A systematic review of hepatitis B virus (HBV) drug and vaccine escape mutations in Africa: A call for urgent action

Abstract

International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with associated mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.

In Silico Analysis of Genetic Diversity of Human Hepatitis B Virus in Southeast Asia, Australia and New Zealand

“…In our study, there was very little information linked to clinical diseases available on the NCBI nucleotide database for the collected genomes. Interestingly, in our study, escape mutations associated with risk of failed immunoprophylaxis [37][38][39][40][41][42] occurred significantly for genotypes A and C (totally 18%), compared to non-A/C genotypes (totally 10.6%) (X 2 = 10.588, df = 1, p = 0.001138), given that most currently used HBV vaccines are generated from genotype A or C strains [29,30]. Due to the unavailability of relevant clinical information for these entries in GenBank, vaccine status for these sequences is unknown.…”

“…Mutations across the major hydrophilic region (MHR) of HBsAg, where determinant a is located, disrupt the conformation of surface antigen, affect protein hydrophilicity and alter the binding of neutralizing antibodies. This allows HBV to escape host immune responses for clearance [35,36], resulting in failed immunoprophylaxis [37][38][39][40][41][42]. RT mutations are involved in the development of drug-resistant viral strains and loss of efficacy of nucleos(t)ide analogs and anti-viral drugs.…”

Modelling cost-effectiveness of tenofovir for prevention of mother to child transmission of hepatitis B virus infection in South Africa

“…Limited resources and infrastructure have impeded antenatal diagnosis and treatment of HBV (27), and stratification of HBsAg-positive antenatal women with HBV DNA level and/or HBeAg to determine eligibility for TDF incurs further cost. Given that TDF is becoming more accessible for HBV treatment in Africa (10,32), and has a well-established safety record as a result of antenatal use in HIV infection, treating all HBsAg positive women should be safe and practical, as well as cost-effective. As this option is simple to implement, it is therefore also most likely to be successful.…”

“…There is a potential risk that increasing population exposure to TDF may increase selection of resistance (32). However, the genetic barrier to TDF resistance is high, and more data are needed to determine the prevalence and clinical significance of putative drug resistance mutations.…”

Quasispecies dynamics in disease prevention and control

“…Selection of resistant mutants has been described for virtually any chemical type of antiviral agent directed to any step of the infectious cycle of DNA or RNA viruses, including important pathogens, such as herpesviruses, picornaviruses, IV, HBV, and hepatitis C virus (HCV). Several reviews and articles have covered the theoretical basis of drug resistance, and consequences for treatment management [as examples see (Domingo et al, 2001b) and previous versions in Progress in Drug Research (Richman, 1994(Richman, , 1996Ribeiro and Bonhoeffer, 2000;Domingo et al, 2001aDomingo et al, , 2012Menendez-Arias, 2013;Perales, 2018;Mokaya et al, 2018;Nitta et al, 2019;Pawlotsky, 2019), and the articles in the Current Opinion of Virology volume edited by L. Menendez-Arias and D. Richman (Menendez-Arias and Richman, 2014)]. Therefore, the general mechanisms that confer adaptability to viruses are very effective in finding drug-escape pathways through molecular mechanisms that are summarized in Section 8.5.…”