Diabetes, Male Sex, and Low HBsAg, HDV RNA, and ALT Predict Spontaneous HDV Suppression in Chronic Hepatitis D

Overview

Chronic hepatitis D (CHD) is one of the most aggressive forms of viral hepatitis. It occurs only in people who already have hepatitis B virus (HBV) infection, because hepatitis D virus (HDV) depends on HBV to complete its life cycle. When HDV remains active for a long time, it can accelerate liver inflammation, scarring, cirrhosis, liver failure, and liver cancer.

This study examined a large cohort of adults with untreated chronic hepatitis D in Mongolia to better understand who is more likely to experience spontaneous HDV suppression, meaning the virus becomes undetectable without antiviral treatment. The findings are clinically important because they may help doctors identify patients who are at lower or higher risk of ongoing HDV replication while newer anti-HDV therapies continue to emerge.

Why this study matters

For years, clinicians have known that persistent HDV replication is a bad prognostic sign. However, less is known about the natural history of CHD in untreated patients, especially which baseline factors might predict spontaneous decline or loss of HDV RNA over time.

That question is especially relevant in places where HDV is common, such as parts of Asia and Eastern Europe. If doctors can recognize factors associated with spontaneous suppression, they may be better able to monitor patients, counsel them about risk, and decide who should be prioritized for treatment once access to HDV-directed therapies is available.

Study design

Researchers reviewed 1,610 adults with chronic hepatitis D who had never received treatment and who underwent at least three HDV RNA tests at the Liver Center in Mongolia between 2015 and 2025.

Patients were grouped according to their final HDV RNA status:
1. Suppression: HDV RNA below 50 IU/mL or loss of HBsAg, the hepatitis B surface antigen
2. Persistent infection: HDV RNA 50 IU/mL or higher

The team used Kaplan-Meier analysis to estimate how often spontaneous suppression occurred over time, and Cox regression to identify independent predictors.

Main findings

The median age at baseline was 40.5 years, and 44.5% of patients were male. Over a median follow-up of 3.9 years, with an interquartile range of 2.1 to 5.9 years, 136 patients, or 8.4%, achieved spontaneous HDV suppression.

The cumulative incidence of suppression increased with time:
– 7.8% at 5 years
– 23.3% at 8 years

This shows that spontaneous suppression does happen in a meaningful minority of patients, although most continue to have detectable infection over time.

Independent predictors of spontaneous suppression

Several baseline features were linked to a greater chance of spontaneous HDV suppression:
– Diabetes: adjusted hazard ratio [aHR] 2.13; 95% confidence interval [CI] 1.21-3.74
– Male sex: aHR 1.61; 95% CI 1.19-2.40

In contrast, higher baseline levels of several laboratory markers were associated with a lower chance of spontaneous suppression:
– HBsAg: aHR 0.42; 95% CI 0.31-0.55
– HDV RNA: aHR 0.74; 95% CI 0.62-0.89
– ALT: aHR 0.35; 95% CI 0.21-0.57

In simple terms, patients who started with lower hepatitis B surface antigen levels, lower HDV viral load, and lower ALT were more likely to later suppress HDV on their own. ALT is an enzyme that rises when the liver is inflamed or injured, so lower baseline ALT may reflect less active liver inflammation at the time of evaluation.

How to interpret the diabetes finding

One of the most interesting results was the association between diabetes and spontaneous HDV suppression. The study found that diabetes independently predicted a higher chance of suppression. This does not mean diabetes protects the liver or should ever be considered beneficial; rather, it may reflect complex interactions between metabolism, immune function, liver biology, and viral replication.

At present, the study shows an association, not a direct causal mechanism. Additional research is needed to understand why diabetes appeared linked to HDV suppression in this cohort.

Clinical significance

The risk of liver-related events was significantly lower in patients who experienced HDV suppression than in those with persistent replication. This is consistent with the broader understanding that reducing or eliminating HDV activity improves liver outcomes.

In practice, the findings may help clinicians in several ways:
– identify patients who may be more likely to remain stable without immediate escalation
– prioritize closer follow-up for patients with high HBsAg, high HDV RNA, or elevated ALT
– support shared decision-making as new anti-HDV therapies become available
– improve prognostic counseling for patients with chronic hepatitis D

Still, spontaneous suppression is not something clinicians can reliably predict with certainty on an individual basis. The results should complement, not replace, regular monitoring, fibrosis assessment, and overall clinical judgment.

Background on HDV and HBV

HDV is a defective virus that cannot propagate without HBV. People with both viruses are often sicker than those with HBV alone. This dual infection can lead to faster progression to cirrhosis and a higher risk of complications.

HBsAg, or hepatitis B surface antigen, is a key marker of HBV infection. Lower HBsAg levels may indicate a smaller amount of HBV-related viral support available for HDV. That may partly explain why lower HBsAg levels were associated with a greater chance of spontaneous HDV suppression.

ALT, or alanine aminotransferase, is commonly used to assess liver injury. In CHD, persistently elevated ALT often signals active immune-mediated liver damage and ongoing viral replication. Lower baseline ALT, therefore, may identify a subgroup with less active disease.

Strengths and limitations

This study has several strengths. It included a large number of patients, used repeated HDV RNA measurements, and evaluated long-term natural history in a real-world setting. The follow-up period was also long enough to capture meaningful spontaneous changes in viral status.

However, there are limitations to keep in mind:
– It was an observational study, so it cannot prove cause and effect
– The findings come from a single center in Mongolia, which may limit generalizability to other populations
– Details about liver fibrosis stage, immune status, and other unmeasured factors may also influence suppression risk
– The study focused on untreated patients, so the results may not apply to people receiving modern antiviral or investigational HDV therapy

Implications for future treatment

As anti-HDV therapies continue to develop, clinicians need better tools to identify which patients are most likely to benefit from treatment and which may remain at higher risk of progression. This study suggests that baseline HBsAg, HDV RNA, and ALT levels, along with sex and diabetes status, could become part of future risk stratification strategies.

In the meantime, patients with chronic hepatitis D should continue to receive individualized follow-up, including liver function tests, viral monitoring, and assessment for fibrosis or cirrhosis. For those with advanced disease or persistent replication, treatment should be considered promptly when available.

Bottom line

In this large Mongolian cohort of untreated chronic hepatitis D, spontaneous HDV suppression occurred in a minority of patients but became more common over time. Diabetes and male sex were associated with a higher likelihood of suppression, while higher baseline HBsAg, HDV RNA, and ALT predicted a lower likelihood.

These findings improve understanding of the natural course of chronic hepatitis D and may help guide prognosis and future treatment planning in the era of emerging HDV therapies.