Validation of Baveno VII criteria and other non-invasive diagnostic algorithms for clinically significant portal hypertension in hepatitis delta.

BACKGROUND AND AIMS: Non-invasive tests (NIT) for clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD) lack validation in patients infected with hepatitis D virus (HDV). METHODS: HDV-cACLD patients (LSM ≥10 kPa or histological METAVIR F3/F4 fibrosis) who underwent paired HVPG and NIT assessment at Medical University of Vienna or Hannover Medical School between 2013 and 2023 were retrospectively included. Liver stiffness measurement (LSM), von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) were assessed. Individual CSPH risk was calculated according to previously published models (ANTICIPATE, 3P/5P). The diagnostic performance of Baveno-VII criteria and refined algorithms (Baveno-VII-VITRO, Baveno-VII-SSM) was evaluated. The prognostic utility of NIT was investigated in the main and an independent, multicenter validation cohort. RESULTS: Fifty-one patients (HVPG ≥10 mmHg/CSPH prevalence: 62.7%, varices: 42.2%) were included. LSM (25.8 [17.2-31.0] vs. 14.0 [10.5-19.8] kPa; p<0.001), VITRO (n=31, 3.5 [2.7-4.5] vs. 1.3 [0.6-2.0] %/[G/L]; p<0.001), and SSM (n=20, 53.8 [41.7-75.5] vs. 24.0 [17.0-33.9] kPa; p<0.001) were significantly higher in CSPH patients. Composite CSPH risk models yielded excellent AUROC (ANTICIPATE: 0.885, 3P: 0.903, 5P: 0.912). Baveno-VII criteria ruled out CSPH with 100% sensitivity and ruled in CSPH with 84.2% specificity. The Baveno-VII 'grey zone' (41.1%) was significantly reduced by Baveno-VII-VITRO or Baveno-VII-SSM, while maintaining diagnostic accuracy. Hepatic decompensation within two years occurred only in patients who had CSPH or met Baveno-VII rule-in criteria. The prognostic value of NIT was confirmed in the validation cohort comprising 92 patients. CONCLUSIONS: Standalone and composite NIT/ diagnostic algorithms are useful for CSPH diagnosis in HDV-cACLD patients. Thus, NIT may be applied to identify and prioritize patients with CSPH for novel antiviral treatments against CHD. IMPACT AND IMPLICATIONS: Non-invasive tests (NIT) for clinically significant portal hypertension (CSPH) have been developed to identify compensated advanced chronic liver disease (cACLD) patients at risk for decompensation, but conflicting data has been published regarding the accuracy of liver stiffness measurement (LSM) for the staging of fibrosis in patients infected with hepatitis D virus (HDV). In our study including 51 HDV-cACLD patients, NIT, i.e., most importantly, the ANTICIPATE model based on LSM and platelet count, but also lab-based approaches, i.e., 3P/5P model and the von Willebrand factor to platelet count ratio (VITRO), and spleen stiffness measurement (SSM) yielded high AUROC for CSPH. Moreover, only patients with CSPH or high non-invasively assessed CSPH-risk were at risk for decompensation within two years, and the prognostic value of NIT was confirmed in a validation cohort. Thus, NIT should be applied and updated in yearly intervals in clinical routine to identify HDV-cACLD patients at short-term risk and may guide prioritization for novel antiviral treatment options.

Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.

Liver stiffness measurement as a noninvasive method for the diagnosis of liver cirrhosis in patients with chronic hepatitis D virus infection.

BACKGROUND: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited. AIMS: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients. METHODS: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies. RESULTS: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB-4], and 0.69 [AAR]). The optimal cut-off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut-off for diagnosing non-advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients. CONCLUSIONS: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut-offs of <10.2 and < 15.2 kPa reliably diagnose non-advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients.

Clinical long-term outcome of hepatitis D compared to hepatitis B monoinfection.

BACKGROUND AND AIMS: Hepatitis D virus (HDV) infection causes the most severe form of chronic viral hepatitis. However, it is still unclear to what extent the underlying cirrhosis may contribute to disease progression. The aim of this study was to compare the long-term outcome of HDV infection with HBV monoinfection in a single-center cohort of both non-cirrhotic and cirrhotic patients. METHOD: We retrospectively studied 175 patients with chronic hepatitis D (CHD) who were followed for at least 6 months (median of 6.3 (0.6-23.6) years). In addition, we selected 175 patients with HBV monoinfection (CHB) who were matched for gender, age, region of origin, HBeAg status, and bilirubin. Liver-related clinical end points were defined as hepatic decompensation (ascites, encephalopathy, variceal bleeding), liver transplantation, HCC, or liver-related death. RESULTS: Clinical complications developed earlier (4.6 vs. 6.2 years) and more frequently (35.4% vs. 12.6%, p < 0.01) in CHD patients. In a multivariate Cox regression, HDV infection was independently associated with the development of end points (p < 0.01; HR: 3.0; 95% CI 1.4-6.4). However, in cirrhotic patients there were no significant differences between HBV and HDV in the development of end points. Besides, CHB patients with cirrhosis developed more frequently HCC (35.5%) than CHD patients with cirrhosis (18.5%). CONCLUSION: Our results confirmed that HDV leads to a faster progression to cirrhosis compared to HBV. However, once cirrhosis is present, not HDV but the underlying cirrhosis is the dominate intrinsic risk factor for the development of liver-related end points and for the progression to HCC.

Quality-of-life scores improve after 96 weeks of PEG-IFNa-2a treatment of hepatitis D: An analysis of the HIDIT-II trial.

BACKGROUND & AIMS: Infection with the hepatitis D virus (HDV) causes the most severe form of viral hepatitis with a high risk to develop clinical complications of liver disease. In addition, hepatitis delta has been shown to be associated with worse patient-reported outcomes. Until recently, only pegylated interferon alfa could be used to treat hepatitis delta. METHODS: Here, we investigated quality of life (QOL) as assessed by the Short Form 36 Health Survey (SF-36) in patients undergoing antiviral therapy with pegylated interferon alfa (PEG-IFNa-2a)-based treatment in the HIDIT-II trial. HIDIT-II was a randomized prospective trial exploring PEG-IFNa-2a with tenofovir disoproxil (TDF) or placebo for 96 weeks in patients with compensated hepatitis delta. Surveys completed by 83 study participants before, during, and after treatments were available. RESULTS: Overall, we observed a reduced QOL of HDV patients compared with a reference population, both in physical as well as mental scores. Interestingly, PEG-IFNa-2a treatment showed only minor impairment of the QOL during therapy. Moreover, HDV-RNA clearance was not associated with relevant changes in physical or social SF-36 scores, whereas an improvement of fibrosis during treatment was associated with increased QOL. Overall, slight improvements of the QOL scores were observed 24 weeks after the end of treatment as compared with baseline. TDF co-treatment had no influence on QOL. CONCLUSIONS: Overall, our findings suggest that PEG-IFNa-2a was reasonably tolerated even over a period of 96 weeks by hepatitis D patients reporting SF-36 questionnaires. Of note, several patients may benefit from PEG-IFNa-2a-based therapies with off-treatment improvements in quality of life.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Bile acid increase during bulevirtide treatment of hepatitis D is not associated with a decline in HDV RNA.

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+-taurocholate co-transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p = .0029) and evidence of portal hypertension (p = .0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = -0.577; p = .0078; rho = -0.635, p = .0026; rho = -0.577, p = .0077; rho = -0.519, p = .0191; rho = -0.564, p = .0119 and rho = -0.393, p = .087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV-induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed.

Sofosbuvir plus velpatasvir for 8 weeks in patients with acute hepatitis C: The HepNet acute HCV-V study.

Background & Aims: EASL guidelines recommend 8 weeks of treatment with sofosbuvir plus velpatasvir (SOF/VEL) for the treatment of acute or recently acquired HCV infection, but only 6- and 12-week data are available. Therefore, the aim of this study was to evaluate the safety and efficacy of a shortened 8-week SOF/VEL treatment for acute HCV monoinfection. Methods: In this investigator-initiated, prospective, multicentre, single-arm study, we recruited 20 adult patients with acute HCV monoinfection from nine centers in Germany. Patients received SOF/VEL (400/100 mg) as a fixed-dose combination tablet once daily for 8 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). Results: The median HCV RNA viral load at baseline was 104,307 IU/ml; the distribution of HCV genotypes was as follows: GT1a/1b/2/3/4: n = 12/1/1/3/3. Thirteen (65%) of the 20 patients were taking medication for HIV pre-exposure prophylaxis. SVR12 was achieved in all patients who complied with the study protocol (n = 18/18 [100%], per protocol analysis), but the primary endpoint was not met in the intention-to-treat analysis (n = 18/20 [90%]) because two patients were lost to follow-up. One serious adverse event (unrelated to study drug) occurred during 12 weeks of post-treatment follow-up. Conclusions: The 8-week treatment with SOF/VEL was well tolerated and highly effective in all adherent patients with acute HCV monoinfection. Early treatment of hepatitis C might effectively prevent the spread of HCV in high-risk groups. Clinical Trial Number: NCT03818308. Impact and implications: The HepNet acute HCV-V study (NCT03818308), an investigator-initiated, single-arm, multicenter pilot study, demonstrates the efficacy and safety of 8 weeks of daily treatment with the fixed-dose combination sofosbuvir/velpatasvir (400/100 mg) in patients with acute hepatitis C virus (HCV) infection. All patients who completed therapy and were followed-up achieved sustained virologic response. Thus, early treatment with SOF/VEL which might effectively prevent the spread of HCV in high-risk groups can be recommended for patients with acute HCV monoinfection.

Kinetics and predictive value of HBcrAg, HBV RNA and anti-HBc during bulevirtide treatment of chronic HDV-infected patients.

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real-life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti-HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93-4.78) vs. 3.4 logU/ml (IQR 2-4.68), p=0.002). A similar trend was shown for anti-HBc between BL and 6M. Levels of HBcrAg or anti-HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti-HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes.

Intra-host analysis of hepaciviral glycoprotein evolution reveals signatures associated with viral persistence and clearance.

Even 30 years after the discovery of the hepatitis C virus (HCV) in humans there is still no vaccine available. Reasons for this include the high mutation rate of HCV, which allows the virus to escape immune recognition and the absence of an immunocompetent animal model for vaccine development. Phylogenetically distinct hepaciviruses (genus Hepacivirus, family Flaviviridae) have been isolated from diverse species, each with a narrow host range: the equine hepacivirus (EqHV) is the closest known relative of HCV. In this study, we used amplicon-based deep-sequencing to investigate the viral intra-host population composition of the genomic regions encoding the surface glycoproteins E1 and E2. Patterns of E1E2 substitutional evolution were compared in longitudinally sampled EqHV-positive sera of naturally and experimentally infected horses and HCV-positive patients. Intra-host virus diversity was higher in chronically than in acutely infected horses, a pattern which was similar in the HCV-infected patients. However, overall glycoprotein variability was higher in HCV compared to EqHV. Additionally, selection pressure in HCV populations was higher, especially within the N-terminal region of E2, corresponding to the hypervariable region 1 (HVR1) in HCV. An alignment of glycoprotein sequences from diverse hepaciviruses identified the HVR1 as a unique characteristic of HCV: hepaciviruses from non-human species lack this region. Together, these data indicate that EqHV infection of horses could represent a powerful surrogate animal model to gain insights into hepaciviral evolution and HCVs HVR1-mediated immune evasion strategy.

Imprint of unconventional T-cell response in acute hepatitis C persists despite successful early antiviral treatment.

Unconventional T cells (UTCs) are a heterogeneous group of T cells that typically exhibit rapid responses toward specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct-acting antiviral (DAA)-mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal-associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double-negative αß T cells (DNT cells) before, during, and after DAA-mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near-to-normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex-vivo in acute HCV infection, which subsequently normalized during the treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type-specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long-lasting imprints within UTCs remain over time.

Long-Lasting Imprint in the Soluble Inflammatory Milieu Despite Early Treatment of Acute Symptomatic Hepatitis C.

BACKGROUND: Treatment with direct-acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C virus (HCV) with DAAs may normalize most SIMs. METHODS: In this study, we made use of a unique cohort of acute symptomatic hepatitis C patients who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay measuring 92 proteins. RESULTS: Profound SIM alterations were observed in acute HCV patients, with marked upregulation of interleukin (IL)-6 and CXCL-10, whereas certain mediators were downregulated (eg, monocyte chemoattractant protein-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (eg, CDCP1, IL-18). Of note, SIMs that were downregulated before DAA treatment remained suppressed, whereas others that were initially unchanged declined to lower values during treatment and follow-up (eg, CD244). CONCLUSIONS: Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu compared with both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained.

HBcrAg Levels Are Associated With Virological Response to Treatment With Interferon in Patients With Hepatitis Delta.

Standard treatment of hepatitis delta virus (HDV) infection remains pegylated-interferon alfa (peg-IFNα) in most centers, which is not only associated with rather low efficacy but several adverse events. Hepatitis B core-related antigen (HBcrAg) is linked to intrahepatic covalently closed circular DNA levels and has previously been suggested as response predictor in IFN-based treatment of hepatitis B virus (HBV) mono-infection. This study aimed to investigate the value of HBcrAg in the management of patients with HBV/HDV co-infection undergoing peg-IFNα treatment. The Hep-Net-International-Delta-Hepatitis-Intervention Trial-2 study included 120 patients co-infected with HBV/HDV. Patients were treated for 96 weeks with peg-IFNα and either tenofovir or placebo. Ninety-nine patients with HDV-RNA results 24 weeks after end of treatment (FU24) were included in this analysis, of whom 32 patients (32.3%) had undetectable HDV RNA at FU24. HBcrAg was measured at baseline, week 12, 24, 48, 96, and FU24. HBcrAg levels showed no significant correlation with HDV RNA but were significantly linked to treatment outcome. HBcrAg levels < 4.5 log IU/mL at baseline, week 24, and week 48 had high negative predictive value (NPV) for achieving undetectable HDV RNA at FU24 (81.8%, 87.1% and 95.0%, respectively). Similarly, HBcrAg levels at week 96 were significantly higher in patients with viral relapse until FU24 (3.0 vs. 3.63 log IU/mL; P = 0.0089). Baseline, week 24, and week 48 HBcrAg levels were also associated with the likelihood of achieving HBsAg level < 100 IU/mL at FU24 (HBcrAg < 3.0 log IU/mL: NPV 91.7%, 90.4% and 92.3%, respectively). Test statistics improved when combining HBcrAg with additional viral and clinical parameters. Conclusion: HBcrAg is linked to treatment response to peg-IFNα in patients with HBV/HDV co-infection and could be a promising marker to determine treatment futility.

Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients.

ABSTRACT: Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2-14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51-16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80-2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89-0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8-8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7-8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6-13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3-7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.