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Incomplete HBV DNA Suppression
When Good Enough Isn’t: What to Do for Incomplete HBV DNA Suppression

Released: December 16, 2025

Mark Sulkowski
Mark Sulkowski, MD, FAASLD
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Key Takeaways
  • Nucleos(t)ide analogues for treatment of chronic HBV infection are safe and effective, but do not lead to functional cure in most people and may not completely suppress HBV replication for some.
  • Novel drugs targeting other stages in the HBV replication cycle may be the key to functional cure or complete HBV DNA suppression for individuals with persistent HBV viremia.

I have been using nucleos(t)ide analogues to treat my patients with chronic hepatitis B virus (HBV) infection for more than 2 decades and, for the most part, have been satisfied with their safety, tolerability, and effectiveness, with a couple of exceptions.

Limitations of Nucleos(t)ide Analogues
The first limitation of these antivirals is that they do not lead to hepatitis B surface antigen (HBsAg) loss (functional cure) in most people I treat. (Other functional cure therapies are being investigated, but by some estimates, fewer than one third of people might have HBsAg low enough to even be eligible for future functional cure therapies, and even those who are eligible may not achieve functional cure.)

The second limitation of current antivirals is that they do not completely suppress HBV replication for some individuals, despite the lack of drug resistance and excellent adherence to daily pill-taking. For people with slow or incomplete HBV DNA suppression without any obvious explanation, I am left with the question: What should I do? My concern is that ongoing HBV replication, even at a low level, might increase the risk of hepatocellular carcinoma (HCC) over time and might lead to antiviral drug resistance, particularly for entecavir.

A Case of Persistent HBV DNA
I was recently referred a patient with newly diagnosed chronic HBC infection, characterized by hepatitis B e antigen (HBeAg) positivity with an alanine aminotransferase of approximately 60 U/L, HBV DNA of approximately 4 million IU/mL, and minimal liver disease, as determined by blood test. Despite indications for HBV screening, he had not been diagnosed until one of his parents was found to have HCC.

The recommended clinical management was crystal clear: Start antiviral therapy and HCC surveillance with liver imaging and serum α-fetoprotein every 6 months. He started tenofovir alafenamide (TAF) with excellent adherence (confirmed by pharmacy refill records on the electronic medical record). After 12 months of receiving TAF, his HBV DNA was approximately 750 IU/mL. This was not unexpected, as clinical trial data show that only approximately two thirds of HBeAg-positive participants treated with TAF or tenofovir disoproxil fumarate (TDF) achieve HBV suppression (< 29 IU/mL) after 48 weeks of treatment.

So, no problem: We continued TAF and checked again in 6 months. At that point, this person’s HBV DNA level was approximately 300 IU/mL. “Now what?” I asked myself. Should I continue to monitor for HBV DNA suppression over a more extended period? Should I switch the antiviral drug? Should I add another nucleos(t)ide analogue for dual therapy?

I reassured my patient that his disease was not progressing, and I continued to prescribe TAF for him. However, with his parent’s history of HCC, the ideal treatment outcome would be undetectable HBV DNA.  

Progress Toward New Options
Why do not we have more options to target multiple steps of the HBV replication cycle? For other chronic infections, like hepatitis C and HIV, multiple steps in the virus lifecycle are targeted with combinations of direct-acting antivirals. For example, hepatitis C cure can be achieved by targeting the HCV NS5A protein in combination with either a drug targeting HCV NS5B polymerase or the NS3/4a protease. 

Since the approval of lamivudine in 1998, we have been treating chronic HBV infection with drugs targeting the HBV polymerase. Can we do better? I think the answer is almost certainly yes. Novel, potent antivirals for hepatitis B are currently under investigation in clinical trials, including drugs that target HBV RNA translation, and others that target HBV capsid assembly.

Targeting capsid assembly holds the promise of inhibiting HBV replication by blocking the development of new virions upstream of where the HBV polymerase inhibitors, like tenofovir, work. Capsid assembly modulators (CAMs) may even block another critical step in the HBV life cycle, the replenishment of covalently closed circular DNA (cccDNA). cccDNA serves as the template for HBV and is essential to persistence of the infection. Interventions that decrease cccDNA have been elusive, but CAMs may be able to achieve this goal. 

At the 2025 Liver Meeting in Washington, DC, I was excited to see data showing the potent antiviral activity of a once-daily oral CAM, pevifoscorvir. Reduction of HBV proteins in some patients receiving this drug may reflect its impact on cccDNA. Pevifoscorvir is currently being evaluated as monotherapy vs TDF in a phase II clinical trial (NCT06963710). If successful, one must wonder if it might be a future option to replace the standard therapy of tenofovir for a patient like mine with persistent detectable HBV DNA. In the meantime, I plan to push on with tenofovir.

Your Thoughts
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Most people will not be eligible for functional cure and, therefore, may need better chronic suppressive therapy.

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