HDV RNA and liver disease progression: What do we know?
Authors: Alexander J. Stockdale, Elisabetta Degasperi
Journal: Hepatology (2023)

HDV is a small defective RNA virus that requires the presence of HBV HBsAg to enter liver cells, generate new virions, egress, and propagate.1 It is estimated that chronic HDV infection affects about 12 million people worldwide representing 5% of HBsAg-positive carriers.2 The highest HDV prevalence is found in Central Asia and West and Central Africa.2 Chronic HDV infection is generally considered the most severe form of viral hepatitis, characterized by high rates of progression to cirrhosis and its complications, HCC, and liver decompensation.1 Recently, some cohort studies have questioned this characterization by observing relatively milder disease outcomes, particularly among patients without baseline cirrhosis.3,4 Until recently, administration of interferon (IFN) alpha has represented the only therapeutic option for the treatment of HDV infection; however, treatment is associated with significant side effects and characterized by suboptimal efficacy, leading to only 20%–30% off-treatment response rates. Recently, the new HBV-HDV entry inhibitor bulevirtide has been approved in Europe for the treatment of compensated chronic HDV infection. In phase 2 and 3 trials, bulevirtide has demonstrated efficacy with virological or biochemical responses occurring in over half of patients by 48 weeks, coupled with a good safety profile that has been confirmed in real-life reports also in patients with advanced liver disease and clinically significant portal hypertension.5 While HDV RNA undetectability has been identified by joint American Association for the Study of Liver Diseases—European Association for the Study of the Liver (AASLD-EASL) societies as a key treatment end point both on-therapy and off-therapy,6 it is important to understand if this surrogate end point could also result in a significant clinical benefit. Therefore, assessing the relationship between HDV replication and hard clinical end points is crucial, not only to understand the natural history of infection but also to determine the potential clinical benefit of new treatments. In this issue of Hepatology, Gish et al7 conducted a meta-analysis of 12 studies involving a total of 4,876 patients with the primary aim of investigating the association between HDV RNA status and liver-related morbidity and mortality. Patients with positive HDV RNA status carried a higher risk of liver-related complications, such as progression to compensated cirrhosis (risk ratio 1.74; 95% CI: 1.24–2.45), decompensation (HR 3.82; 95% CI: 1.60–9.10), and HCC development (HR 2.97; 95% CI: 1.87–4.70). Additionally, HDV RNA replication was associated with a higher risk of undergoing liver transplant (HR 7.07; 95% CI: 1.61–30.99) and increased liver-related mortality (HR 3.78; 95% CI: 2.18–6.56) compared to patients with negative HDV RNA. The review has been conducted rigorously; however, there are significant limitations relating to the available underlying primary data. One crucial point in this analysis is the definition of the HDV RNA-negative group. Indeed, both patients who became HDV RNA-negative because of IFN treatment, and patients with a spontaneous viral clearance or false-positive HDV antibodies (who were anti-HDV-positive and HDV RNA-negative at the beginning of follow-up) were included in this group. These subpopulations in the HDV RNA-negative comparator group could experience differential risks of disease progression, rendering it difficult to delineate the effect of treatment response from past infections. In older studies, the use of low-sensitivity HDV RNA assays and assays with impaired performance at diagnosing the Africa-specific genotypes 5–8 could have led to misclassification of the viremic status of patients. Finally, the use of a single HDV RNA assessment could have misclassified patients with spontaneously fluctuating viremia or late HDV relapses, which are frequently observed after IFN treatment. The design of the included studies presents limitations to generalizability. Eleven of the 12 included studies were from retrospective cohorts, and one was a randomized trial of pegylated IFN-2α or adefovir (Hep-Net-International-Delta-Hepatitis-Intervention-Study 1). Data included in the meta-analysis were all from European tertiary centers, except for one study from Taiwan. Risk of bias assessment identified critical (18%) or severe (64%) risk of bias relating to confounding, participant selection, outcome ascertainment, and missing data in observational studies. The inclusion of data from retrospective cohort studies and one randomized trial that commenced recruitment almost 20 years ago have observed outcomes from patients diagnosed in a historical era of selective HDV testing, when awareness of HDV was more limited and screening was focused on patients with rapidly progressive liver disease, or for whom specific risk factors for infection were elicited. Accordingly, it is important to consider that the findings of this meta-analysis may not represent the true community HDV population. This analysis has used aggregate rather than individual patient data. Aggregate analysis limits the capacity to adjust for relevant patient-level covariates, which are likely to be the source of the significant observed heterogeneity. The authors attempted meta-regression and subgroup analysis to estimate the impact of baseline cirrhosis (dichotomized at above or below 50%) on disease outcomes; however, both analyses lacked sufficient power due to a small number of studies. Moreover, other patient-related and virus-related factors are recognized drivers of liver disease progression in HDV infection. Older age, male sex, baseline liver fibrosis, and European and Asian ethnicity compared to African descent have been associated with disease progression,3 while other patient comorbidities such as type 2 diabetes, metabolic syndrome as well as alcohol consumption are likely to play an important role in determining clinical outcomes. At the viral level, some HDV genotypes (1 and 3) have been linked with more aggressive disease phenotypes, while HDV-5 has been associated with better responses to IFN treatment. Moreover, co-infections such as HIV or HCV, and the use of nucleos(t)ide analogue treatment for concomitant HBV co-infection may influence outcomes. Unfortunately, none of these factors could be considered in this meta-analysis due to the lack of individual patient data. Future meta-analysis using individual patient data would facilitate a more detailed understanding of the drivers of HDV disease progression beyond HDV RNA alone. Alongside hazard ratios which consider time-to-event data, the authors have also included studies that reported ORs for the relationship between HDV RNA and clinical events and have estimated corresponding risk ratios. This type of analysis does not account for ascertainment time or censoring due to loss of follow-up. Accordingly, differential observation time in the HDV RNA-positive and RNA-negative groups could lead to ascertainment bias in these comparisons from which risk ratios have been estimated. Despite all these potential limitations, this review confirms the importance of HDV RNA to stratify the risk of disease progression and provides an opportunity to consider future research needs for hepatitis D. We now need prospective studies including patients diagnosed from unselective universal testing of all HBsAg-positive patients, with the use of modern sensitive and pan-genotypic HDV RNA assays to diagnose viremia, so we can understand and predict factors that cause disease progression. There is mounting evidence that selective testing recommendations for HDV have led to under-ascertainment of HDV infection, with the attendant risks of failing to recognize patients who have elevated risks of disease progression and HCC. In a single tertiary center study of 11,190 patients with HBV in the United States, 18% of 88 newly diagnosed patients with HDV had no identified risk factors, and for 50% of patients, sexual risk factors were not recorded to enable risk stratification according to guideline recommendations.8 In another US Veterans Affairs study, 80% of the 1468 patients with HBsAg positive considered to have a high-risk profile for HDV did not have HDV testing.9 Consistent evidence of advanced disease progression among patients with HDV at the time of diagnosis from multiple cohort studies highlights the need for earlier HDV diagnosis, particularly in the era of emerging effective therapies.3,4,8 In Spain, after the introduction of reflex anti-HDV testing for HBsAg diagnoses, a 5-fold increase in case detection of HDV was observed.10 Aside from improvements in case detection, moving to universal, automatic HDV testing among all HBsAg-positive people will also improve our understanding of the epidemiology and the true spectrum of HDV disease expression. A serious limitation in our understanding of HDV is the lack of natural history data from American, Asian, or African settings where most of the global burden of HDV is distributed. Cohort data from these populations are urgently needed to co-ordinate effective public health responses. A provisional estimate of the population attributable fraction for HDV using a case-control comparison estimated that 18% of cirrhosis and 20% of HCC cases observed among people with hepatitis B were caused by HDV co-infection.2 The implication is that many cirrhosis, HCC, and liver-related deaths, which we attribute to hepatitis B globally, are instead caused by HDV co-infection due to underdiagnosis. A further research priority is an assessment of the relevance of HDV RNA loss as a biomarker for clinically important outcomes among patients on treatment with novel HDV agents, relative to the alternative surrogate end points of a 2-log10 decrease in HDV RNA proposed by the Food and Drug Administration. We need to properly understand the disease burden of HDV, the rate and determinants of disease progression and to be able to accurately identify patients who have the greatest need for treatment. One of the smallest known human pathogens may be making an outsized contribution to liver disease and liver-related deaths globally.