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 prog- nosis 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 trans- plantation, 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 cere- brovascular 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 eligibility criteria for DAA regimens that have recently been PBS-listed for the treatment of HCV do not distinguish between people with compensated versus decompensated liver disease, with the exception of PrOD, which is 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). It should be noted, however, that people with decompensated liver disease were not enrolled in the key registration studies used to define the product labels; that data specific to this important population continue to emerge; and that regimens that have been evaluated for this population have not always been identical to those trialled in patients with compensated liver disease. Some of the recommendations for this population are based on expert opinion.
The efficacy of a number of DAA regimens in people with decompensated liver disease has been formally evaluated in recent clinical trials. 66-72 Current data support the combination of sofosbuvir plus ledipasvir plus ribavirin for 12 weeks as the first-line regimen for Gt 1 HCV, with ribavirin started at a low oral dose of 600 mg daily. This regimen was evaluated for 12 versus 24 weeks in the SOLAR-1/2 studies — there was no benefit of extending treatment to 24 weeks. 66,67 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 dacla- tasvir 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%.56,67,70,73 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%56,67,70,73) than in those with Child–Pugh B scores.
Patients with Gt 3 HCV and decompensated liver disease are harder to cure. 71 Although data are limited, we recommend treatment with sofosbuvir plus daclatasvir plus ribavirin for 24 weeks’ duration in this group (Table 7). 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. When used, ribavirin should be started at the lower dose of 600 mg daily in this population. If a patient does not tolerate ribavirin, treatment duration should be extended to 24 weeks regardless of HCV genotype. People with Child–Pugh C cirrhosis are at highest risk of ribavirin-related toxicity, especially anaemia; treatment for 24 weeks’ duration with no ribavirin may be most suitable for this group. 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 × 10 9 /L, bilirubin level > 170 μmol/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 × ULN
People with decompensated liver disease should not be treated with PrOD 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 baselin 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, predic- tive 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. 71,73 Antiviral therapy may be started with the intent of suppression and prevention of post-transplant HCV recurrence (see Section on treatment of HCV after transplantation: treatment of people on the transplant list). Alternatively, these individuals may be best served with HCV treatment after transplanta tion. 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,
|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 weeks||B1|
|• sofosbuvir + daclatasvir ± ribavirin for 12 or 24 weeks||B1|
|The first-line treatment regimen for chronic Gt 3 HCV infection and decompensated liver disease is (see Table 7):|
|• sofosbuvir + daclatasvir + ribavirin for 24 weeks||B1|
|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
|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 weeks||C2|
|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).|