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. 2023 Jan 9:9:1057194.
doi: 10.3389/fmed.2022.1057194. eCollection 2022.

Acute and chronic HBV infection in central Argentina: High frequency of sub-genotype F1b, low detection of clinically relevant mutations and first evidence of HDV

Gonzalo M Castro  1 , María J Sosa  1 , Paola E Sicilia  1 , María I Riberi  2 , Claudia Moreno  1 , Rodolfo Cattaneo  3 , José D Debes  4 , María G Barbás  1 , Analía E Cudolá  1 , María B Pisano  5 , Viviana E Ré  5
Affiliations

Acute and chronic HBV infection in central Argentina: High frequency of sub-genotype F1b, low detection of clinically relevant mutations and first evidence of HDV

Gonzalo M Castro et al. Front Med (Lausanne). .

Abstract

Introduction: Genomic analysis of hepatitis B virus (HBV) identifies phylogenetic variants, which may lead to distinct biological and clinical behaviors. The satellite hepatitis D virus (HDV) may also influence clinical outcomes in patients with hepatitis B. The aim of this study was to investigate HBV genetic variants, including clinically relevant mutations, and HDV infection in acute and chronic hepatitis B patients in central Argentina.

Methods: A total of 217 adult HBV infected patients [acute (AHB): n = 79; chronic (CHB): n = 138] were studied; 67 were HBV/human immunodeficiency virus (HIV) coinfected. Clinical and demographic data were obtained from medical records. Serological markers were determined. Molecular detection of HBV and HDV was carried out by RT-Nested PCR, followed by sequencing and phylogenetic analysis.

Results: Overall, genotype (gt) F [sub-genotype (sgt) F1b] was the most frequently found. In AHB patients, the gts/sgts found were: F1b (74.7%) > A2 (13.9%) > F4 (7.6%) > C (2.5%) > A1 (1.3%). Among CHB patients: F1b (39.1%) > A2 (23.9%) > F4 (18.2%) > D (9.4%) > C and F6 (3.6% each) > A1, A3 and B2 (0.7% each). The distribution of sgt A2 and gt D was significantly different between HBV mono and HBV/HIV coinfected patients [A2: 15.9% vs. 35.7% (p < 0.05), respectively and D: 14.6% vs. 1.8% (p < 0.05), respectively]. Mutation frequency in basal core promoter/pre-Core (BCP/pC) region was 35.5% (77/217) [AHB: 20.3% (16/79), CHB: 44.2% (61/138)]. In the open reading frame (ORF) S, mutations associated with vaccine escape and diagnostic failure were detected in 7.8% of the sequences (17/217) [AHB: 3.8% (3/79), CHB: 10.1% (14/138)]. ORF-P amino acid substitutions associated with antiviral resistance were detected in 3.2% of the samples (7/217) [AHB: 1.3% (1/79), CHB 4.3%, (6/138)]. The anti-HDV seropositivity was 5.2% (4/77); one sample could be sequenced, belonging to gt HDV-1 associated with sgt HBV-D3.

Discussion: We detected an increase in the circulation of genotype F in Central Argentina, particularly among AHB patients, suggesting transmission advantages over the other genotypes. A low rate of mutations was detected, especially those with antiviral resistance implications, which is an encouraging result. The evidence of HDV circulation in our region, reported for the first time, alerts the health system for its search and diagnosis.

Keywords: Argentina; HBV; antiviral resistance; genotypes; hepatitis B virus; mutant.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Maximum likelihood phylogeny of acute hepatitis B samples from Córdoba, Argentina. Maximum likelihood phylogenetic tree obtained using sequences of 1,169 nucleotides, resulting from concatenated sequences of the S (471 nucleotides) and BCP-pC genomic regions (698 nucleotides) of acute hepatitis B samples from central Argentina and reference sequences from each genotype or subgenotype available at GenBank. The phylogenetic tree was constructed with MEGA v.6 (bootstrap: 1000 replicates). References: A1, light blue; A2, blue; C, yellow; F1b, red; F4, light green.
FIGURE 2
FIGURE 2
Maximum likelihood phylogeny of chronic hepatitis B samples from Córdoba, Argentina. Maximum likelihood phylogenetic tree obtained using sequences of 1,169 nucleotides, resulting from concatenated sequences of the S (471 nucleotides) and BCP-pC genomic regions (698 nucleotides) of chronic hepatitis B samples from central Argentina and reference sequences from each genotype or subgenotype available at GenBank. The phylogenetic tree was constructed with MEGA v.6 (bootstrap: 1000 replicates). References: A1, light blue; A2, blue; A3, lavender; B, fuchsia; C, yellow; D, orange; F1b, red; F4, light green; F6, green.
FIGURE 3
FIGURE 3
Genotype/sub-genotype distribution in acute hepatitis B (AHB) and chronic hepatitis B (CHB) patients. (A) Genotype/sub-genotype distribution in AHB patients (left), AHB monoinfected patients (center), and acute HBV/HIV co-infected patients (right). (B) Genotype/sub-genotype distribution in CHB patients (left), CHB monoinfected patients (center), and chronic HBV/HIV co-infected patients (right). References: A1, light blue; A2, blue; A3, lavender; B, fuchsia; C: yellow; D: orange; F1b: red; F4: light green; F6: green; *p < 0.05; **p < 0.001.
FIGURE 4
FIGURE 4
Absolute frequency of mutations obtained for three genomic regions of hepatitis B virus (HBV) [open reading frame (ORF)-S, ORF-P, ORF-pC/C] of 217 patients with acute (AHB) and chronic (CHB) infection. Some of the mutations were found simultaneously.
FIGURE 5
FIGURE 5
Maximum likelihood phylogenetic tree obtained using sequences of 326 nucleotides, corresponding to the partial HDAg region of hepatitis D virus (HDV), constructed with MEGA v.6 (bootstrap: 1000 replicates). The tree includes the positive sample obtained (violet diamond) and the reference sequences from each genotype available at GenBank.
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