Hepatitis B virus (HBV) viraemia may persist or rebound in adults receiving nucleos/tide analogue (NA) treatment; a number of factors may collectively reduce the success of treatment in mediating long-term HBV suppression.

We illustrate a complex case where multiple factors contribute to non-suppressed HBV viral load (VL) on NA treatment.

We raise awareness of diverse factors which may be contributing to non-suppressed HBV VL, and advocate for improved clinical pathways and comprehensive data collection to improve care and address knowledge gaps surrounding VL non-suppression on treatment.

In line with international goals to eliminate viral hepatitis as a public health threat by 2030,1 there is a global drive to diagnose, treat and prevent hepatitis B virus (HBV) infection. Nucleos/tide analogue (NA) agents suppress HBV DNA to below quantifiable thresholds in the majority of people receiving treatment. However, viraemia persists in a proportion of those offered treatment (up to 20% after 1 year in a recent population analysis2), attributed to a range of influences which may include drug resistance due to the selection of polymorphisms (resistance-associated mutations (RAMs)) in the viral reverse transcriptase (RT). Resistance is predictably selected by exposure to lamivudine (3TC), which also influences susceptibility to entecavir (ETV) and adefovir (ADV).3 In contrast, resistance to tenofovir (TFV) is uncommon due to a high genetic barrier.4 5

We here describe the case of an adult in whom HBV viraemia has not been consistently suppressed on treatment, to highlight a vulnerable population with risk factors for virological breakthrough.

An adult man received treatment for HBV and HIV coinfection over a period of 26 years in a central London clinic (figure 1). We retrospectively reviewed data from his routine clinical records.

Summary details of non-suppression of HBV VL in an adult prescribed with antiviral therapy. (A) Timeline showing antiviral treatment for HBV, HIV and HCV, showing years since diagnosis on x-axis. (B) Timeline showing trends in viral loads for HBV, HIV and HCV, in addition to CD4+ count, quantitative HBsAg (qHBsAg) and HBeAg status (NB: x-axis not to scale). (C) Timeline showing ALT and liver elastography scores (NB: x-axis not to scale). (D) Resistance-associated mutations (RAMs) listed in EASL guidance8 mapped to the HBV polymorphisms identified in HBV sequenced from this individual through Sanger and Illumina sequencing. 3TC, lamivudine; ADV, adefovir; ALT, alanine aminotransferase; ART, antiretroviral therapy; EASL, European Association for the Study of the Liver; ETV, entecavir; FTC, emtricitabine; FS, fibroscan (liver elastography), HBeAg, hepatitis B ‘e’ antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VL, viral load.

At initial diagnosis, HBV viral load (VL) was 8.5 log10 IU/mL and hepatitis B ‘e’ antigen (HBeAg) was positive. He screened negative for hepatitis D virus infection. Antiretroviral therapy (ART) was commenced, with HIV suppression from 3.7 log10 RNA copies/mL to undetectable. Subsequently, HBV was diagnosed and HBV VL progressively suppressed on HBV-active regimens containing 3TC (from baseline), switched to ADV (year 8) and then TFV (year 12), prescribed in line with changing guidelines. HBeAg was undetectable by year 13 (although he did not develop anti-HBe). He received successful intercurrent treatment for hepatitis C virus infection.

Due to illness and emergency hospital admissions unrelated to bloodborne virus infection, he was unable to sustain NA treatment, with documented gaps at intervals between years 22 and 25. HIV and HBV rebounded, with associated liver inflammation (peak alanine aminotransferase (ALT) 902 IU/L), and HBeAg status reverted to positive. On reinstating HBV-active ART (including TFV and emtricitabine), HIV VL suppressed within 1 month, but HBV VL remained persistently elevated between 3.3 and 9.9 log10 IU/mL (figure 1).

A clinical diagnostic laboratory identified the presence of a resistance mutation at position 181 in the HBV RT sequence (A181T) and reported potential drug resistance to 3TC, ADV and telbivudine. HBV Illumina sequence analysis6 demonstrated dual infection with HBV genotypes A and G (online supplemental methods), and confirmed the A181T polymorphism, although only in a minority of quasi-species (figure 1B). Alongside support to optimise adherence, ETV was added (in keeping with clinical guidelines7 8), followed by an HBV virological response to 2.4 log10 IU/mL after 1 month and 3.2 log10 IU/mL at 4 months.

A number of factors can collectively reduce the success of NA treatment for HBV, including high baseline VL, HIV coinfection, exposure to historical regimens with low genetic barrier to resistance, therapy interruptions, physical and mental health comorbidities and complex barriers to continuity of care. These are inter-related and are likely to have a cumulative influence.

Individuals with these characteristics may be in vulnerable or marginalised groups, are unlikely to be eligible for clinical studies, and may experience social stigma and discrimination. These influences mitigate against their inclusion in laboratory data, clinical cohorts and trials.4 There is a need for focus on equitable representation of the real-world challenges of life-long therapy to fill this current ‘blind spot’ (further discussed in our Editorial 9).

The contribution of drug resistance is doubtful in our patient, as A181T alone is not a recognised cause of tenofovir disoproxil fumarate resistance10; a resistant phenotype would typically require multiple associated RAMs. More clinical and in vitro data are still needed to ascertain the relative contributions of different RAMs, alone and in combination. Adding HBV active agents, and providing adherence support, resulted in progressive reduction in viraemia over time to <2000 IU/mL, but not to undetectable.

Persistent HBV viraemia poses risks of transmission and long-term inflammatory/fibrotic liver disease (indicated by elevated ALT in this case), highlighting the need for intervention. Service improvements should focus on flexible, patient-centric access to information, consistent supplies of medication, avoiding out-of-pocket costs and providing access to peer support, particularly for those coping with other health and/or social challenges and for whom there are barriers to care access. As HBV treatment eligibility expands and we work towards elimination targets, research is needed to better determine the factors that contribute to the presence and impact of persistent viraemia, and to optimise surveillance and clinical intervention.

Consent obtained directly from patient(s).

This study involves human participants and was approved by the South East Coast–Brighton & Sussex Research Ethics Committee (study title: Characterising and modifying immune responses in chronic viral hepatitis; REC reference: 11/LO/0421; IRAS project ID: 43993). Written informed consent was obtained.