipasvir 90 mg, orally, daily

±

Ribavirin 600 mg, orally, daily*

1

12 weeks

(24 weeks if ribavirin-intolerant)

DAA = direct-acting antiviral; PBS = Pharmaceutical Benefits Scheme; SVR = sustained virological response at least 12 weeks after treatment.
* Ribavirin starting dose should be 600 mg daily, with dose adjustment according to tolerance.
† Ribavirin is not PBS-listed for use in combination with sofosbuvir + ledipasvir.
Notes: The combination of sofosbuvir + velpatasvir + ribavirin is the only DAA regimen to include a specific indication for treating decompensated HCV liver disease. A number of the DAA regimens evaluated in recent studies enrolling subjects with decompensated liver disease have not been submitted to the Therapeutic Goods Administration/Pharmaceutical Benefits Advisory Committee and are therefore not reflected in the PBS listing. All patients should be treated by a specialist experienced in the management of decompensated liver disease. SVR may be associated with improvement in liver function (see text). Regimens containing the protease inhibitors glecaprevir, voxilaprevir or grazoprevir (glecaprevir + pibrentasvir, sofosbuvir + velpatasvir + voxilaprevir, and elbasvir + grazoprevir) are contraindicated in people with decompensated liver disease.