Chronic hepatitis D (CHD) is a severe form of chronic viral hepatitis. The estimated hepatitis delta prevalence in Spain is around 5% of patients with hepatitis B. Reimbursement of new antiviral therapies (Bulevirtide, BLV) was delayed in our country until February 2024. We aimed to characterize the clinical profile of patients with HDV/HBV infection in Spain and current barriers in their management at the time of BLV approval.
MethodMulticenter registry including patients with positive anti-HDV serology actively monitored in 30 Spanish centers. Epidemiological, clinical and virological variables were recorded at the start of follow-up and at the last visit.
ResultsWe identified 329 anti-HDV patients, 41% were female with median age 51 years. The most common geographical origin was Spain (53%) and East Europe (24%). Patients from Spain were older and had HCV and HIV coinfection probably associated to past drug injection (p<0.01). HDV-RNA was positive in 138 of 221 assessed (62%). Liver cirrhosis was present at diagnosis in 33% and it was more frequent among viremic patients (58% vs 25%, p<0.01). After a median follow-up of 6 (3–12) years, 44 (16%) resolved infection (18 spontaneously and 26 after Peg-INF). An additional 10% of patients developed cirrhosis (n=137) during follow-up (45% had portal hypertension and 14% liver decompensation). Liver disease progression was associated to persisting viremia.
ConclusionOne-third of the patients with CHD already have cirrhosis at diagnosis. Persistence of positive viremia is associated to rapid liver disease progression. Importantly, barriers to locally determine/quantify HDV-RNA were present.
La hepatitis crónicaD (HCD) es una forma grave de hepatitis viral. Aproximadamente el 5% de los pacientes con hepatitis B en España presentan HCD. La aprobación de bulevirtida (BLV), un antiviral contra el VHD, se retrasó en nuestro país hasta febrero de 2024. Nuestro objetivo fue caracterizar el perfil clínico de los pacientes con infección por HCD en España, así como las barreras existentes en su manejo.
MétodoRegistro multicéntrico que incluye pacientes con serología anti-VHD positiva en seguimiento activo en 30 centros españoles. Se registraron variables epidemiológicas, clínicas y virológicas al inicio del seguimiento y en la última visita.
ResultadosSe identificaron 329 pacientes anti-VHD, el 41% eran mujeres con una mediana de edad de 51años. El origen geográfico más común fue España (53%) y Europa del Este (24%). Los pacientes españoles eran de mayor edad y presentaban coinfección por VHC y VIH, probablemente asociada a consumo de drogas inyectadas (p<0,01). El ARN-VHD fue positivo en 138 de 221 evaluados (62%). Al momento del diagnóstico, el 33% ya tenían cirrosis hepática, y esto fue más frecuente entre los pacientes virémicos (58% vs 25%, p<0,01). Tras una mediana de seguimiento de 6 (3-12) años, 44 (16%) resolvieron la infección (18 de forma espontánea y 26 después de Peg-INF). Un 10% adicional desarrolló cirrosis (n=137) durante el seguimiento (el 45% tenían hipertensión portal y el 14%, descompensación hepática). La progresión de la enfermedad hepática se asoció con la persistencia de la viremia.
ConclusiónUn tercio de los pacientes con HCD ya tienen cirrosis en el momento del diagnóstico. La persistencia de una viremia positiva se asocia con una rápida progresión de la enfermedad hepática. Se detectaron barreras para determinar/cuantificar localmente el ARN-VHD.
Hepatitis D, caused by the Hepatitis D virus (HDV) previously named Hepatitis Delta, is a coinfection that occurs in individuals previously infected with the hepatitis B virus (HBV). This disease poses a significant global health challenge, as it can result in more severe liver disease and an accelerated progression toward cirrhosis and liver cancer. Coinfection with HDV has important clinical implications. Patients with HDV have a higher likelihood of developing chronic liver disease, liver cirrhosis, and hepatocellular carcinoma compared to those monoinfected with HBV.1 The high rate of liver disease progression in Hepatitis Delta is a cause for concern as it entails a greater disease burden and an increased risk of serious complications. Therefore, improving our understanding of the epidemiology, diagnosis, treatment, and natural history of Hepatitis Delta is crucial.
In terms of epidemiology, Hepatitis D is considered endemic in certain regions of the world, particularly in areas with high prevalence of hepatitis B such as Eastern Europe, Sub-Saharan Africa, and parts of Asia. It is estimated that globally, around 15–20 million people are infected with HDV.2,3 The knowledge of hepatitis D prevalence in Spain is primarily based on several studies conducted in different populations. The estimated prevalence of HDV infection among HBsAg+ population is Spain is between 2 and 5%.2,4–7 However, it is important to acknowledge that the existing studies have certain limitations. Firstly, the sample sizes in some of these studies were relatively small, which may not fully capture the true prevalence of hepatitis D in the entire HBsAg+ population. Furthermore, the diagnostic techniques used in these studies varied, with some relying on serological testing and others on viral load assessment. The lack of universal “reflex” polymerase chain reaction (PCR) testing for HDV-RNA contributes to the underestimation of the global viremic HDV prevalence. These differences in diagnostic approaches may introduce variability in the reported prevalence rates.
Until recently, the only recommended treatment option for chronic HDV had been pegylated interferon alpha (PEG-IFN) that has limited long-term efficacy and is frequently associated with unfavorable side effects.8 Bulevirtide (BLV), a pharmacologic blocker of the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), which allows entry of HDV and HBV into hepatocytes, has been reimboursed by the Spanish Medicament Agency for the treatment of patients with chronic HDV and compensated liver disease in February 2024.9 Other pharmacological agents are currently under investigation.1 To estimate the needs of novel antiviral therapies we aimed at updating epidemiological data of patients with HDV infection and active follow-up by a multicenter registry involving 30 Hospitals in Spain.
MethodsRetrospective data from anti-HDV positive patients with active follow-up between 2021 and 2023 were collected within a national registry within the Spanish Association for the Study of the Liver (AEEH) in a RedCap database. Patients with history of liver transplantation were excluded. All patients had at least 1 year of follow-up. Data on epidemiological characteristics (age, sex, country of origin, transmission risk factors, other viral coinfections) were collected. HBV status (HBsAg, HBeAg, HBV-DNA) as well as antiviral therapies for HDV and HBV were also recorded. In addition, a small questionnaire regarding availability of HDV-RNA diagnosis testing was collected. Data on the rate of conducted HDV-RNA-PCR tests within seropositive patients was investigated. The number of patients that had never been tested for HDV-RNA or of those who showed undetectable test results (e.g., results below the lower limit of quantification (LLQ) of the used HDV-RNA-PCR tests) were recorded. Liver disease status characteristics were assessed at diagnosis and last follow-up. Hepatocellular carcinoma (HCC) was diagnosed as established by current clinical guidelines.10 Portal hypertension (PH) was defined by hepatic venous pressure gradient [HVPG]≥6mmHg, varices observed during upper gastrointestinal endoscopy or hepatic decompensation (ascites, hepatic encephalopathy). Liver cirrhosis (LC) was defined by a liver stiffness≥15kPa detected by vibration controlled transient elastography (TE-LSM), histological F4-fibrosis, or presence of portal hypertension (PH). Patient records were anonymized. This study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of the Hospital Clínic of Barcelona (EC Vote No. 2022-0960).
Continuous variables are reported as median and interquartile range (IQR) and categorical variables are reported as absolute and relative frequencies. Groups were compared using the Mann–Whitney U test for continuous variables when appropriate and the Fisher exact test for categorical variables. Statistical significance was established as a two-sided p value of .05. The analysis was performed with Stata/IC 14.2 for Mac (StataCorp, Texas).
ResultsPatients baseline characteristicsOverall, 329 anti-HDV positive patients were included in the registry by the participating centers within the study period. The main characteristics of the cohort are depicted in Table 1. Briefly, 41% were female, with median age 51 (IQR: 42–56) years. A small proportion of patients (5%) were >65 years old. The most common geographical origin was Spain (53%) and East Europe (24%). We compared HDV infection characteristics between patients from Spain and migrants. We observed that autochthonous patients were older (45 vs 37 years; respectively), reported previous drug use and, thus, had more frequently HCV and HIV coinfection (p<0.01) (Table 2).
Baseline patients’ characteristics of the overall cohort at first visit.
| Variables | All |
|---|---|
| n=329 | |
| Sex (female), n (%) | 135 (41) |
| Age (years), median (IQR) | 51 (42–56) |
| Age (years) categories, n (%) | |
| <18 | 2 (0.6) |
| 18–29 | 19 (5.8) |
| 30–39 | 49 (15) |
| 40–49 | 78 (24) |
| 50–59 | 133 (41) |
| 60–69 | 41 (12) |
| 70–79 | 6 (1.8) |
| Origin, n (%) | |
| Spain | 173 (53) |
| East Europe | 79 (24) |
| Africa | 48 (15) |
| Others | 27 (8) |
| PWID, n (%) | 48 (15) |
| HCV coinfection, n (%) | 58 (18) |
| HIV coinfection, n (%) | 30 (9) |
| Virological markers | |
| HDV-RNA positivea, n (%) | 138 (62) |
| HBeAg positive, n (%) | 54 (16) |
| HBV-DNA positive, n (%) | 216 (70) |
| Antiviral treatment | |
| Interferon experienced, n (%) | 94 (29) |
| Nucleos(t)ide analogsb, n (%) | 191 (66) |
| Liver disease | |
| TE-LSM (kPa)c, median (IQR) | 9.2 (6.1–14.3) |
| Cirrhosis, n (%) | 108 (33) |
| Portal hypertension, n (% of cirrhosis) | 44 (41) |
| Liver decompensation, n (% of cirrhosis) | 15 (14) |
| Hepatocellular carcinoma, n (%) | 4 (1.2) |
IQR: interquartile range, PWID: people who inject drugs, HCV: hepatitis C virus, HIV: human immunodeficiency virus, HDV: hepatitis D virus, HBeAg: hepatitis B e antigen, HBV: hepatitis B virus, TE-LSM: transient elastography liver stiffness measurement, kPa: kilopascal.
Differences between Spanish-born and foreign-born patients.
| Variables | Spainn=173 (53%) | Abroadn=154 (47%) | p-Value¶ |
|---|---|---|---|
| Sex (male), n (%) | 103 (60) | 90 (58) | 0.91 |
| Age (years), median (IQR) | 45 (35–51) | 37 (28–44) | 0.001 |
| PWID, n (%) | 38 (22) | 10 (6) | <0.001 |
| HCV coinfection, n (%) | 48 (28) | 10 (6) | <0.001 |
| HIV coinfection, n (%) | 25 (15) | 4 (3) | <0.001 |
| HDV-RNA positivea, n (%) | 71 (65) | 67 (59) | 0.4 |
| TE-LSM (kPa)b, median (IQR) | 10.2 (5.9–16.1) | 8.8 (6.2–16.3) | – |
| Liver disease at first visit | |||
| Cirrhosis, n (%) | 58 (34) | 49 (32) | – |
| Portal hypertension, n (% of cirrhosis) | 23 (40) | 21 (42) | – |
| Follow-up time (years), median (IQR) | 8.4 (5–20) | 4.1 (1.9–7.7) | <0.001 |
IQR: interquartile range, PWID: people who inject drugs, HCV: hepatitis C virus, HIV: human immunodeficiency virus, HDV: hepatitis D virus, TE-LSM: transient elastography liver stiffness measurement, kPa: kilopascal.
To understand the characteristics of centers regarding access to HDV-RNA testing, a survey was conducted at the initiation of data collection (2022) among the participating centers in the study. HDV-RNA determination was available in 60% of centers (locally in 40% whereas the remaining 20% needed to ship the sample to an external laboratory). HDV-RNA quantification was available only in 2 centers (16%) by in house technique. Of those with HDV viremia assessment (221, 67% of the cohort), HDV-RNA was positive in 138 (62%).
When evaluating liver disease in the overall cohort, we observed that 108 (33%) patients at diagnosis accomplished liver cirrhosis criteria. The prevalence of portal hypertension was 13% in the overall cohort and 41% of those with cirrhosis, including 15 who had already decompensation at first visit. Regarding HCC, only 4 patients (1.2% of the overall cohort) were diagnosed with HCC at first visit. The presence of liver cirrhosis was similar regardless origin but portal hypertension was more frequent among Spanish-born individuals (Table 2). Nevertheless, patients with active infection at first visit presented more advanced liver disease with higher TE-LSM values (10.4 vs 6.9kPa) and higher prevalence of cirrhosis and portal hypertension (43% vs 22% and 18% vs 7%; respectively) (all p<0.05) (Suppl Table 1).
Liver-related outcomes during follow-upAfter a median follow-up of 6 (3-12) years liver disease progressed in a significant proportion of patients. The number of patients with cirrhosis increased from 108 to 137 (41.6%, representing a >10% increase from baseline). Of these, 62 had portal hypertension (PH) (45%, 5% increase from baseline). During follow-up, 5 additional patients developed liver decompensation and 7 patients were diagnosed of HCC (all patients with cirrhosis) (Fig. 1A). The presence of cirrhosis and PH was significantly more frequent among HDV-RNA-detectable than in HDV-RNA undetectable patients at the end of follow-up (45% and 17%, p<0.01; 25% and 10% p<0.01; respectively) (Fig. 1B). When analysing the differences between patients with or without cirrhosis at last follow-up, we observed that patients developing cirrhosis were more frequently from Spain (probably influenced by age and the presence of HCV/HIV coinfection), were HDV-RNA positive at first or last visit and had higher TE-LSM values at first evaluation (Table 3). As expected, median TE-LSM values at last follow-up were significantly higher among patients with cirrhosis (15.1 vs 6.4kPa, p<0.05). When performing a multivariate analysis of the baseline variables associated to the risk of developing cirrhosis at follow-up (excluding those with cirrhosis at first visit, n=310) only TE-LSM at diagnosis remained as an independent predictor of cirrhosis development (OR 1.30 [1.25–1.54] p<0.01) and, if excluding TE-LSM, only HDV-RNA positivity remained the main baseline factor associated to cirrhosis development in last follow-up (OR 1.70 [1.02–1.40] p<0.05).
Liver disease progression throughout follow-up. (A) Differences in number of patients with cirrhosis, portal hypertension (PH), liver decompensation (LD) and hepatocellular carcinoma (HCC) at first and last follow-up. (B) Differences in proportion of patients with cirrhosis and portal hypertension at first and last follow-up according to HDV-RNA status (detectable or undetectable). HDV: hepatitis D virus; FU: follow-up.
Comparison between patients with and without cirrhosis at baseline and at last follow-up.a
| Variables | No cirrhosisn=185 (57%) | Cirrhosisn=137 (43%) | p-Value¥ |
|---|---|---|---|
| Sex (female), n (%) | 85 (45) | 48 (35) | 0.053 |
| Age (years), median (IQR) | 51 (39–56) | 52 (43–57) | 0.2 |
| Origin, n (%) | |||
| Spain | 86 (47) | 83 (61) | 0.01 |
| East Europe | 41 (22) | 36 (26) | |
| Africa | 37 (20) | 11 (8) | |
| Others | 21 (11) | 6 (5) | |
| PWID, n (%) | 19 (10) | 26 (20) | 0.049 |
| HCV coinfection, n (%) | 24 (13) | 32 (23) | 0.017 |
| HIV coinfection, n (%) | 11 (6) | 18 (14) | 0.03 |
| Follow-up (years), median (IQR) | 6.7 (3–11) | 6.6 (3–14) | 0.08 |
| Virological markers at first visit | |||
| HDV-RNA positive*, n (%) | 65 (51) | 72 (78) | <0.001 |
| HBeAg positive, n (%) | 33 (18) | 21 (15) | 0.76 |
| HBV-DNA positive, n (%) | 130 (70) | 83 (60) | 0.07 |
| Virological markers at last follow-up | |||
| HDV-RNA positive¥, n (%) | 51 (37) | 67 (63) | <0.001 |
| HBeAg positive, n (%) | 20 (11) | 12 (9) | 0.43 |
| HBV-DNA positive, n (%) | 89 (48) | 43 (32) | 0.002 |
| Antiviral treatment at last follow-up | |||
| Interferon experienced, n (%) | 49 (26) | 44 (32) | 0.32 |
| Nucleos(t)ide analogs, n (%) | 83 (45) | 105 (77) | <0.001 |
| TE-LSM (kPa) | |||
| At first visit**, median (IQR) | 6.7 (5–8.8) | 15.7 (11–21) | <0.001 |
| At last follow-up**, median (IQR) | 6.4 (5.2–8.3) | 15.1 (10.4–21.5) | <0.05 |
IQR: interquartile range, PWID: people who inject drugs, HCV: hepatitis C virus, HIV: human immunodeficiency virus, HDV: hepatitis D virus, HBeAg: hepatitis B e antigen, HBV: hepatitis B virus, TE-LSM: transient elastography liver stiffness measurement, kPa: kilopascal.
At baseline, 138 of 221 (62%) patients had detectable viremia (a positive HDV-RNA PCR test result). During follow-up, HDV-RNA was assessed in a total of 278 (84%) patients. Forty-four (15%) achieved HDV RNA undetectability (18 spontaneously and 26 after Peg-INF treatment). When stratifying patients into three groups according to HDV RNA evolution during follow-up (always negative, always positive, HDV-RNA clearance), we observed that liver disease progressed more in patients persisting with positive viremia (Table 4). Indeed, at last follow-up 55% of viremic patients had diagnosis of cirrhosis whereas the latter was detected only in 27% of patients with negative viremia and in 39% of patients who cleared the infection (p<0.001). A similar difference was observed regarding portal hypertension and liver decompensation. Although the number of HCC events was low, there was a trend toward lower incidence of HCC among patients with persistent undetectable viremia.
Differences between patients according to viremic evolution during follow-up (always negative, always positive, clearance).a
| Variables | HDV-RNA negativen=101 (36%) | HDV-RNA positiven=133 (48%) | HDV-RNA clearancen=44 (16%) | p-Value¥ |
|---|---|---|---|---|
| Sex (female), n (%) | 42 (42) | 62 (47) | 13 (30) | 0.12 |
| Age (years), median (IQR) | 52 (43–56) | 51 (41–56) | 50 (40–57) | 0.17 |
| Origin (Spain), n (%) | 54 (54) | 67 (51) | 24 (55) | 0.90 |
| PWID, n (%) | 10 (10) | 19 (15) | 7 (17) | 0.67 |
| HCV coinfection, n (%) | 16 (16) | 18 (14) | 9 (21) | 0.51 |
| HIV coinfection, n (%) | 8 (8) | 10 (8) | 5 (12) | 0.73 |
| Interferon experienced, n (%) | 12 (12) | 49 (37) | 26 (59) | <0.001 |
| Follow-up (years), median (IQR) | 6 (2–11) | 6 (2.5–9) | 8 (5–14) | 0.01 |
| Liver disease at first visit | ||||
| TE-LSM (kPa)b, median (IQR) | 6.7 (5.2–10.5) | 10.4 (7.6–16.6) | 8.8 (5.9–16.3) | <0.001 |
| Cirrhosis, n (%) | 25 (25) | 58 (43) | 12 (27) | 0.007 |
| Portal hypertension, n (% of cirrhosis) | 10 (40) | 22 (38) | 6 (50) | 0.35 |
| Liver decompensation, n (% of cirrhosis) | 3 (12) | 8 (14) | 2 (17) | 0.03 |
| Hepatocellular carcinoma, n (%) | 1 (1) | 2 (1.5) | 0 (0) | 0.34 |
| Liver disease at last visit | ||||
| TE-LSM (kPa)c, median (IQR) | 6.9 (5.3–10.1) | 9.1 (6.7–16.5) | 6.8 (5.3–14.8) | 0.013 |
| Cirrhosis, n (%) | 27 (27) | 72 (55) | 17 (39) | <0.001 |
| Portal hypertension, n (% of cirrhosis) | 11 (41) | 38 (53) | 5 (29) | 0.001 |
| Liver decompensation, n (% of cirrhosis) | 1 (4) | 14 (19) | 3 (17) | 0.033 |
| Hepatocellular carcinoma, n (%) | 1 (1) | 5 (4) | 2 (5) | 0.34 |
HDV: hepatitis D virus, IQR: interquartile range, PWID: people who inject drugs, HCV: hepatitis C virus, HIV: human immunodeficiency virus, TE-LSM: transient elastography liver stiffness measurement, kPa: kilopascal.
Gender differences in incidence, presentation, natural history, and outcomes exist for common liver diseases. However, there is limited information on the effect of gender on the natural history of chronic Hepatitis Delta. Overall, the available data suggest that there may not be significant gender differences in the prevalence and outcomes of hepatitis delta infection among patients. In our study, age at diagnosis was similar between men and women but men were more frequently former PWID and had HCV (but not HIV) coinfection suggesting different transmission routes in both groups (Suppl Table 2). Importantly, the proportion of active infection at diagnosis was similar in both groups. Accordingly, the presence of advanced liver disease (cirrhosis, portal hypertension and liver decompensation) was comparable between both sexes. At last visit, although the proportion of liver cirrhosis was slightly higher among men (45% vs 35%, p=0.05), the prevalence of portal hypertension and liver decompensation was comparable between groups, confirming that female sex is not a significant protective factor against HDV-associated rapidly progressing course of the disease (Fig. 2). On the other hand, most HCC cases were detected in men highlighting the potential protective role of hormones in hepatocarcinogenesis and the probable influence of other co-factors such as alcohol and tobacco (unavailable information in this registry).
Discussion
This study provides significant data on the characteristics of patients with HDV infection and active follow-up in Spain. The information derived from this study is relevant as the first antiviral against HDV has been recently approved in our country. Our data highlight the remarkable late diagnosis in the HDV population as up to one-third of the patients already have advanced liver disease when evaluated at the first assessment in specialized care. The frequency of late diagnosis in HDV is higher than that for HCV and HBV in Spain (23%).11 One of the reasons for this finding may be the barriers encountered in HDV diagnosis. Both the EASL and Spanish guidelines recommend HDV screening in all HBsAg+ patients12,13; however, it is estimated that screening rate is suboptimal.14 For those with anti-HDV positivity, HDV-RNA must be assessed to evaluate the presence of active viremia. The most effective method to generate estimates of the prevalence of HDV at the national level and to find undiagnosed individuals is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and, ideally, HDV-RNA testing of all anti-HDV-positive individuals.15 Only one of the centers in Spain had implemented HDV reflex testing at the time of the survey. In this center, implementation of HDV reflex testing led to a 5-fold increase in the number of HBV cases diagnosed with hepatitis D in their study.14 In addition, our survey in 2022 pointed out that HDV-RNA qualitative assay was not available in 40% of the centers and the test was externalized in 20%. The latter highlights the barriers in HDV diagnosis and management in many centers in Spain.
In addition, our data support the crucial role of viremia for prognosis in chronic HDV. In our cohort, 62% of patients were viremic at the time of first visit and, during a 6-year follow-up period, 44 patients (31%) achieved HDV-RNA undetectability. Of them, 26 had received Interferon therapy and 18 cleared HDV-RNA spontaneously. The latter is in accordance with previously reported data.16
We observed significant differences in terms of liver disease progression throughout the whole study period between viremic patients and those that had resolved the infection whereas patients achieving HDV-RNA clearance had an intermediate outcome reinforcing the need of prompt effective antiviral therapy to achieve HDV-RNA negativization.
Our data also shows that, contrarily to other European countries,17 autochthonous cases still represent a significant burden of HDV-related liver disease. Spanish patients were usually older and had higher HCV and HIV coinfection suggesting that parenteral drug use was the main transmission mode in this population. Nevertheless, despite younger age, foreign-born patients had a similar prevalence of advanced liver disease at diagnosis. Previous studies in Spain observed a decreasing prevalence of hepatitis delta in PWID patients and, concomitantly, an increased prevalence of HDV infection among immigrant population.2,4–7 The decline in HDV circulation among active PWID in Spain may reflect the effect of universal HBV vaccination and needle exchange programs. Whereas migratory flows from endemic areas plus underdiagnosis due to limited access to conventional health circuits may advocate for a change in the epidemiological HDV pattern in our country in the mid-term remains to be determined.
Another interesting finding from our study is the comparison from a gender-based perspective. Liver diseases usually affect more men than women and in the setting of viral hepatitis, but previous reports have suggested that female sex is associated to a slower progression of liver disease.18 However, data is scarce in the setting of HDV infection. The findings of our study suggest that there are no significant gender differences in the population with HDV co-infection. The proportion of positive viremia was similar between both sexes and, despite males presenting more factors associated to liver fibrosis progression (HCV and HIV coinfection), the prevalence of advanced liver disease at diagnosis was similar. In addition, liver disease progressed equally in both groups, especially when analysing the presence of portal hypertension or liver decompensation. In contrast, as in other liver disease-related ethiologies, most HCC cases were diagnosed among men.
Due to the retrospective nature of our study, we also acknowledge several limitations in our study. First, HDV-RNA status was unknown in 38% of patients. Also, we cannot discard test-dependent bias in viremia diagnosis due to the use of in-house techniques with heterogenous lower limit of detection. Second, although the study includes a significant number of centers, a high number of patients were included in specialized referral or transplant centers, which might have led to an overestimation of disease severity. Finally, qualitative HDV RNA data, HDV genotype and other co-variables (alcohol use) were not available, thus we could not evaluate the influence of these variables in liver disease progression.
In summary, our study emphasizes the burden and severity of HDV infection, if untreated. An improvement in screening and diagnostic tools (reflex testing and high sensitivity HDV-RNA assays) is key and need to be optimized in our country.
Authors’ contributionAll authors contributed to data acquisition. SRT, SL and XF performed data analysis and drafted the content of the manuscript. All authors reviewed the manuscript and approved its final content.
Informed consentWe have followed our facility’s protocols on the publication of patient data.
FundingGilead Sciences contributed to the development of the project by financing the registry platform set up but did not participate in data collection or analysis.
Conflict of interestSL and XF: Advisory Gilead. SL: grants from Gilead. MB: Advisory Abbvie, Gilead, Roche, GSK, Altimmune and Janssen. MR: Advisory and speaker fees from Gilead. MM: speaker for Gilead and MSD. IF: speaker and consultant for Janssen, Abbvie, MSD and Gilead. The remaining authors do not report COI.
The followings are the supplementary data to this article:
