Research article Chronic hepatitis D associated with worse patient- reported outcomes than chronic hepatitis B Authors Maria Buti, Maria Stepanova, Adriana Palom, Mar Riveiro-Barciela, Fatema Nader, Luisa Roade, Rafael Esteban, Zobair Younossi Correspondence mbuti@vhebron.net (M. Buti). Graphical abstract Chronic hepatitis D have worse patient-reported outcomes than those with chronic hepatitis B PATIENTS METHODS FINDINGS Questionnaires Matched group CHB CHD reported worse n = 82 Chronic liver scores: disease - Worry questionnaire - Abdominal symptoms Functional assessment of - Physical well-being chronic illness - Emotional well-being therapy-fatigue CHD n = 43 Work productivity and activity - Higher activity impairment impairment Highlights Lay summary  Patient-reported outcomes (PROs) have been Chronic hepatitis D (CHD) is a viral disease that causes studied in patients with chronic hepatitis B and C. rapid evolution to liver cirrhosis, amongst other se- vere complications, when compared to patients with  There are no data on PROs for chronic hepatitis D. chronic hepatitis B (CHB). Health-related quality of life  Several scores of health-related quality of life are in chronic hepatitis C and CHB has been reported worse in patients with chronic hepatitis D than in widely, but no studies have been performed on those with chronic hepatitis B. patient-reported outcomes in patients with CHD. Re- sults showed that CHD patients reported worse out-  PROs are useful for evaluation of quality of life in comes in psychological domains such as worry and clinical trials during and after treatment. emotional well-being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in comparison with patients with CHB. https://doi.org/10.1016/j.jhepr.2021.100280 Research article Chronic hepatitis D associated with worse patient-reported outcomes than chronic hepatitis B Maria Buti,1,2,* Maria Stepanova,3 Adriana Palom,1 Mar Riveiro-Barciela,1,2 Fatema Nader,3 Luisa Roade,1,2 Rafael Esteban,1,2 Zobair Younossi4,5 1 Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus and Universitat Autònoma de Barcelona, Barcelona, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; 3Center for Outcomes Research in Liver Disease, Washington, DC, USA; 4Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA; 5Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA JHEP Reports 2021. https://doi.org/10.1016/j.jhepr.2021.100280 Background & Aims: Health-related quality of life (HRQoL) determined by patient-reported outcomes (PROs) is impaired in chronic hepatitis B (CHB) and C patients, but there are no data regarding patients with chronic hepatitis D (CHD). The aim of this study was to assess PRO scores in untreated patients with CHD and compare them with those obtained for patients with CHB. Methods: Patients with CHD completed 3 PRO instruments (Chronic Liver Disease Questionnaire [CLDQ], Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F], and Work Productivity and Activity Impairment [WPAI]), and the results were compared with those of patients mono-infected with CHB. Results: In total, 125 patients were included: 43 with CHD and 82 with CHB. Overall, baseline PROs showed differences between both groups. Several assessments, such as the worry score from CLDQ (p = 0.0118), functional well-being from FACIT- F (p = 0.0281), and activity impairment from WPAI (p = 0.0029) showed a significant trend to worse scores in patients with CHD than with CHB. In addition, the linear regression model supports the finding that having CHD as opposed to having CHB was a predictor of a higher worry score (CLDQ) and a higher activity impairment (WPAI). Conclusions: In this first assessment in CHD, PROs recorded in patients with CHD showed a significant impairment in some domains of HRQoL questionnaires in comparison with those with CHB. Studies in larger cohorts with lengthier follow-up are needed to fully assess patient-reported quality of life over the course of CHD. Lay summary: Chronic hepatitis D (CHD) is a viral disease that causes rapid evolution to liver cirrhosis, amongst other severe complications, when compared to patients with chronic hepatitis B (CHB). Health-related quality of life in chronic hepatitis C and CHB has been reported widely, but no studies have been performed on patient-reported outcomes in patients with CHD. Results showed that CHD patients reported worse outcomes in psychological domains such as worry and emotional well- being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in com- parison with patients with CHB. © 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Introduction Several studies performed in different countries showed that Chronic liver diseases, particularly liver cirrhosis and hepato- PRO scores are impaired during the natural course of HCV cellular carcinoma, have been associated with reductions in infection and are poorer in patients with liver cirrhosis than in health-related quality of life (HRQoL) and poorer patient- those with mild fibrosis.8–10 Hepatitis C therapy based on inter- reported outcomes (PROs).1–3 Regardless of the aetiology of feron demonstrated a decline in quality of life during therapy11 liver disease, patients with chronic viral hepatitis, alcoholic liver and a later improvement when HCV elimination was ach- disease, or fatty liver disease can have impaired HRQoL, and this ieved.12,13 Therapy based on oral direct-acting antivirals (DAAs) poses a significant economic burden on society.4,5 has dramatically changed the management of CHC patients, Health-related outcomes and PROs have both been exten- providing effective treatment with improvements in HRQoL sively investigated in patients with chronic hepatitis C (CHC).6,7 during and after therapy.14,15 A recent study found that chronic hepatitis B (CHB) and CHC patients had worse PRO scores when Keywords: Viral hepatitis; Health-related quality of life; Chronic Liver Disease they tested positive for viraemia, than after viral suppression or Questionnaire; Functional Assessment of Chronic Illness Therapy–Fatigue; Work sustained virological response, when there was a substantial Productivity Activity Impairment. improvement.16 Received 24 December 2020; received in revised form 8 March 2021; accepted 9 March Chronic hepatitis D (CHD) is the most severe form of chronic 2021; available online 17 March 2021 viral disease,17 often leading to liver cirrhosis.18,19 HDV requires * Corresponding author. Address: Liver Unit, Hospital Universitario Valle Hebron, Paseo Valle Hebron 119, Barcelona 08035, Spain the simultaneous presence of HBV to be infectious and fully E-mail address: mbuti@vhebron.net (M. Buti). Research article express its pathogenicity and, therefore, HDV infection always and hepatic elastography (>13.5 kPa) or liver biopsy showing a occurs in the presence of HBV.20 Worldwide, 5% of chronically fibrosis stage > −F5 according to the Ishak score. infected HBV patients are also infected with HDV, which yields This study was approved by the Vall d’Hebron Hospital ethics an estimated 20 million people with HDV infection.21,22 Current committee (PR[AG]247/2018), and was conducted in compliance therapy for patients with CHD is interferon alpha (IFNa) or with the principles of the Declaration of Helsinki, good clinical pegylated interferon alpha (peg-IFNa).23,24 Recently, a new drug, practice guidelines, and local regulatory requirements. Patients bulevirtide, a first class entry inhibitor has obtained conditional gave oral consent once the study was explained, and all data authorisation by the European Medicines Agency (EMA) to treat were anonymised. hepatitis D.25 PROs were assessed during the patients’ regular visits to the Individuals with CHD are 2–3 times more prone to develop hospital. All instruments were given to the patients to complete liver cirrhosis than those who are mono-infected by HBV.26,27 In on their own just before the visit. To avoid bias in the answers, addition, among anti-HDV-positive patients, those with active the site staff and patients were blinded to the most recent HDV infection are more likely to develop liver cirrhosis and analytical results at the time PROs were filled out. clinical events than those who have persistently undetectable HDV viraemia.28 PROs have not been previously evaluated in Methods patients with CHD, despite the severity of this liver disease. The PRO questionnaires used were the Chronic Liver Disease CHD patients are a heterogeneous population, not only in Questionnaire (CLDQ), the Functional Assessment of Chronic terms of liver damage, but also regarding their virologic profile, Illness Therapy-Fatigue (FACIT-F) and the Work Productivity and as a result of the interactions between HDV and HBV.29 The Activity Impairment (WPAI).32 majority of patients with CHD have HDV replication and simul- The CLDQ, the first liver-specific instrument developed, in- taneous suppression of HBV replication either spontaneously or cludes 29 items in the following domains: Abdominal Symptoms, induced by nucleos(t)ide analogues (NAs) treatment. However, a Fatigue, Systemic Symptoms, Activity, Emotional Function, and small percentage of them have both HDV and HBV replication or Worry. The CLDQ responses are rated on a scale of 1–7, ranging even spontaneously clear HDV replication.23 The impact of the from having a problem or experiencing a symptom ‘all of the virologic profile can influence PROs as it occurs in patients with time’ to ‘none of the time’, respectively. Thus, higher scores CHB and CHC. indicate better HRQOL. The original CLDQ was shown to have The aims of this study were to compare PROs between pa- construct validity in studies on chronic liver diseases.33 tients with CHD and CHB, and also to the impact of the detection The FACIT-F questionnaire is a fatigue-specific PRO instru- of HDV-RNA on PROs. ment that includes 4 well-being domains (physical, emotional, social, and functional), and a fatigue subscale.34 It is designed as a scale of 0–160, where the higher the score, the higher the Patients and methods HRQoL. Patients The WPAI–Specific Health Problem is used to evaluate In this study, consecutive HBsAg-positive patients with anti-HDV impairment in patients’ daily activities and work productivity antibodies were prospectively enrolled in Hospital Vall d’Hebron associated with a specific health problem (in this study, HDV or (Barcelona, Spain) from January 2018 to December 2019. The HBV infection). The Work Productivity Impairment domain is a inclusion criteria were age over 18 years, HBsAg-positive and sum of the Absenteeism (lost hours of work) and Presenteeism with presence of anti-HDV (with or without HDV-RNA) for more (self-reported decreased productivity while working) domains; than 6 months, lack of significant comorbidities or other extra- it is assessed only in employed patients. The Activity Impairment hepatic manifestations, no antiviral therapy other than NAs for domain focuses on impairment in daily activities other than CHB, and a willingness and ability to answer questionnaires in work and is assessed in all participants regardless of their the Spanish language.30 Patients were excluded if they had employment status.35 The sum of specific health problem previous hepatic decompensation, hepatocellular carcinoma, co- impairment and impairment attributable to other health reasons infection with HIV or HCV, or other major conditions that could is equal to impairment attributable to all health reasons. WPAI affect quality of life assessment.31 A homogenous group of CHB outcomes are expressed as impairment percentages, with higher patients testing negative to anti-HDV antibodies and meeting the numbers indicating greater impairment and less productivity. same inclusion and exclusion criteria was used as the comparator. Statistical analysis In both groups, demographic, educational level, and Continuous variables are expressed as the mean ± SD, and cat- employment status were collected, as well as clinical and labo- egorical variables as n (%). In pairwise comparisons of clinical ratory data (platelet levels, alanine aminotransferase [ALT], parameters and PRO scores between groups of interest (e.g. pa- aspartate aminotransferase [AST], HBeAg, HDV-RNA, HBV-DNA, tients with HDV vs. patients with HBV mono-infection, or HDV liver stiffness measurements, hepatitis B treatment received, patients with and without detectable viraemia), the chi-square clinical events, and history of mental illness). HDV-RNA was test and the Mann-Whitney U test were used for categorical quantified using an in-house one-step RT-qPCR. The World and continuous parameters, respectively. As mono-infected CHB Health Organization international standard of quantification was patients were different from CHD patients by a number of clinical used (with a lower limit of detection [LLOD] of 100 IU/ml and a parameters potentially confounding PRO scores, we also utilised lower limit of quantification [LLOQ] of 575 IU/ml). HBV-DNA was a case-control design via selecting matched CHB controls for quantified by a commercial real-time RT-PCR technique with an CHD patients. Matching was done using a propensity score LLOD of 10 IU/ml and an LLOQ of 20 IU/ml. Liver cirrhosis was which included age, sex, history of depression or mood disor- defined by clinical and hepatic ultrasound findings, non-invasive ders, ALT, AST, and platelet count; the propensity scores were markers (fibrosis-4 [FIB-4], AST to platelet ratio index [APRI]), then fed to a maximum weight bipartite matching algorithm for JHEP Reports 2021 vol. 3 j 100280 2 Table 1. Demographic, serologic, virologic, and clinical data of the study cohort. Chronic hepatitis D Chronic hepatitis B No. cases = 43 No. cases = 82 p value Age, years 47.3 ± 11 51.8 ± 15.3 0.1892 Male sex, n (%) 27 (63) 49 (59.8) 0.7413 Caucasian, n (%) 34 (79) 58 (70.7) 0.3151 Primary education, n (%) 22 (51) 45 (56) 0.6404 Secondary education or higher, n (%) 21 (49) 36 (44) 0.6403 Employed, n (%) 32 (74) 48 (58.5) 0.0789 Housewives, n (%) 9 (21) 9 (11) 0.1396 BMI 26.1 (±3.8) 32.0 (±47.6) 0.6651 ALT, IU/ml 68.4 (±69.0) 29.4 (±28.9) <0.0001 AST, IU/ml 61.1 (±57.1) 28.5 (±17.9) <0.0001 Platelets, ×109/L 179.8 (±75.1) 219.9 (±66.5) 0.0061 Hepatic elastography, kPa 10 (6.1-18.1) 4.8 (4.2-5.9) <0.0001 APRI 1.20 (±1.60) 0.409 (±0.568) <0.0001 FIB-4 2.61 (±2.95) 1.62 (±1.78) 0.0037 HDV RNA positive, n (%) 26 (60) 0 (0) - HBV DNA positive, n (%) 11 (26) 41 (50) 0.0085 HBeAg, n (%) 4 (11) 5 (6) 0.3893 NA treatment, n (%) 27 (63) 32 (39) 0.0115 History anxiety or panic disorder, n (%) 15 (35) 25 (30.5) 0.6167 History depression or mood disorder, n (%) 3 (7) 10 (12.2) 0.3639 All continuous variables are described as median ± IQR, all categorical variables are described as n (%). The Chi-square test and Mann-Whitney U test were used for categorical and continuous parameters, respectively. Values of p <−0.05 were considered statistically significant. ALT, alanine aminotransferase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4; NA, nucleos(t)ide analogues. 1:1 matching. Values of p <−0.05 were considered statistically Patients with CHD patients had significantly higher ALT and significant and p <0.10 were considered to indicate a trend AST levels (p <0.0001), and higher levels of hepatic elastography (owing to the small sample size). (p <0.0001), APRI (p <0.0001), and FIB-4 (p = 0.0037) than those with CHB mono-infection. Results Patient-reported outcomes in patients with CHD and CHB Baseline characteristics of patients with CHD and CHB All patients included completed the Spanish versions of the In total, 125 questionnaires were administered to 43 CHD pa- CLDQ, FACIT-F, and WPAI. The total time needed to fill out the tients and 82 CHB patients at the inclusion of the study. Baseline questionnaires ranged from 8 to 15 min. demographics, educational status, clinical characteristics, and At study inclusion, the mean CLDQ total score was 5.77 ± 1.06 HDV and HBV serologic and virologic markers are shown in in patients with CHD and 5.88 ± 0.94 in patients with CHB Table 1. (p = 0.73). Patients with CHD had a significantly worse worry In both groups the majority of patients were male, Cauca- score (p = 0.0118) than patients with CHB. There were no other sians, with a mean age of 50.2±14.2 years, and employed. Pa- differences in the CLDQ scores for the various domains between tients with primary and secondary or higher educational levels these groups. were around 50% in both CHD and CHB groups. Table 2. Demographic, serologic, virologic, and clinical data of the matched CHD vs. CHB cohort. Chronic hepatitis D Chronic hepatitis B No. cases = 35 No. cases = 35 p value Age, years 47.2 ± 12.0 52.0 ± 17.1 0.3351 Male sex, n (%) 22 (62.9) 26 (74.3) 0.3031 Caucasian, n (%) 28 (80.0) 24 (68.6) 0.2740 Employed, n (%) 25 (71.4) 21 (60.0) 0.3138 BMI 25.5 ± 3.3 39.4 ± 73.4 0.1323 ALT, IU/mL 46.3 ± 33.5 40.8 ± 40.7 0.1747 AST, IU/mL 42.9 ± 25.5 36.5 ± 25.0 0.1153 Platelets, ×109/L 178.7 ± 77.3 206.5 ± 54.7 0.0941 APRI 0.932 ± 1.308 0.584 ± 0.829 0.0896 FIB-4 2.48 ± 3.14 1.95 ± 2.45 0.3627 HDV RNA positive, n (%) 19 (54.2) 0 (0) - HBV DNA positive, n (%) 10 (28.6) 17 (48.6) 0.0856 HBeAg, n (%) 2 (6.9) 4 (11.8) 0.5118 NA treatment, n (%) 21 (60) 15 (42.9) 0.1513 History anxiety or panic disorder, n (%) 13 (37.1) 9 (25.7) 0.3031 History depression or mood disorder, n (%) 2 (5.7) 2 (5.7) 1.0000 All continuous variables are described as median ± IQR, all categorical variables are described by number and percentage. The Chi-square test and Mann-Whitney U test were used for categorical and continuous parameters, respectively. Values of p < −0.05 were considered statistically significant. ALT, alanine aminotransferase; APRI, AST to platelet ratio index; AST, aspartate aminotransferase; FIB-4, fibrosis-4; NA, nucleos(t)ide analogues. JHEP Reports 2021 vol. 3 j 100280 3 Research article CHD 100 CHB mean PRO, on a 0-100 scale 90 80 70 60 50 40 om T-F ** m ity W ese ism l LD y s e : W ic ** * Ac ism ** y :A A e na be * * g g u t ro tal S o ell- g * l Q tem n in i ca nc a l w ing : E iv al y ity Q atig iv LD otio l w ei b d CI I: CLD orr e I: tee Fa ll-be t W rk p To in ct l w ein C To e s c tiv te na e l l - b A du LD : F en PA n o Q: Q lF na -b u :S LD : e C DQ tig Q PA bst io ell a LD t Q Pr ot l w L A ** p <0.05 C Fu c i C C I: Em ica I: tio C * p <0.10 W PA ys W PA Ph W Fig. 1. Patient-reported outcomes comparing patients with chronic hepatitis D and chronic hepatitis B from a baseline characteristic matched cohort. All parameters were normalised to a scale of 0–100 for a comprehensible comparison. The Student t test and Mann-Whitney U test were used for parametric and non-parametric categories, respectively. Values of p < −0.05 were considered statistically significant. CHB, chronic hepatitis B; CHD, chronic hepatitis D; CLDQ, Chronic Liver Disease Questionnaire; EWB, emotional well-being; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fatigue; FS, fatigue scale; FWB, functional well-being; PWB, physical well-being; SWB, social well-being; WPAI, Work Productivity Activity Impairment. The total FACIT-F score on a scale of 0–160 was 131.4 ±24.5 in significantly different between cases and controls (all p >0.05; patients with CHD and 128.1 ± 25.2 in patients with CHB Table 2). (p = 0.3285). A better functional well-being score was observed The mean CLDQ total score was 5.76 ± 1.06 in those patients in CHD than in CHB (p = 0.0281), with no other significant dif- with CHD and 6.27 ± 0.53 in controls with CHB (p = 0.07). Pa- ferences in other domains. The results of the WPAI questionnaire tients with CHD had a significantly worse worry score showed that patients with CHD had a higher activity impairment (p = 0.0021) and more abdominal symptoms (p = 0.0364) than score than patients with CHB (p = 0.0029). No other differences patients with CHB. There were no other differences in other were observed in other domains (Table S1). CLDQ domains. In multivariate analysis, a generalised linear regression model The total FACIT-F score on a scale of 0–160 was 129.4 ± 24.5 in showed that having CHD as opposed to having CHB, was an in- patients with CHD and 136.8 ± 14.2 in patients with CHB dependent predictor of a worse worry score (beta = -0.34, (p = 0.4416). Poorer physical well-being (p = 0.0036) and p = 0.0394) and high activity impairment (beta = +0.13, emotional well-being (p = 0.0541) was observed in CHD than in p = 0.0010). CHB, with no other significant differences in other domains. The Regarding educational levels in all patients, results showed results of the WPAI questionnaire showed that patients with that patients with secondary or higher education (N = 57) had CHD had a higher activity impairment score than patients with better HRQoL than those with none or primary educational level CHB (p = 0.0008). No other differences were observed in other (N = 67) in the abdominal, activity, emotional, fatigue, and sys- domains (Fig. 1 and Table S2). temic domains of the CLDQ, as well as in all domains of the FACIT-F. Patient-reported outcomes in relation to the presence of Regarding employment status, those with full time or part hepatitis D viraemia time jobs (N = 80) had significantly higher HRQoL scores than Within the CHD group (N = 43), PROs were analysed in relation those who were unemployed (N = 45) in the physical, social, and to the presence of hepatitis D viraemia. Twenty-six (60%) pa- fatigue domains of the CLDQ, as well as the abdominal, activity, tients had persistently detectable HDV-RNA (active infection) fatigue, systemic, and worry domains of FACIT-F. When studying and 17 (40%) patients had undetectable HDV-RNA. There were no the housewife (N = 18) vs. non-housewife (N = 107) population, differences in the overall scores for the 3 questionnaires relative data revealed better HRQoL in the housewife group (physical, to those with persistently undetectable HDV-RNA (all p >0.10). emotional, and fatigue domains of CLDQ, and abdominal, activity, PROs were also evaluated in relation to the HDV viraemia fatigue, systemic, and worry domains of FACIT-F). levels. Patients with high levels (> −2,000 IU/ml) of baseline HDV- Very similar reproducible results were observed when RNA (N = 19, 44%) proved to have higher activity impairment on studying the CHD group and CHB group separately. the WPAI questionnaire than those with low HDV-RNA levels (<2,000 IU/ml) (p = 0.024). Patient-reported outcomes in CHD- and CHB-matched patients Patient-reported outcomes in relation to liver cirrhosis Of all patients with CHD who were included, n = 35 had a No patients with CHB presented liver cirrhosis at baseline or at 1 matched control with CHB. In this analysis again the majority of year of follow-up. Patients with CHD with and without liver patients with CHD were male, Caucasian, and employed. Neither cirrhosis at baseline were compared. Results showed that pa- ALT, AST, and platelet levels nor APRI and FIB-4 scores were tients with CHD and liver cirrhosis (N = 14) had a worse CLDQ JHEP Reports 2021 vol. 3 j 100280 4 systemic score than those without liver cirrhosis (N = 29), patients with CHB, where suppression of viral replication has p = 0.0442. been associated with better PROs scores. Only among patients with HDV-RNA levels >2,000 IU/ml, a significant impairment of activity has been observed in relation with those with low or Discussion undetectable HDV-RNA levels. In our patients with CHD, HBV- This is, to our knowledge, the first study reporting HRQoL DNA levels were very low or suppressed because of the inhibit- through the evaluation of CLDQ, FACIT-F, and WPAI question- ing effect of HDV over HBV and/or NAs treatment, as has been naires in patients with CHD. Overall, the study shows that pa- previously reported in several studies.23 In CHC patients, an tients with CHD have higher HRQoL impairments than patients improvement has been described in HRQoL after DAA treatment with CHB, especially in the worry, emotional, physical, and ac- and subsequent elimination of hepatitis C.45,46 The lack of an tivity impairment domains. effective and safe curative treatment for either CHD or CHB could Accurate HRQoL assessment can provide valuable information also contribute to the absence of differences between the 2 for clinical practice and designing public health policies.36,37 groups. PROs evaluated using CLDQ, FACIT-F, and WPAI tools have been Significant differences between educational level, employ- widely validated for CHC and CHB. However, there are no data for ment status, and housewife population results are in line with CHD. It is well known that the individual and subjective nature of those observed in other general population studies47–49 and even a patient’s perception, together with social and cultural in- in chronic disease populations.50 No associations were observed fluences, make HRQoL difficult to measure.38–40 in CHD or CHB groups separately. The CLDQ has been designed as a liver-disease-specific Our study has some limitations. First, the number of patients questionnaire, that is reliable, reproducible, easy to use, and with CHD included is small owing to the limitations in the in- has been well-validated in patients with CHC or CHB16,41 and is clusion criteria, no comorbidities, no previous therapy with anchored by a 2-week recall period. interferon, and compensated liver disease. Second, all patients Fatigue is a common symptom in chronic liver disease, and were enrolled in an academic centre with an active liver trans- various questionnaires can be used to evaluate it. FACIT-F has plant program that probably had patients with more severe been widely used in hepatitis C patients and it is easy to hepatitis D than those observed in other centres. perform.30 In studies comparing PROs related to fatigue in pa- New therapies for hepatitis D infection are emerging, such tients with CHB or CHC and in the general population, poorer as lonafarnib, REP2139, other drugs used for hepatitis B, scores were found in patients with chronic viral disease, with no and combinations of drugs with different mechanisms of ac- differences between the 2 conditions.42 In our study, there was a tion.51 These drugs have the potential effect to eliminate tendency for patients with CHD to have a poorer well-being hepatitis D with different safety profiles. Therefore, it will be score, which has also been shown in studies with CHB. fundamental to monitor PROs during the course of these new Overall, PRO scores are reported to be poorer in patients with therapies. CHC than with CHB, which could be explained by a weaker In conclusion, PROs estimating HRQoL in patients with CHD systemic and differentiated inflammatory impact of HBV infec- showed to be more impaired than those observed in CHB. tion.43,44 Similarities in the systemic effects of HDV and HBV HDV viraemia does not seem to impact on PROs unless the chronic infection could justify the smaller differences in HRQoL levels of HDV-RNA are high. This first results in HRQoL in found here. patients with CHD need to be validated in a larger cohort of An intriguing finding of our study is that the presence of patients. hepatitis D viraemia did not impact in PROs as has been seen in Abbreviations Please refer to the accompanying ICMJE disclosure forms for further ALT, alanine aminotransferase; APRI, AST to platelet ratio index; details. AST, aspartate aminotransferase; CHB, chronic hepatitis B; CHC, chronic hepatitis C; CHD, chronic hepatitis D; CLDQ, Chronic Liver Disease Authors’ contributions Questionnaire; DAA, direct-acting antivirals; EMA, European medicines Guarantor of the article and responsibility for the integrity of the work as agency; FACIT-F, Functional Assessment of Chronic Illness Therapy–Fa- a whole, from inception to published article: MB. Designed the study: MB, tigue; FIB-4, Fibrosis-4; HRQoL, health-related quality of life; IFN, inter- FN, ZY. Collected the clinical and laboratory data: LR, AP. Carried out the feron; LLOD, lower limit of detection; LLOQ, lower limit of quantification; analysis and interpretation of data: MS, MRB. Drafted the manuscript: LR, NAs, nucleos(t)ide analogues; pegIFN, pegylated interferon; PROs, pa- AP. Reviewed the manuscript: MB, MRB, ZY, FN. Approved the final tient-reported outcomes; WPAI, Work Productivity and Activity version of the article: all authors Impairment. Data availability statement Financial support The data that support the findings of this study are available from the This study received support in part from the Instituto de Salud Carlos III corresponding author upon request. (PI17/02233). Supplementary data Conflicts of interest Supplementary data to this article can be found online at https://doi.org/1 MB and RE have served as a speaker and advisory board member for 0.1016/j.jhepr.2021.100280. Gilead, Roche, and Arbutus. MRB has served as a speaker for AbbVie and Gilead. ZY has received research funds from Intercept, Merck, BMS, and References Siemens, and has served as consultant for Gilead, Terns, Viking, Intercept, [1] Younossi ZM, Stepanova M, Younossi I, Pan CQ, Janssen HLA, Merck, Abbvie, Novartis, BMS, Shionogi, and Siemens. Papatheodoridis G, et al. 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