What are the treatment options for drug-resistant Hepatitis B Virus (HBV) infection?

Treatment Options for Drug-Resistant Hepatitis B Virus (HBV) Infection

Tenofovir is the preferred treatment option for most drug-resistant HBV infections due to its high genetic barrier to resistance and effectiveness against multiple resistance patterns. 1

Understanding Drug Resistance in HBV

• Drug resistance occurs when HBV develops genetic mutations that reduce susceptibility to antiviral medications, typically manifesting as virologic breakthrough (increase in serum HBV DNA by ≥1 log10 above nadir) in a compliant patient 1
• Resistance is more common with medications that have a low genetic barrier (lamivudine, telbivudine, adefovir) compared to those with high genetic barriers (entecavir, tenofovir) 1
• Sequential monotherapies with agents having low barriers to resistance should be strictly avoided due to the high risk of developing multi-drug resistant strains 1

Management Based on Specific Resistance Patterns

Lamivudine Resistance

• Switch to tenofovir (add adefovir if tenofovir is not available) 1
• The response to tenofovir monotherapy is not influenced by the presence of lamivudine resistance 1

Adefovir Resistance

• If patient was nucleos(t)ide analogue (NA) naïve before adefovir: Switch to entecavir or tenofovir 1
  • Entecavir may be preferred in patients with high viremia 1
• If patient had prior lamivudine resistance: Switch to tenofovir and add a nucleoside analogue 1
• Limited data suggest that tenofovir monotherapy may be sufficient for patients with adefovir resistance 1

Telbivudine Resistance

• Switch to or add tenofovir (add adefovir if tenofovir is not available) 1

Entecavir Resistance

• Switch to or add tenofovir (add adefovir if tenofovir is not available) 1
• For patients with partial response to entecavir but HBV DNA <1000 IU/mL after 1 year, continuing entecavir may achieve viral suppression by 2 years 1
• For patients with higher residual HBV DNA levels, switching to tenofovir monotherapy or tenofovir plus entecavir combination therapy is recommended 1

Tenofovir Resistance

• Tenofovir resistance has not been definitively detected to date 1, 2
• If confirmed, reasonable options include:
  • Add entecavir, telbivudine, lamivudine, or emtricitabine 1
  • Switch to entecavir if patient has not been previously treated with lamivudine 1
  • Add entecavir for patients with prior lamivudine resistance 1

Management of Partial or Inadequate Virologic Response

• For patients taking drugs with low genetic barriers (lamivudine, telbivudine, clevudine, adefovir): Switch to a high-genetic-barrier drug (entecavir or tenofovir) 1
• For patients taking drugs with high genetic barriers (entecavir, tenofovir): Continue treatment with regular monitoring for viral breakthrough 1
  • Patients with declining serum HBV DNA levels may continue the same agent given the rise in virological response rates over time and very low risk of resistance 1
• In case of viral breakthrough: Implement rescue therapy according to genotypic resistance analysis 1

Combination Therapy Considerations

• In patients with multidrug resistance, combination therapy may be necessary 3, 4
• Entecavir plus tenofovir is a commonly used combination for patients with multiple drug resistance patterns 1, 3
• For patients with decompensated liver disease and detectable HBV DNA, combination therapy might be preferred to prevent resistance 1

Newer Treatment Options

• Tenofovir alafenamide (TAF), a newer tenofovir prodrug, has been developed with improved safety profile compared to tenofovir disoproxil fumarate (TDF) 2
• TAF is at least as effective as TDF with higher rates of ALT normalization and significantly fewer kidney and bone mineral density issues 2
• No emergence of drug resistance has been found with TAF use 2
• European Association for the Study of the Liver suggests selecting TAF or entecavir instead of TDF in patients >65 years old and in those with risk of osteoporosis or renal abnormalities 2

Monitoring Recommendations

• Monitor HBV DNA levels every 3-6 months to detect viral breakthrough early 1
• Genotypic resistance testing should be performed in compliant patients with confirmed virological breakthrough 1
• Early treatment adaptation as soon as viral load increases has demonstrated clinical and virological benefits 1

Common Pitfalls to Avoid

• Sequential monotherapy: Avoid sequential use of agents with low genetic barriers as this leads to multidrug resistance 1, 5
• Delayed recognition of resistance: Monitor HBV DNA regularly to identify resistance early before biochemical breakthrough occurs 1
• Misattribution of virologic breakthrough: Most cases of virologic breakthrough in clinical practice are due to nonadherence rather than true resistance, especially with newer agents like entecavir and tenofovir 1
• Inadequate follow-up: Patients with drug-resistant HBV require close monitoring with both clinical and laboratory evaluations 1