Evidence of Tenofovir Resistance in Chronic Hepatitis B Virus (HBV) Infection: An Observational Case Series of South African Adults

Abstract

ABSTRACTIntroductionTenofovir 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 RAMs in individuals with detectable HBV viraemia on TDF treatment.MethodsWe 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 analysed to determine the genotype and identify potential TDF RAMs, based on a pre-defined list of polymorphisms.ResultsAmong 66 individuals with chronic HBV, we identified three meeting our phenotypic definition for TDF resistance, of whom two were coinfected with HIV. The sequences grouped as genotypes A1 and D3. In one participant, the consensus HBV sequence had ten 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.DiscussionOur findings add to the evidence that RAMs in HBV RT can 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.Contribution to the Field StatementTreatment of chronic hepatitis B virus (HBV) infection with nucleos(t)ide analogues (NAs) is one of the key strategies that needs to be upscaled in order to achieve the 2030 United Nations elimination target for viral hepatitis. Tenofovir disoproxil fumarate (TDF) is widely recommended for the treatment of chronic HBV infection because it has a high genetic barrier to resistance. However, TDF resistance associated mutations (RAMs) have been reported, but data are limited, with a need for further investigation. Within a cross-sectional cohort of adults with chronic HBV infection recruited in Cape Town, South Africa, we describe combinations of HBV polymorphisms in three adults with detectable HBV viraemia whilst on TDF treatment. This is the first evidence of potential TDF resistance in adults being treated for chronic HBV in Africa and it adds to the growing evidence of TDF resistance globally. It remains necessary to advocate for the development of new antiviral treatments for chronic HBV infection if we are to attain elimination targets.