Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by the presence of elevated transaminases, hypergammaglobulinemia, autoantibodies, and typical histologic findings (interface hepatitis, lymphoplasmacytic portal infiltrate).1 Although AIH was the first liver disease to be targeted with an effective treatment, it is still a challenging condition. In fact, its management has not substantially changed over the last 40 years, consisting of the induction of response with steroids and maintaining this with a steroid-sparing drug, usually azathioprine (AZA).1,2 In this regard, the European Association for the Study of the Liver (EASL)1 and the American Association for the Study of Liver Diseases (AASLD)2 recommend using predniso(lo)ne and AZA as the first therapeutic option in these patients. AASLD guidelines also suggest the use of budesonide with AZA as an alternative agent in patients without cirrhosis or a severe acute presentation.1–3
Budesonide is a synthetic corticosteroid with local anti-inflammatory effects and a more favorable safety profile compared with predniso(lo)ne.4 This safer profile is the consequence of lower systemic exposure to the drug, as >90% of the drug is eliminated in hepatic first-pass clearance.5,6 Studies published in the 90s evidenced the potential benefit of budesonide in AIH.7 However, it was not until 2005 that a phase II clinical trial showed that budesonide was effective in the induction of response in naive patients with AIH.8 These results were confirmed in a phase III randomized trial comparing budesonide plus AZA and prednisone plus AZA as first-line treatment.6 In this trial, the authors showed that budesonide was not only effective but was also superior to prednisone in achieving biochemical response (BR) in patients with AIH.6
Nevertheless, the use of budesonide in the real-life setting is far from widespread,4 being even avoided in some centers.9 This is probably due to the limited information on the subgroup of patients who may benefit from budesonide treatment. Thus, we aimed to: (1) describe the use of budesonide as a first-line drug in a large cohort of untreated AIH patients, (2) compare its safety and efficacy with prednisone in the real-world clinical practice, and (3) identify the profile of patients who would benefit from budesonide.
MATERIALS AND METHODS
We performed a retrospective, multicenter cohort study of patients diagnosed with AIH in 21 referral centers in Spain participating in the ColHai (the Spanish Registry for Cholestatic and Autoimmune Liver Diseases) registry. The inclusion criteria were: (1) the diagnosis of AIH using the simplified International Autoimmune Hepatitis Group criteria (score ≥6) always including a liver biopsy,10 (2) 18 years of age or older at diagnosis, and (3) induction therapy with either prednisone or budesonide in combination with AZA. The exclusion criteria were: (1) previous treatment with any immunosuppressive drug, (2) the presence of variant forms of AIH, or (3) any other active liver disease that could interfere with treatment response or evaluation.
For this project, we defined 2 cohorts: (a) the budesonide cohort, including previously untreated patients who received budesonide as the first-line drug, and (b) the prednisone cohort, in which naive patients were treated with prednisone as first-line treatment.
The study was approved by the institutional review board at Marqués de Valdecilla University Hospital (internal code: 2020.275) and complied with the provisions of the Good Clinical Practice guidelines and the Declaration of Helsinki.
Data collected for the analysis
Data were anonymized and collected from medical records by each local investigator and were centrally compiled and analyzed. In terms of baseline characteristics, we recorded demographic variables, the presence of other medical conditions, including autoimmune and metabolic comorbidities, as well as serologic, histologic, laboratory, and treatment parameters. Induction and maintenance drugs and doses were also collected. Finally, evolutionary events and treatment-related adverse events (AEs) were also analyzed.
As per guidelines,1,2 BR was defined as complete normalization of both serum transaminases and IgG. The upper limit of normality (ULN) at each center was used for the definition of transaminases and IgG normalization. Rapid responders were defined as patients who presented a decrease of transaminases of >80% 8 weeks after treatment initiation.11 The presence of cirrhosis was recorded at each center according to the typical clinical, ultrasound, and histologic characteristics (METAVIR stage 4 or Ishak stage 6). Acute severe autoimmune hepatitis (AS-AIH) was defined by the presence of jaundice and significant liver dysfunction evidenced by an international normalized ratio >1.5 in patients with a time between the onset of symptoms and presentation of <26 weeks.12
The initial doses of budesonide, prednisone, and AZA were collected from all patients. Dates of dose modification and drug withdrawal were collected when available. Cumulative doses were calculated by multiplying the daily dose of the drug by the number of days in treatment with that dose and then, adding up the cumulative dosage until that time. The equivalence of budesonide to prednisone was calculated according to previous publications and clinical trials in liver diseases,13 assuming that 3 mg of budesonide is equivalent to 10 mg of prednisone.
The primary endpoint was BR at any time, and at 6 and 12 months after starting immunosuppressive treatment. Secondary endpoints were the occurrence of steroid-associated AEs and the use of budesonide as a first-line drug in patients with AIH.
Quantitative variables were expressed as median and interquartile range (IQR, 25th–75th percentiles). Categorical variables were presented as absolute frequencies and percentages. An inverse probability of treatment weighting (IPTW) propensity score (PS) method was used to balance the 2 cohorts (budesonide and prednisone). The parameters included in the final PS model were: age (years), sex (male vs. female), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), international normalized ratio, total bilirubin, IgG, the inverse of IgG, IgG squared, the square root of IgG, antinuclear antibodies, anti–smooth muscle antibodies, cirrhosis (yes vs. no), and the inverse of ALT. The balance between baseline parameters of each cohort was assessed, before and after the application of IPTW weights, stabilized by treatment prevalence, and by means of standardized mean differences (STD).14,15 A STD >20% was considered unbalanced.16 The Fisher exact test was used to compare categorical variables and for quantitative or ordinal variables we used nonparametric methods: Mann-Whitney (2 groups) or Kruskal-Wallis (>2 groups) tests for independent data, and the Wilcoxon signed-rank test (2 groups) or the Friedman test (>2 groups) for dependent data. Logistic regression was used to determine associations between treatment and clinical characteristics. Results of the univariable and multivariable logistic regression are presented as OR and 95% CI.
The level of significance was set at 5% (2-sided). IPTW analyses were performed using SAS V.9.4 software (SAS Institute). All other analyses and statistical tests were performed using Stata Statistical Software: Release 14.1; StataCorp LLC).
Twenty-one centers from the ColHai registry treating 2763 patients with AIH participated in the study. One hundred fifty-one patients (5.4%) receiving budesonide as the first-line drug between 2009 and 2020 were enrolled in the study (budesonide cohort). In addition, 446 patients treated with prednisone at these centers were included as the control group (prednisone cohort). Controls were selected to match the same year of the diagnosis of AIH. Considering that budesonide is not recommended for patients with cirrhosis or those with AS-AIH, we excluded these patients from the present analysis. Patients not receiving AZA were also excluded. Therefore, 381 patients were analyzed, 276 patients treated with prednisone, and 105 patients receiving budesonide. The baseline characteristics of the patients included in the study are summarized in Table 1. Briefly, most patients were women (n = 268, 70%) with a median age of 61 (IQR: 47.8–70.2) and 110 patients (28.9%) presented at least 1 immune-mediated comorbidity, being autoimmune thyroid diseases (n = 48, 12.6%) the most prevalent. Patients treated with budesonide had statistically significant lower values of AST (128 vs. 642 IU/L), ALT (198 vs. 753 IU/L), ALP (119 vs. 160 IU/L), GGT (98 vs. 176 IU/L), total bilirubin (1 vs. 2.2 mg/dL), and ferritin levels (150 vs. 253 ng/mL). The median budesonide, prednisone, and AZA starting doses were 9 mg (IQR: 9–9), 50 mg (IQR: 30–60), and 50 mg (IQR: 50–50), respectively. As shown in Table 1, there were no significant differences in the cumulative doses of corticosteroids and AZA at 6 and 12 months.
TABLE 1 -
Baseline characteristics of the cohort after excluding patients with cirrhosis, AS-AIH, and those not treated with AZA
||Global cohort (N = 381)
||Budesonide (N = 105)
||Prednisone (N = 276)
|Female sex [n (%)]
|Age [median (IQR)] (y)
|Other AI disease [n (%)]
|AST [median (IQR)] (IU/L)
|ALT [median (IQR)] (IU/L)
|ALP [median (IQR)] (IU/L)
|GGT [median (IQR)] (IU/L)
|Bilirubin [median (IQR)] (mg/dL)
|INR [median (IQR)]
|Ferritin [median (IQR)]a (μg/L)
|Ferritin >2.1 × ULN [n (%)]a
|ANA ≥1/80 [n (%)]
|ASMA ≥1/40 [n (%)]
|IgG [median (IQR)] (mg/dL)
|Interface hepatitis [n (%)]
|Lymphoplasmacytic infiltration [n (%)]
|Biliary changes [n (%)]
|Simplified AIH score [median (IQR)]
|Induction dose [median (IQR)]
|Cumulative doses at 6 mob [median (IQR)]
|Cumulative doses at 12 mob [median (IQR)]
|Cumulative doses of AZA at 6 mob [median (IQR)]c
|Cumulative doses of AZA at 12 mob [median (IQR)]c
aFerritin was available in 241 patients.
bCumulative doses available in 183 patients (out of 381 without cirrhosis, AS-AIH and treated with AZA). Doses are expressed in cumulative doses of prednisone (converted from budesonide in patients treated with this drug).
cCumulative doses available in 374 patients.
Abbreviations: AI, autoimmune; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AS-AIH, acute severe autoimmune hepatitis; ASMA, anti–smooth muscle antibodies; AST, aspartate aminotransferase; AZA, azathioprine; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; IQR, interquartile range; ULN, upper limit of normal.
Budesonide was completely withdrawn in 34 (32%) and 62 (59%) patients at 6 and 12 months, respectively. At 6 months, 22 (65%) patients had stopped budesonide after achieving BR, 8 (24%) due to lack of response, 1 (2%) due to AEs, and in 3 (9%) cases by patients’ decision. At 12 months, 43 (69%) patients discontinued budesonide after achieving BR, 12 (19%) due to lack of response, 2 (3%) due to AEs, and the remaining cases (5%) by patient’s decision. Prednisone was withdrawn in 58 (21%) and 95 (34%) patients at 6 and 12 months of starting treatment, respectively. At 6 months, the drug was discontinued in 50 (86%) patients after achieving BR, 5 (9%) as a consequence of AEs, and 3 (5%) by patients’ decision. At 12 months, 84 (88%) stopped prednisone after achieving BR, 6 (7%) due to AEs, and 5 (5%) in the context of the patient’s decision. Differences in drug withdrawal rate at both time points were p = 0.057 at 6 months and p < 0.001 at 12 months.
After a median follow-up period of 5.6 years (IQR: 3.2–8.9), complete BR was documented in 294 (77%) patients. The median time to BR was 4.4 months (IQR: 2.1–8.8). In the prednisone cohort, 240 (87%) patients achieved BR during follow-up (Figure 1A), with a median time to BR of 4.9 months (IQR: 2.2–9.3). BR at 6 and 12 months after starting immunosuppressive treatment was attained in 143 (52%) and 199 (72%) patients, respectively (Figure 1B, C). In the budesonide cohort, BR was achieved in 54 (51%) patients during follow-up (Figure 1A), with a median time to BR of 3.1 months (IQR: 1.5–6.9). At 6 and 12 months of treatment, BR was documented in 39 (37%) and 51 (49%) patients, respectively (Figure 1B, C). The median values of transaminases, IgG, and doses at 6, 12 months and last follow-up according to the presence or absence of BR are shown in Supplemental Table 1 (https://links.lww.com/HEP/A13). The occurrence of BR was significantly higher in patients treated with prednisone at any time during follow-up (p < 0.001), at 6 months (p = 0.010), and 12 months (p < 0.001).
The probability of achieving BR was also significantly higher in the prednisone group at 6 months (OR = 0.54; 95% CI: 0.34–0.87), at 12 months (OR = 0.36; 95% CI: 0.23–0.58) and during the follow-up (0.16; 95% CI: 0.09–0.27). Figure 2 shows the Kaplan-Meier curve with the probability of achieving BR during follow-up. Variables with a p value <0.1 in the univariate analysis were included the multivariate analysis using a stepwise logistic regression model. As ferritin >2.1 × ULN and IgG <1.9 × ULN have been described as predictive factors of treatment response,2 they were also included in the model. Treatment with prednisone (vs. budesonide) and ferritin levels > 2.1 × ULN were independently associated with the probability of BR at 6 months (OR = 0.16; 95% CI: 0.05–0.47), and at 12 months (OR = 0.29; 95% CI: 0.10–0.82). At any time during follow-up both prednisone treatment (vs. budesonide, OR = 0.15; 95% CI: 0.07–0.33) and IgG <1.9 × ULN (OR = 0.35; 95% CI: 0.15–0.86) were significantly associated with a higher probability of BR (Supplemental Table 2, https://links.lww.com/HEP/A14).
Finally, for a more accurate evaluation of the impact of treatment in achieving BR and to minimize the potential selection bias, an IPTW-PS was performed. After the application of IPTW the cohort was adequately balanced for comparisons between groups. The pre-IPTW and post-IPTW STD are summarized in Supplemental Table 3 (https://links.lww.com/HEP/A15). Patients treated with budesonide presented a lower probability of achieving BR at any point during follow-up with an OR of 0.20 (95% CI: 0.11–0.38; p < 0.001), and at 6 (OR = 0.51; 95% CI: 0.29–0.89; p = 0.019) and 12 months (OR = 0.41; 95% CI: 0.23–0.73; p = 0.003) (Figure 3).
BR in the entire cohort
Considering that this work is based on real-life clinical practice, the probability of achieving BR with prednisone and budesonide was also evaluated in the whole cohort (n = 597) including patients with cirrhosis, AS-AIH, and without AZA treatment. The baseline characteristics of cohort are shown in Supplemental Table 4 (https://links.lww.com/HEP/A16).
During the follow-up, 465 patients (77.9%) achieved BR. In the budesonide group, 57 patients (37.7%), 75 patients (49.7%), and 80 patients (53%) achieved response at 6 and 12 months and during follow-up, respectively. In patients treated with prednisone, BR was achieved in 217 (48.7%), 301 (67.5%), and 385 (86.3%) at 6 and 12 months and during follow-up.
After the application of the IPTW-PS, and once balance was adequate (Supplemental Table 3, https://links.lww.com/HEP/A15), patients treated with budesonide also presented a lower probability of achieving BR at any point during follow-up with an OR of 0.25 (95% CI: 0.14–0.46; p < 0.001) and at 12 months (OR = 0.51; 95% CI: 0.29–0.90; p = 0.022) after starting treatment (Supplemental Figure 1, https://links.lww.com/HEP/A19). We also identified a trend towards a lower probability of BR at 6 months (OR = 0.64; 95% CI: 0.36–1.19; p = 0.166).
Besides steroid treatment, no other baseline characteristic was associated with BR at 6 or at 12 months. Nevertheless, rapid responders measured by rapid ALT decline or combined rapid AST plus ALT decline presented a higher probability of achieving BR both at 6 and 12 months of treatment (Supplemental Table 5, https://links.lww.com/HEP/A17). When this analysis was performed in both cohorts separately, rapid response was also strongly associated with the probability of BR in patients treated with prednisone, but not in those receiving budesonide (Supplemental Table 6, https://links.lww.com/HEP/A18).
Profile of patients who will benefit from budesonide
Finally, we wanted to identify the subgroup of patients with AIH in whom budesonide obtained a similar BR rate as compared with prednisone. We found that in patients with low baseline transaminases, BR rates were similar between the budesonide and prednisone cohorts. Indeed, in patients with transaminase levels ≤2 × ULN, the BR rates were 71.4% in the budesonide cohort and 70.6% in the prednisone cohort (p = 0.942). In addition, lower GGT values at baseline were significantly associated with a higher rate of BR (p = 0.015) (Table 2).
TABLE 2 -
Baseline characteristics of patients without cirrhosis and without acute severe autoimmune hepatitis treated with budesonide+azathioprine and prednisone+azathioprine according to the achievement of biochemical response
||Responders (N = 54)
||Nonresponders (N = 51)
||Responders (N = 240)
||Nonresponders (N = 36)
|Female sex [n (%)]
|Age [median (IQR)] (y)
|Other AI disease [n (%)]
|AST [median (IQR)] (IU/L)
|ALT [median (IQR)] (IU/L)
|ALP [median (IQR)] (IU/L)
|GGT [median (IQR)] (IU/L)
|Bilirubin [median (IQR)] (mg/dL)
|INR [median (IQR)]
|ANA≥1/80 [n (%)]
|ASMA≥1/40 [n (%)]
|IgG [median (IQR)] (mg/dL)
|Ferritin [median (IQR)] (ng/mL)
|Biliary changes [n (%)]
Abbreviations: AI, autoimmune; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, antinuclear antibodies; ASMA, anti–smooth muscle antibodies; AST, aspartate aminotransferase; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; IQR, interquartile range.
Steroid-related AEs were documented in 113 (22%) patients, appearing in 91 (24.2%) patients treated with prednisone and in 22 (15.9%) patients treated with budesonide (p = 0.047). These differences vanished when patients with cirrhosis were excluded from the analysis, showing a similar incidence of AEs in both groups (p = 0.119).
In terms of specific AEs, only the presence of osteoporosis was significantly higher in the prednisone group (Table 3). However, this increased risk was also associated with age, as patients older than 60 years had a significantly higher risk of osteoporosis (OR = 5.19; 95% CI: 1.15–23.4). The presence of cirrhosis did not significantly increase the risk of osteoporosis. The development of AEs was not associated with the cumulative doses of prednisone or budesonide (p = 0.697).
TABLE 3 -
Most frequent adverse events during follow-up
This study evaluated the effectiveness of budesonide in a real-life scenario and found that this drug was not as effective as prednisone. AIH patients treated with budesonide had a lower probability of achieving BR than those treated with prednisone as the first-line drug. The incidence of BR was steadily superior in the prednisone group not only during follow-up but also at 6 and 12 months. Only patients with transaminase levels <2 × ULN had similar BR when treated with budesonide or prednisone.
Although clinical practice guidelines recommend budesonide as an adequate alternative to prednisone, its use is far from widespread. In fact, the use of budesonide as either a first- or second-line drug is low as reported in several studies.17 A recently published survey evaluating real-life clinical management of AIH in 33 centers around the world showed that budesonide was not the induction therapy in any case,9 emphasizing the perceived marginal usage of this drug. Consistent with these data, in the present study, we show that budesonide is far from being the preferred drug, as it was only indicated in 5.4% of patients newly diagnosed with AIH. Budesonide-treated patients were significantly different from those receiving prednisone, reinforcing the preconceived idea that budesonide is reserved for a particular subgroup of patients. In fact, budesonide was mainly employed in patients with low baseline transaminases, suggesting that this drug is preferred in patients with less severe disease.
The efficacy of budesonide was demonstrated in a randomized clinical trial published in 2010 comparing the 2 drugs in adults with AIH.6 This study showed that budesonide was an effective drug in this scenario6 and led to the recommendation of the use of budesonide as an alternative to prednisone by international clinical practice guidelines.1,2 Interestingly, this trial also showed that budesonide was not only effective but also superior to prednisone. While 47% of patients treated with budesonide reached the primary endpoint of the study, only 18.4% of patients treated with prednisone did so. The explanation for these unexpected results probably lies in the design of the trial and the definition of the primary endpoint. In fact, this endpoint included not only the achievement of BR but also reaching it in the absence of steroid-related AEs. However, this unconventional endpoint was also used in a similar trial carried out in a pediatric AIH population.18 Nonetheless, the results were notably different: the primary endpoint was only achieved in 16% and 15% of patients treated with budesonide and prednisone, respectively, without identifying statistical differences between the 2 treatment arms.18 In addition, it is important to highlight that prednisone induction doses in the former trial6 were lower than the prednisone doses used in the current study. To clarify the potential influence of dosage on outcomes, we recorded not only the initial doses used in each patient but also the cumulative doses of both drugs. We found that the cumulative doses at 6 and 12 months were similar in both cohorts (p = 0.529 and 0.994, respectively) and were not associated with the probability of achieving BR. Therefore, we consider that the differences in initial doses did not influence the results. It is important to note that, to compare cumulative corticosteroid doses, we assumed that 9 mg of budesonide were equivalent to 30 mg of prednisone. This was the equivalence employed in the randomized clinical trial evaluating the efficacy of budesonide in AIH.6 However, the actual equivalence between these 2 drugs is not completely clear and a few studies conducted in patients with inflammatory bowel disease suggested that 9 mg of budesonide were clinically equivalent to 40 mg of prednisone.19
Beyond these trials, the body of evidence is scarce.20–22 In fact, the small amount of information available includes a very limited number of patients treated with budesonide, many of whom were diagnosed with variant syndromes, and in some cases, the definition of BR did not conform to what is recommended by the current international guidelines.
Unlike these studies, which were underpowered for obtaining robust information and conclusions, our work was endowed with a larger number of patients from many different referral centers, overcoming potential single-center limitations. Moreover, once the differential profile of patients according to drug choice had been identified, the design of the IPTW analysis allowed direct comparison between groups after achieving an appropriate balance. As mentioned above, patients treated with budesonide were less likely to achieve BR than those treated with prednisone. However, these results should not be taken as an indication of a lack of efficacy of the drug. Forty-nine percent of patients treated with budesonide reached BR during follow-up, which is similar to that reported in the original trials. In fact, we found that patients with transaminases levels below 2-fold ULN at diagnosis had a similar probability of achieving BR as patients treated with prednisone.
After having documented the inferiority of budesonide with respect to prednisone, we wanted to identify predictive factors that may determine higher odds of reaching BR. Besides the treatment, we did not identify any other baseline factor with predictive capacity. In this scenario, an evolutionary event has recently been shown to predict BR. The results of a large multicenter European study showed that patients treated with prednisone who presented a reduction of AST ≥80% after 8 weeks on treatment-rapid responders, had a higher probability of achieving BR at 6 and at 12 months after treatment initiation.11 In our cohort, we identified that rapid responders had a greater likelihood of BR at 6 and at 12 months. Although Pape et al.11 showed that this predictive ability was related to a rapid AST decline, we identified that ALT as well as the combined reduction of both AST plus ALT, but not AST alone, were related to a higher probability of BR at these time points. Notwithstanding, when stratified by treatment arms, this prediction ability persisted only in the prednisone cohort (not in budesonide-treated patients).
Regarding the development of AEs, we identified differences between the 2 groups: patients treated with prednisone had a higher incidence of AEs. However, when patients with cirrhosis were excluded, the emergence of toxicities was not significantly different between the 2 groups. These results suggest that the stage of liver fibrosis explains, at least in part, the higher risk of AEs observed in patients treated with prednisone. We did not identify differences in the appearance of severe AEs, except for osteoporosis. Nevertheless, we found that the emergence of osteoporosis was also related to age, as patients older than 60 years were at higher risk. We did not find any influence of cumulative drug doses on the development of AEs. However, these data should be interpreted with caution because the rate of AEs reported here is lower than that of the former trial. This is probably the consequence of the retrospective study design, as many nonsevere steroid-related AEs might not have been registered in the medical records by the treating physicians, leading to underreporting of their appearance. However, a recent Dutch work showed that not only prednisone exposure increased the risk of AEs, but also treatment with budesonide significantly increased the risk of cataracts and bone fractures.4
Our study is not free of limitations, mostly linked to the retrospective design of the study. First, the choice of induction therapy was at the discretion of each treating physician, lacking predefined criteria for drug choice and leading to the described baseline differences disclosed in the manuscript. Nevertheless, the design of the IPTW analysis helped to overcome this potential limitation. Second, the AEs may have been underreported and/or underdiagnosed, as mentioned above. Third, we cannot provide information about the modified hepatitis activity index or liver stiffness, as this information was not available for revision in some centers.
In summary, we identified that the use of budesonide in the real-life setting was low and was associated with a lower probability of achieving BR with respect to prednisone. However, budesonide was associated with a lower rate of AEs. Although we did not identify any baseline predictor of response, a rapid decrease of ALT or ALT plus AST was associated with a higher probability of BR in patients treated with prednisone. Patients with low transaminase levels at diagnosis (<2 × ULN) had similar BR with both corticosteroid treatments and might benefit from the lower number of AEs associated with budesonide treatment.
CONFLICTS OF INTEREST
Álvaro Díaz-González. is on the speakers’ bureau for and received grants from Intercept. Manuel Hernández-Guerra consults for Bayer, Intercept, and Orphalan. He received grants from AbbVie and Gilead. Víctor Sapena consults for LEO Pharma. He received grants from Bayer. Mar Riveiro-Barciela is on the speakers’ bureau for and received grants from Gilead. She is on the speakers’ bureau for Grifols. Rosa M Morillas advises and is on the speakers’ bureau for Avanz. She is on the speakers’ bureau for Gilead and AbbVie. Anna Soria received grants from Tillots, Ferring, Norgine, Alfasigma, Jansen, and Abbvie. Carmen Álvarez-Navascúes advises and is on the speakers’ bureau for Gilead and AbbVie. She is on the speakers’ bureau for Intercept. Montserrat García Retortillo is on the speakers’ bureau for and received grants from Gilead and AbbVie. She is on the speakers’ bureau for Intercept. María-Carlota Londoño is on the speakers’ bureau for and received grants from Intercept. The remaining authors report no conflicts of interest.
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