Combatting Hepatitis B Virus Drug Resistance: Insights and Innovations

Kang Du^*
*Correspondence: Kang Du, Department of Life Science, Jilin Agricultural University, Changchun, China, Email:

Introduction

Hepatitis B virus (HBV) infection is a major global health issue, affecting over 250 million people worldwide. Chronic HBV infection can lead to severe liver complications, including cirrhosis and hepatocellular carcinoma, making it a significant cause of morbidity and mortality. Antiviral therapy has revolutionized the management of chronic HBV infection, with drugs such as Nucleotide Analogs (NAs) effectively suppressing viral replication and reducing the risk of disease progression [1]. However, the emergence of drug resistance mutations poses a significant challenge to the long-term efficacy of antiviral treatment. Hepatitis B virus (HBV) infection remains a significant global health burden, with millions of people affected worldwide. Antiviral therapy is a cornerstone in managing chronic HBV infection, but the emergence of drug resistance mutations poses a challenge to treatment efficacy. This article explores the prevalence of HBV drug resistance mutations, their impact on treatment outcomes, and strategies to mitigate their effects. By understanding the molecular mechanisms underlying drug resistance and implementing tailored therapeutic approaches, we aim to improve patient care and combat the spread of drug-resistant HBV strains [2].

Description

HBV drug resistance mutations can arise spontaneously or under the selective pressure of antiviral therapy, leading to reduced susceptibility to Nucleotide Analogs (NAs). The prevalence of drug resistance mutations varies depending on factors such as treatment duration, drug potency, and patient adherence. Common drug-resistant HBV variants include mutations in the viral polymerase gene, such as rtM204V/I associated with resistance to lamivudine and rtA181T/V conferring resistance to adefovir and entecavir. Furthermore, the prevalence of HBV drug resistance mutations can vary geographically, with certain regions exhibiting higher rates of resistance due to differences in antiviral treatment practices and HBV genotypes. In addition to mutations in the viral polymerase gene, other regions of the HBV genome, such as the precore and basal core promoter regions, may also harbor drug resistance mutations that impact treatment outcomes.

Understanding the prevalence and distribution of drug-resistant HBV variants is essential for informing treatment decisions and designing effective therapeutic strategies. Routine monitoring of HBV viral load and genotypic resistance testing is recommended for patients undergoing long-term antiviral therapy to detect the emergence of drug resistance mutations early and adjust treatment regimens accordingly. Moreover, efforts to improve patient adherence to antiviral therapy and optimize treatment protocols can help minimize the risk of drug resistance and maximize the long-term effectiveness of HBV treatment. The presence of drug resistance mutations can compromise the efficacy of antiviral therapy, leading to virological breakthrough, disease progression, and the need for alternative treatment strategies. Patients with drug-resistant HBV strains may experience persistent viremia and liver inflammation despite ongoing antiviral treatment, increasing the risk of liverrelated complications and hepatocellular carcinoma [3]. Furthermore, the transmission of drug-resistant HBV variants poses a threat to public health, potentially limiting treatment options for newly infected individuals.

Moreover, the impact of drug resistance mutations on treatment outcomes extends beyond individual patients to public health concerns. The transmission of drug-resistant HBV variants can occur through horizontal transmission among individuals or vertical transmission from mother to child during childbirth. In settings with high rates of HBV transmission, the circulation of drug-resistant strains can compromise the effectiveness of vaccination and antiviral treatment programs, leading to increased morbidity and mortality from HBV-related liver disease.

Efforts to mitigate the impact of drug resistance on treatment outcomes and public health include surveillance of drug-resistant HBV variants, implementation of comprehensive prevention and treatment strategies, and development of new antiviral agents with improved resistance profiles [4]. By monitoring the prevalence and distribution of drug resistance mutations, healthcare providers can tailor treatment regimens to individual patients and optimize the use of available antiviral agents. Additionally, promoting adherence to antiviral therapy and implementing measures to prevent HBV transmission can help reduce the emergence and spread of drug-resistant HBV strains, ultimately improving treatment outcomes and reducing the burden of HBV-related liver disease on a global scale.

HBV drug resistance mutations primarily affect the viral polymerase enzyme, disrupting its ability to incorporate nucleotide analogs into the growing viral DNA chain. This results in reduced drug efficacy and viral replication, allowing drug-resistant HBV variants to persist and propagate in the presence of antiviral therapy. Additionally, compensatory mutations in other regions of the HBV genome may enhance viral fitness and replication capacity, further contributing to the emergence and spread of drug resistance.

Furthermore, the molecular mechanisms of HBV drug resistance involve complex interactions between the viral polymerase enzyme and nucleotide analogs. Drug resistance mutations in the viral polymerase gene alter key amino acid residues involved in nucleotide binding, polymerase activity, and fidelity of DNA synthesis. These mutations can reduce the efficiency of nucleotide analog incorporation into the viral DNA chain or confer a competitive advantage to drug-resistant HBV variants by enhancing their replication fitness.

Compensatory mutations in other regions of the HBV genome, such as the basal core promoter and precore regions, may also play a role in modulating viral replication and drug resistance. These compensatory mutations can restore viral fitness and replication capacity in the presence of drug-resistant mutations, allowing drug-resistant HBV variants to persist and proliferate despite the selective pressure of antiviral therapy. Understanding the molecular mechanisms of HBV drug resistance is essential for developing novel therapeutic strategies that target specific viral proteins or pathways involved in drug resistance. By elucidating the underlying mechanisms of drug resistance, researchers can identify potential drug targets and design inhibitors that prevent the emergence and spread of drug-resistant HBV variants, ultimately improving treatment outcomes for patients with chronic HBV infection.

Several strategies have been proposed to mitigate the impact of HBV drug resistance, including combination therapy, sequential therapy, and the development of novel antiviral agents targeting alternative viral proteins or pathways. Combination therapy with multiple NAs or the addition of pegylated interferon-alpha can suppress viral replication more effectively and reduce the risk of drug resistance emergence. Sequential therapy, involving the sequential use of different antiviral agents with non-overlapping resistance profiles, can delay the emergence of drug resistance and prolong treatment efficacy.

Additionally, combination therapy has been shown to improve treatment outcomes and reduce the risk of virological breakthrough in patients with chronic HBV infection. By targeting multiple steps in the viral replication cycle or different viral proteins, combination therapy can enhance antiviral efficacy and prevent the emergence of drug resistance mutations. Furthermore, combination therapy regimens that include drugs with complementary resistance profiles, such as Nucleotide Analogs (NAs) with distinct resistance mutations, can provide broader coverage against drug-resistant HBV variants. Sequential therapy, involving the sequential administration of different antiviral agents, offers another approach to mitigating drug resistance in chronic HBV infection [5]. By alternating between drugs with non-overlapping resistance profiles, sequential therapy can delay the emergence of drug resistance mutations and prolong treatment efficacy. Moreover, sequential therapy regimens that incorporate immune modulators, such as pegylated interferonalpha, can enhance antiviral immunity and reduce the risk of viral rebound after discontinuation of antiviral therapy.

The development of novel antiviral agents targeting alternative viral proteins or pathways represents a promising avenue for overcoming drug resistance in chronic HBV infection. By exploiting vulnerabilities in the HBV replication cycle or host-virus interactions, novel antiviral agents can circumvent existing drug resistance mechanisms and provide alternative treatment options for patients with drug-resistant HBV strains. Overall, a multifaceted approach incorporating combination therapy, sequential therapy, and the development of novel antiviral agents is essential for effectively mitigating drug resistance and improving treatment outcomes in chronic HBV infection.

Conclusion

The high prevalence of HBV drug resistance mutations represents a significant challenge in the management of chronic HBV infection. Understanding the molecular mechanisms underlying drug resistance and implementing tailored therapeutic approaches are essential for optimizing treatment outcomes and preventing the spread of drug-resistant HBV strains. By leveraging insights from molecular virology and clinical research, we can develop innovative strategies to combat HBV drug resistance and improve patient care in the fight against hepatitis B.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Skrzat-Klapaczyńska, Agata, Marcin Paciorek, Andrzej Horban and Justyna D. Kowalska. "Factors associated with the risk of upper respiratory tract bacterial infections among HIV-positive patients." Plos One 17 (2022): e0270770.

   Google Scholar, Crossref, Indexed at

2. Weber, M. S. R., J. J. Duran Ramirez, M. Hentzien and M. Cavassini, et al. "Time Trends in Causes of Death in People with HIV: Insights from the Swiss HIV Cohort Study." Clin Infect Dis (2024).

   Google Scholar, Crossref, Indexed at

3. Skrzat-Klapaczyńska, Agata, Justyna D. Kowalska, Bartłomiej Matłosz and Agnieszka Bednarska, et al. "Non-AIDS-defining bacterial infections in patients with HIV infection." Przegl Epidemiol 73 (2019).

   Google Scholar, Crossref, Indexed at

4. Johnson, Tanner M., Donald G. Klepser, Sara H. Bares and Kimberly K. Scarsi. "Predictors of vaccination rates in people living with HIV followed at a specialty care clinic." Hum Vaccin Immunother 17 (2021): 791-796.

   Google Scholar, Crossref, Indexed at

5. Jilich, David, Agata Skrzat‐Klapaczyńska, Lukas Fleischhans and Dominik Bursa, et al. "National strategies for vaccination against COVID‐19 in people living with HIV in Central and Eastern European region." HIV Med 23 (2022): 546-552.

   Google Scholar, Crossref, Indexed at