Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: An observational case series of South African adults

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Abstract

Introduction

Tenofovir disoproxil fumarate (TDF) is widely recommended for treatment of chronic hepatitis B virus (HBV) infection because it is safe, affordable and has a high genetic barrier to resistance. TDF resistance associated mutations (RAMs) have been reported, but data are limited, particularly for Africa. We set out to identify potential RAMs in individuals with detectable HBV viraemia on TDF treatment.

Methods

We recruited adults with chronic HBV infection from Cape Town, South Africa, identifying individuals with a TDF resistance phenotype, defined as persistent HBV vireamia despite >12 months of TDF treatment. We sequenced HBV DNA using MiSeq Illumina with whole genome target enrichment, and sought potential TDF RAMs, based on a pre-defined list of polymorphisms.

Results

Among 66 individuals with chronic HBV (genotypes A and D), three met our clinical definition for TDF resistance, of whom two were coinfected with HIV. In one participant, the consensus HBV sequence contained nine polymorphisms that have been described in association with TDF resistance. Significant treatment non-adherence in this individual was unlikely, as HIV RNA was suppressed. TDF RAMs were also present in HBV sequences from the other two participants, but other factors including treatment non-adherence may also have had a role in failure of HBV DNA suppression in these cases.

Discussion

Our findings add to the evidence that RAMs in HBV reverse transcriptase may underpin a TDF resistant phenotype. This is the first time these RAMs have been reported from Africa in association with clinical evidence of TDF resistance.

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Most cited references 17

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Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission

Graham Cooke, Isabelle Andrieux-Meyer, Tanya L. Applegate … (2019)

Viral hepatitis is a major public health threat and a leading cause of death worldwide. Annual mortality from viral hepatitis is similar to that of other major infectious diseases such as HIV and tuberculosis. Highly effective prevention measures and treatments have made the global elimination of viral hepatitis a realistic goal, endorsed by all WHO member states. Ambitious targets call for a global reduction in hepatitis-related mortality of 65% and a 90% reduction in new infections by 2030. This Commission draws together a wide range of expertise to appraise the current global situation and to identify priorities globally, regionally, and nationally needed to accelerate progress. We identify 20 heavily burdened countries that account for over 75% of the global burden of viral hepatitis. Key recommendations include a greater focus on national progress towards elimination with support given, if necessary, through innovative financing measures to ensure elimination programmes are fully funded by 2020. In addition to further measures to improve access to vaccination and treatment, greater attention needs to be paid to access to affordable, high-quality diagnostics if testing is to reach the levels needed to achieve elimination goals. Simplified, decentralised models of care removing requirements for specialised prescribing will be required to reach those in need, together with sustained efforts to tackle stigma and discrimination. We identify key examples of the progress that has already been made in many countries throughout the world, demonstrating that sustained and coordinated efforts can be successful in achieving the WHO elimination goals.

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Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach.

Maud Lemoine, Serge Eholie, Karine Lacombe (2015)

The burden of liver disease may dramatically increase in the near future in Africa, where screening and access to care and treatment are hampered by inadequate disease surveillance, lack of high-quality tools to assess chronic liver disease, and underestimated needs for human and financial resources. Chronic hepatitis may be considered as silent and neglected killer, fuelled by many years of global inertia from stakeholders and policy makers alike. However, the global battle against viral hepatitis is facing a new era owing to the advent of highly effective drugs, innovative tools for screening and clinical follow-up, and recent signs that governments, advocacy groups and global health organizations are mobilizing to advocate universal access-to-treatment. This review details the barriers to prevention, screening and treatment of viral hepatitis on the African continent, focuses on the urgent need for operational and research programmes, and suggests integrated ways to tackle the global epidemic.

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Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue.

Nicolette Louissaint, Ying-Jun Cao, Paul L. Skipper … (2013)

HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) (14)C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4(+) cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58-77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38-76) half-life; Cmax was 20 fmol/million cells (2-63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1-281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials.

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Author and article information

Contributors

Philippa C Matthews

Journal

Journal ID (nlm-ta): J Clin Virol

Journal ID (iso-abbrev): J. Clin. Virol

Title: Journal of Clinical Virology

Publisher: Elsevier Science

ISSN (Print): 1386-6532

ISSN (Electronic): 1873-5967

Publication date PMC-release: 1 August 2020

Publication date (Print): August 2020

Volume: 129

Electronic Location Identifier: 104548

Affiliations

[a ]Nuffield Department of Medicine, University of Oxford, Medawar Building, South Parks Road, Oxford OX1 3SY, UK

[b ]Division of Medical Virology, Stellenbosch University / National Health Laboratory Service Tygerberg, Cape Town, South Africa

[c ]Division of Infectious Diseases, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa

[d ]MRC-University of Glasgow Centre for Virus Research, Bearsden Road, Glasgow, G61 1QH, UK

[e ]Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK

[f ]Big Data Institute, Old Road, Oxford OX3 7FZ, UK

[g ]Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK

[h ]Division of Gastroenterology, Department of Medicine, Stellenbosch University / Tygerberg Academic Hospital, Cape Town, South Africa

[i ]Department of Hepatology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK

[j ]National Institutes of Health Research Health Informatics Collaborative, NIHR Oxford Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK

Author notes

[* ]Corresponding author at: Nuffield Department of Medicine, Medawar Building, South Parks Road, Oxford OX1 3SY, UK. philippa.matthews@ 123456ndm.ox.ac.uk

[1]

These authors contributed equally to this article.

Article

Publisher ID: S1386-6532(20)30290-0 Publisher ID: 104548

DOI: 10.1016/j.jcv.2020.104548

PMC ID: 7408481

PubMed ID: 32663786

SO-VID: 50a63508-a35d-40aa-a71d-e0ef5757ca44

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: An observational case series of South African adults

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Abstract

Introduction

Methods

Results

Discussion

Related collections

Microbiology Independent Research Journal (MIR Journal)

Most cited references 17

Accelerating the elimination of viral hepatitis: a Lancet Gastroenterology & Hepatology Commission

Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach.

Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue.

Author and article information

Contributors

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