Frequency of Hepatitis B Virus Resistance Mutations in Women Using Tenofovir Gel as Pre-Exposure Prophylaxis

Intermittent use of a single antiretroviral agent in the presence of a replicating virus could potentially increase the development of antiviral resistance. The pericoital, before-and-after sex, dosing regimen used in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 tenofovir gel trial meant that women who were infected with hepatitis B virus (HBV) were exposed intermittently to tenofovir during their participation. The impact of this dosing regimen on HBV resistance was assessed by amplification of the HBV polymerase region from 37 stored plasma samples of women who were HBV surface antigen positive. All samples belonged to HBV genotype A. None of the known tenofovir resistance mutations (M240V/I, L180M, A194T, V214A, N238T) were identified in any individuals. While it is reassuring that no resistance mutations were found among women using topical tenofovir, the rapidly expanding access to oral tenofovir-containing HIV pre-exposure prophylaxis (PrEP), with higher systemic exposure to the drug, makes monitoring for potential HBV drug resistance important.

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ATI-2173, a Novel Liver-Targeted Non-Chain-Terminating Nucleotide for Hepatitis B Virus Cure Regimens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00836-20 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Katherine E. Squires ◽

Douglas L. Mayers ◽

Gregory R. Bluemling ◽

Alexander A. Kolykhalov ◽

David B. Guthrie ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Systemic Exposure ◽

Pharmacokinetic Profile ◽

Small Subset ◽

Resistance Mutations ◽

Skeletal Myopathy ◽

B Virus ◽

Inhibitor Resistance ◽

Hbv Model

ABSTRACT ATI-2173 is a novel liver-targeted molecule designed to deliver the 5′-monophosphate of clevudine for the treatment of chronic hepatitis B infection. Unlike other nucleos(t)ides, the active clevudine-5′-triphosphate is a noncompetitive, non-chain-terminating inhibitor of hepatitis B virus (HBV) polymerase that delivers prolonged reduction of viremia in both a woodchuck HBV model and in humans for up to 6 months after cessation of treatment. However, long-term clevudine treatment was found to exhibit reversible skeletal myopathy in a small subset of patients and was subsequently discontinued from development. ATI-2173 was designed by modifying clevudine with a 5′-phosphoramidate to deliver the 5′-monophosphate to the liver. Bypassing the first phosphorylation step of clevudine, the 5′-monophosphate is converted to the active 5′-triphosphate in the liver. ATI-2173 is a selective inhibitor of HBV with an anti-HBV 50% effective concentration (EC50) of 1.31 nM in primary human hepatocytes, with minimal to no toxicity in hepatocytes, skeletal muscle, liver, kidney, bone marrow, and cardiomyocytes. ATI-2173 activity was decreased by viral polymerase mutations associated with entecavir, lamivudine, and adefovir resistance, but not capsid inhibitor resistance mutations. A single oral dose of ATI-2173 demonstrated 82% hepatic extraction, no food effect, and greatly reduced peripheral exposure of clevudine compared with equimolar oral dosing of clevudine. Despite reduced plasma clevudine exposure, liver concentrations of the 5′-triphosphate were equivalent following ATI-2173 versus clevudine administration. By selectively delivering the 5′-monophosphate to the liver, while retaining the unique anti-HBV activity of the 5′-triphosphate, ATI-2173 may provide an improved pharmacokinetic profile for clinical use, reducing systemic exposure of clevudine and potentially eliminating skeletal myopathy.

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Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

The Journal of Infection in Developing Countries ◽

10.3855/jidc.9021 ◽

2017 ◽

Vol 11 (09) ◽

pp. 727-732 ◽

Cited By ~ 1

Author(s):

Liping Wang ◽

Fangzheng Han ◽

Hualing Duan ◽

Fang Ji ◽

Xuebing Yan ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Hbv Infection ◽

Drug Resistant ◽

Resistance Mutations ◽

Hbv Genotype ◽

B Virus ◽

Drug Resistant Mutation ◽

Genotype C ◽

Resistant Mutation

Introduction: Previous studies have indicated that the drug-resistant mutations of hepatitis B virus (HBV) are a major obstacle to antiviral therapy. However, it is still unclear whether there are pre-existent resistance mutations in patients with HBV infection and the relationship between drug-resistant mutation, genotypes, and progression of hepatitis B disease. Methodology: A total of 357 treatment-naïve patients with HBV infection were involved in this retrospective study. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. Results: Lamivudine (LAM) resistance was detected in 8 patients (3.7%) with chronic hepatitis B (CHB), 13 (11.7%) patients with liver cirrhosis (LC), and 6 (21.4%) patients with hepatocellular carcinoma (HCC). Adefovir(ADV)-resistant mutations were detected in 10 (4.6%) patients with CHB, 15 (13.5%) patients with LC and 4 (14.5%) patients with HCC. Both LAM and ADV resistant mutations were detected in 2 patients (0.9%) with CHB, 1 patient (0.9%) with LC and 1 patient (3.6%) with HCC. Significant differences (p <0.01) were observed in the drug-resistance rates among patients with CHB, LC and HCC. Meanwhile, all the drug-resistant mutations were found in patients with HBV genotype C. Conclusions: This study demonstrated higher risk of pre-existing drug-resistant mutations in patients with HBV genotype C comparing to patients with HBV genotype B. Likewise, increasing prevalence of pre-existing drug-resistant mutations was shown, alongside with the progression of the disease.

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The L80I Substitution in the Reverse Transcriptase Domain of the Hepatitis B Virus Polymerase Is Associated with Lamivudine Resistance and Enhanced Viral Replication In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01499-06 ◽

2007 ◽

Vol 51 (7) ◽

pp. 2285-2292 ◽

Cited By ~ 65

Author(s):

Nadia Warner ◽

Stephen Locarnini ◽

Michael Kuiper ◽

Angeline Bartholomeusz ◽

Anna Ayres ◽

...

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Reverse Transcriptase ◽

Resistance Mutations ◽

Hbv Genotype ◽

Lamivudine Resistance ◽

Replication Efficiency ◽

B Virus ◽

High Level

ABSTRACT Long-term lamivudine (LMV) treatment of chronic hepatitis B almost inevitably engenders viral resistance. Mutations that result in the replacement of the methionine at position 204 of the deoxynucleoside triphosphate-binding site of the hepatitis B virus (HBV) reverse transcriptase (rt) by isoleucine, valine, or (rarely) serine (rtM204I/V/S) confer high-level resistance to LMV but reduce replication efficiency. The subsequent selection or coselection of secondary mutations that partially restore replication efficiency is common and may influence drug resistance. Genotyping has shown that LMV treatment can select for HBV rtL80V/I mutants, but their prevalence and phenotype have not been documented. Analysis of a large sequence database revealed that rtL80V/I occurred almost exclusively in association with LMV resistance, and 85% of these isolates encoded rtL80I. Coselection of rtL80V/I occurred in 46% of isolates in which LMV resistance was attributable to rtM204I but only 9% of those in which resistance was attributable to rtM204V. Moreover, rtL80V/I did not occur in HBV genotype A isolates but occurred at similar frequencies in genotype B, C, and D isolates. In vitro phenotyping showed that although the rtL80I mutant by itself replicated less efficiently and was hypersensitive to LMV compared to the replication efficiency and sensitivity of its wild-type parent, the presence of rtL80I enhanced the replication efficiency of rt204I/V mutants without significantly affecting LMV resistance. Molecular modeling revealed that rt80 does not interact directly with the enzyme's substrates. Collectively, these results suggest that coselection of rtL80V/I and rtM204I/V occurs because the former compensates for the loss of replication efficiency associated with the acquisition of LMV resistance, particularly in the case of rtM204I.

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Hepatitis B virus (HBV) viral load, liver and renal function in adults treated with tenofovir disoproxil fumarate (TDF) vs. untreated: a retrospective longitudinal UK cohort study

BMC Infectious Diseases ◽

10.1186/s12879-021-06226-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Tingyan Wang ◽

David A. Smith ◽

Cori Campbell ◽

Jolynne Mokaya ◽

Oliver Freeman ◽

...

Keyword(s):

Viral Load ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Renal Impairment ◽

Clinical Guidelines ◽

Untreated Group ◽

Liver Inflammation ◽

B Virus ◽

The Impact

Abstract Background Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. Methods We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. Results We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. Conclusions Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.

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Hepatitis B Virus Infection in Pregnancy: Immunological Response, Natural Course and Pregnancy Outcomes

Journal of Clinical Medicine ◽

10.3390/jcm10132926 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2926

Author(s):

Sirinart Sirilert ◽

Theera Tongsong

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Pregnancy Outcomes ◽

Natural Course ◽

Hbv Infection ◽

Chronic Hbv Infection ◽

B Virus ◽

Chronic Hbv ◽

Adverse Pregnancy ◽

The Impact

This review aimed to provide an update on the impact of pregnancy on the natural course of hepatitis B virus (HBV) infection and also on the impact of HBV infection on adverse pregnancy outcomes, including mother-to-child transmission (MTCT). For the literature review, original research articles, review articles, and guidelines were narratively reviewed and comprehensively validated. The databases of PubMed, EMBASE, and CINAHL were carefully searched for articles in English on topics related to HBV infection, pregnancy, and vertical transmission from 1960 to May 2021. Immunological changes during pregnancy such as suppression of Th1 response and induction of Th2 immunity lead to an impaired immune reaction to HBV and stimulate viral activity along with the reduction of CD8 T cells to escape immune detection. The impact of pregnancy on the natural course of chronic HBV infection seems to be minimal, while pregnancy can increase morbidity and mortality in the case of advanced HBV hepatitis or cirrhosis. Importantly, hepatitis flare or alanine aminotransferase (ALT) flare can occur during pregnancy and is more common during the postpartum period due to the interaction between HBV and the immune response. Interestingly, the impact of HBV infection on adverse pregnancy outcomes is more serious than ever thought. Updated evidence indicates that pregnancies with chronic HBV infection increase the risk of preterm birth and gestational diabetes, especially in cases of positive hepatitis e antigen (HBeAg).

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