Start UDCA 13-15 mg/kg/day for: 12 months if VCTE

or

TE <10 kPa, MRE <4.3 kPa or 6 months if VCTE or TE ≥ 10kPa, compensated liver disease and no signs of portal hypertension

PBC patients with a lower stage of fibrosis (VCTE or TE < 10 kPa, MRE < 4.3 kPa) may continue UDCA monotherapy for 12 months prior to determining response (ALP < 1.5 x ULN and bilirubin < 1 x ULN) and the need for second-line therapy. For patients with more advanced fibrosis stage (VCTE or TE > 10 kPa), compensated liver disease and no signs of portal hypertension, response (ALP < 1.5 x ULN and bilirubin < 1 x ULN) and the need for second-line treatment should be assessed at 6 months. Based on recent data, clinicians may consider the more stringent criteria (ALP < ULN and bilirubin < 0.6 mg/dL) to assess response in patients with more advanced disease (1).

 

At 6 months, ALP <1.9 x ULN + bilirubin <1.0 x ULN

or

at 12 months: ALP<1.5 x ULN + bilirubin <1.0 x ULN

Lack of biochemical response to UDCA is reported in 25–50% of treated patients (20) and has been associated with a >5-fold increase in risk of progression to cirrhosis, as well as a 3-fold increase in age-adjusted mortality (21). At this time, clinicians are encouraged to use two liver biochemistries as the anchor for clinical judgement when determining candidates for second-line therapy in PBC: ALP and bilirubin levels (2, 5, 22). If elevated above the ULN, bilirubin is more important than ALP for prognosis and in identifying advanced stage of PBC in the absence of Gilbert’s syndrome or another explanation. However, most patients will have elevated ALP levels rather than elevated bilirubin levels. For example, in a patient with a normal ALP, advanced fibrosis stage and bilirubin > ULN, adding a second-line therapy can be considered. Additional factors to consider include the patient’s age and acceptance of additional medications (1).

 

When evaluated after 12 months of treatment with UDCA, serum ALP and bilirubin levels correlate closely with the risk of liver transplant or death. Current guideline documents do not recommend a specific cut-off value for serum ALP or bilirubin beyond which a second drug should be initiated, although it is important to remember that long term survival of patients with PBC whose serum ALP is < 1.5 x ULN and bilirubin is normal is similar to that of the general population (22). However, more recent data suggest that there is additional survival benefit in obtaining normalization of serum ALP and achieving a bilirubin level < 0.6 md/dL (23).

 

Of note, the response to UDCA has been characteristically assessed at 12 months (24); however, there is growing evidence that the response can be reliably predicted after a shorter period of UDCA treatment. A study presented at the 2021 AASLD annual meeting, which included 3,516 UDCA-treated PBC patients, was performed by the GLOBAL PBC Study Group to assess the pattern of biochemical response to treatment. POISE criteria were used to assess the response to treatment. Of those with an inadequate response at 1 year (n = 313, 42%), 210 (67%) would already be identified at 6 months, and 103 (33%) after 1 year. In their conclusion, the authors propose an ALP cut-off value of 1.9 x ULN at 6 months as a threshold for adding second-line therapy (25). By using this cut-off at 6 months, a 90% negative predictive value is achieved, indicating only a 10% risk of “over-treating” patients who may not need second-line therapy. Therefore, clinicians might consider starting second-line therapies for patients with an inadequate biochemical response after 6 months, rather than 12 months, of UDCA (1).

 

Clinically Significant Portal Hypertension (CSPH) or Child-Pugh Class (CPC) B or C

A population-based study using a claims database found that the development of portal hypertension in patients with PBC is an important predictor of liver-related adverse outcomes and survival. Titievsky and colleagues recently presented data from 3,940 PBC patients to evaluate the impact of cirrhosis and portal hypertension on the incidence of decompensating events, liver failure, liver transplant, and death. Of these patients, 3,303 were non-cirrhotic, and 547 had cirrhosis, of whom 260 had portal hypertension, while 255 did not (data were incomplete or missing in 32). The main outcomes of interest were all-cause mortality, liver failure, liver transplant, ascites, variceal bleeding, and hepatic encephalopathy. As compared to patients with PBC without cirrhosis, incidence rates (IR) per 100 patient years (PY) of all-cause mortality was higher in PBC patients with cirrhosis: 8.3 vs. 2.8. For hepatic outcomes, IRs (per 100 PY) were greater among patients with PBC and cirrhosis as compared to patients with PBC without cirrhosis (liver transplant: 3.1 vs. 0.3; liver failure: 34.6 vs. 4.7; and decompensating events: 12.0 vs. 3.7). However, the differences between PBC patients with and without cirrhosis were primarily related to the presence or absence of portal hypertension; patients with compensated cirrhosis and no portal hypertension had risks similar to those of the non-cirrhotic patients. In contrast, PBC patients with compensated cirrhosis and portal hypertension had an incrementally higher risk of all-cause mortality, liver failure, liver transplant, ascites, variceal bleeding, and hepatic encephalopathy compared to PBC patients without cirrhosis or with compensated cirrhosis without portal hypertension. These data suggest that it is presence of portal hypertension, and not merely cirrhosis, that is associated with higher rates of liver-related adverse outcomes and increased mortality in patients with PBC (26).

 

A referral for liver transplantation evaluation may be appropriate for patients with decompensated cirrhosis, portal hypertension or significant impact due to severe pruritus or fatigue even if the MELD score is relatively low (<15). Living donor liver transplant may be an option for some patients (1).

 

UDCA Intolerant

PBC patients with an intolerance to UDCA are candidates for second-line therapy (1).

 

Start OCA 5 mg qd and increase to 10 mg after 3 months based on tolerance

The only currently approved second-line therapy for PBC is OCA. OCA, a farnesoid X receptor (FXR) agonist, received accelerated approval in 2016 in combination with UDCA for adults with PBC and an inadequate biochemical response to UDCA alone or as monotherapy for those with intolerance to UDCA (27). The double-blind, placebo-controlled phase 3 POISE trial demonstrated 12-month efficacy and safety of OCA in patients with PBC who had an inadequate response or were intolerant to UDCA (28), leading to the approval of OCA for PBC (29). Following this study’s completion, patients were offered the opportunity to enter a 5-year open-label extension study. After the 1-year double-blind phase, the patients on placebo started OCA and were then pooled with OCA-treated patients to evaluate the efficacy and safety for up to 6 years. Bowlus and colleagues collected liver biopsies from 17 patients at the time of enrollment in POISE and after 3 years of OCA treatment. In this sub-study, it was observed that long-term OCA treatment in patients with PBC was associated with the improvement or stabilization of disease features, including ductular injury, fibrosis, and collagen morphometry features (1, 30).

 

Despite this growing evidence of effectiveness and safety over the 5-year post-approval, several patients treated with OCA—most with cirrhosis and advanced liver disease—experienced severe liver-related adverse outcomes, including death (27). This led to a label change in 2021 for OCA to limit use in patients with cirrhosis to only those with compensated cirrhosis and no portal hypertension. OCA is now contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension, such as gastroesophageal varices and persistent thrombocytopenia, based on recent FDA guidance. Furthermore, OCA should be permanently discontinued in patients who develop laboratory or clinical evidence of hepatic decompensation, have compensated cirrhosis and develop evidence of portal hypertension, or experience clinically significant hepatic adverse reactions while on treatment (1, 31).

 

The AASLD has also issued a revised guidance statement advising against the use of OCA in patients with advanced cirrhosis, defined as cirrhosis with current or prior evidence of liver decompensation (e.g., encephalopathy, coagulopathy) or portal hypertension (e.g., ascites, gastroesophageal varices, or persistent thrombocytopenia) (3). We agree with the advice to not use OCA in patients with advanced cirrhosis and that physicians should continue to consider second-line therapies in patients with cirrhosis if their liver function is normal and there are no signs of portal hypertension. OCA therapy should not be used in patients with thrombocytopenia (i.e., in those with a platelet count < 120 x 109/L, ascites, esophageal varices,  hepatic encephalopathy), complications of cirrhosis (i.e., spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding) or evidence of hepatic synthetic dysfunction or reduced liver function (prolonged prothrombin time, elevated serum bilirubin, reduced serum albumin) and should be stopped if any of these develop while on treatment. Therefore, patients with cirrhosis receiving OCA should be monitored closely for any evidence of clinical or laboratory decompensation, which would indicate need to discontinue therapy (1). Given the evidence that OCA may increase the lithogenicity of bile, monitoring for symptomatic gallstones would also be appropriate (1, 32).

 

or

Start fenofibrate at a low dose (45-48 mg qd) and titrate up based on tolerance*

In recent years, the use of fibrates in combination with UDCA in PBC has demonstrated improvements in biochemical measures and symptom relief. Fibrates are traditionally lipid-lowering agents, and benefits in PBC are attributed to agonistic properties at the peroxisome proliferator–activated receptor (PPAR). Bezafibrate is the most extensively studied fibrate in PBC. Since bezafibrate is not available in the US, it is the opinion of the authors that fenofibrate could be considered as an alternative second-line therapy in the appropriate patient, at a low dose of 45-48 mg per day and titrated up as tolerated (1).

 

Limited data on fenofibrate has demonstrated improvements in GLOBE and UK-PBC scores (33), significant reduction—and in some cases, normalization—of serum ALP, ALT, AST, and pro-inflammatory cytokines (34), and a lower risk of cirrhosis development and hepatic deterioration (35) in patients with PBC. In 2015, a meta-analysis of 6 studies consisting of 102 PBC patients analyzed fenofibrate use in PBC. All these studies included patients who had inadequate response to UDCA, with fenofibrate added at a dose of 100–200mg daily. The observed effect of fenofibrate was a complete response rate of 69% (95% CI: 53–82%) and an odds ratio of 82.8 (95% CI: 21.6–317.2; P = 0.024). Fenofibrate use was associated with a significant decrease in ALP (-114 U/L; 95% CI: -152–-76; P = 0.0001), a significant decrease in GGT (-92 U/L; 95% CI: -149–-43; P = 0.0004); significant decrease in total bilirubin (-0.11 mg/dL; 95% CI: -0.18–-0.08; P = 0.0008); and a significant decrease in IgM levels (-88 mg/dL; 95% CI: -119–-58; P < 0.0001). Investigators stressed the need for larger-scale, randomized trials to determine the effect of fenofibrate on disease progression, liver-related morbidity, and mortality (36).

 

Consider another second-line therapeutic agent*

If the patient has not responded to the first second-line option (OCA or fibrate) after 3–6 months of therapy or the patient is unable to tolerate the selected second-line treatment, then the other second-line option should be considered. Participation in clinical trials should be discussed and encouraged for appropriate patients who may need additional therapies beyond UDCA, OCA, and off-label fibrates (1).

 

(See: Highlighted Data on Investigational PBC Agents)