Early and effective treatment of PBC significantly reduced the need for liver transplantation due to this disease
Current European and Czech guidelines include obeticholic acid (OCA) as the only registered option for 2nd line treatment of primary biliary cholangitis (PBC). In the Czech Republic, it is approved as a center-specific treatment and was granted permanent reimbursement from public health insurance in May 2022. The use of OCA in the treatment of PBC was also addressed in a symposium that was part of the professional program at this year's XLIX. May Hepatology Days in Olomouc.
Introduction
PBC remains an incurable disease, but early initiation of effective therapy significantly improves the prognosis of patients – and is therefore crucial. This heterogeneous chronic disease progresses slowly and insidiously, significantly affecting patients' quality of life and over several decades can progress to liver cirrhosis with all its consequences, including the potential need for transplantation and the risk of premature death. The risk and speed of progression vary significantly among patients, with PBC prognosis determined by gender and age at diagnosis (progression can be rapid in younger patients, especially men).
MUDr. Soňa Fraňková, Ph.D., from the Institute of Clinical and Experimental Medicine in Prague (IKEM) reminded us that PBC may initially progress asymptomatically, sometimes making it difficult to recognize the disease and potential progression in time – the clinical picture may not correspond to the stage of the disease. Regular monitoring of biochemical markers, especially alkaline phosphatase (ALP) and bilirubin, is important as these are the main indicators of long-term prognosis, correlating with the risk of transplantation and death.
1st and 2nd line treatment
In the list of treatment goals for PBC, the speaker mentioned delaying the end stage liver disease (ESLD), reducing cholestasis, reducing inflammation, slowing the progression of fibrosis, and also highlighted the treatment of comorbidities (bone diseases, accompanying autoimmune diseases) with a focus on quality of life.
The cornerstone of PBC pharmacotherapy is ursodeoxycholic acid (UDCA), but some patients do not tolerate it and 25–50% of patients respond inadequately to 1st line treatment – in these cases, it is appropriate to start 2nd line treatment with obeticholic acid in a timely manner. Regular assessment of response to UDCA should occur at diagnosis and then every 6 months to 1 year. Indicators that a patient is not responding to UDCA include an increase in ALP levels to > 1.5 times the normal after 1 year of treatment, higher bilirubin concentration in advanced stages, and increased levels of other biochemical markers despite UDCA use.
OCA is administered in combination with UDCA in adult patients who do not respond adequately to UDCA, or as monotherapy in adults who do not tolerate UDCA. Obeticholic acid therapy is available in hepatology centers. The speaker emphasized that it is necessary to refer these patients to approved centers in a timely manner.
Long-term treatment and delaying ESLD
The head of the 4th Internal Clinic − Clinic of Gastroenterology and Hepatology of the 1st Faculty of Medicine of Charles University and General University Hospital in Prague Prof. MUDr. Radan Brůha, CSc., added that patients with PBC not responding to UDCA have a higher risk of developing liver complications (ascites, bleeding, encephalopathy). He stated that severe liver complications and disease progression are associated with a higher risk of liver transplantation and death early after proving an inadequate response to UDCA. Already after the first severe liver complication, survival in patients treated with UDCA significantly decreases.
OCA has shown a significant beneficial effect on reducing key prognostic markers of PBC risk, as known from a pooled analysis of the double-blind Phase 3 POISE study and its open-label extension. The primary composite endpoint of the study was achieved by 46% of patients after 12 months of OCA use, and 50–56% after 48–72 months of therapy. During the 6-year treatment with obeticholic acid, the activity of liver enzymes, bilirubin, profibrotic and inflammatory markers decreased; their lower values additionally remained stable throughout the treatment period.
Stabilizing the histological findings
Biochemical response is not the only important parameter. As the speaker noted, patients with advanced fibrosis have worse survival, regardless of biochemical response. Bowlus et al. published a study (CGH 2019), showing that OCA stabilizes histological findings in the liver based on paired biopsies (n = 17). During the AASLD 2019 congress, it was reported that non-invasive fibrosis markers remained stable during the 6-year OCA treatment.
For patients with compensated cirrhosis and their response to OCA, a real-world data cohort of 191 patients with PBC from Italy showed similar responses to those without cirrhosis. For decompensated cirrhosis and cirrhosis with clinically significant portal hypertension, OCA is contraindicated in the USA and should be used very cautiously with dose reduction according to European recommendations.
The author mentioned the comparison of POISE study participants with patients from 2 real-world practice cohorts (Global PBC, UK PBC). In both the study and real practice, patients taking OCA had significantly better transplant-free survival intervals compared to external controls without OCA.
Liver transplantation in PBC: When to consider it?
As stated by Assoc. Prof. MUDr. Jan Šperl, CSc., from IKEM, thanks to early diagnosis and early effective treatment, the disease course has changed, and the proportion of patients progressing to chronic liver failure requiring transplantation is decreasing globally. Most patients with PBC do not need this procedure. It is more often necessary for those diagnosed at a younger age (UDCA failure is more common, and this risk increases with the duration of the treatment). Transplantation remains the only option for treating ESLD in PBC. The speaker rated its long-term results as excellent. Recurrence of PBC in the liver graft is common, but rarely leads to graft failure and retransplantation.
Patients indicated for liver transplantation are those with decompensated cirrhosis (MELD score > 15, Child-Pugh B, expected survival < 1 year with conservative treatment), unacceptable quality of life (uncontrollable pruritus, hepatic encephalopathy unresponsive to treatment), small hepatocellular carcinoma. According to Assoc. Prof. Šperl, unnecessary transplants should be avoided.
The author added that PBC recurrence can be confirmed only histologically. Recurrence may be present histologically even with completely normal liver tests. After transplantation, the titer of antimitochondrial antibodies (AMA) decreases, but they become detectable again later. In PBC recurrence, AMA are present even with a normal histological finding.
Eva Srbová
editor proLékaře.cz
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