HBV transmission from an occult carrier with five mutations in the major hydrophilic region of HBsAg to an immunosuppressed plasma recipient

Coppola, Nicola; Loquercio, Giovanna; Tonziello, Gilda; Azzaro, Rosa; Pisaturo, M.; Costanzo, Gaetano Di; Starace, Mario; Pasquale, Giuseppe; Cacciapuoti, Carmela; Petruzziello, Arnolfo

doi:10.1016/j.jcv.2013.06.020

Cited by 33 publications

(26 citation statements)

References 13 publications

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“…16,20 Mutations at position 145 as well as at positions 100, 109, 118, 134, 144, and 154 have been also detected during HBV reactivation in previous studies (based on clinical case description or lower number of patients). [9][10][11][12][13][14] The slight discrepancies in the patterns of S-HBsAg mutations reported in our and other studies can be mainly ascribed to the inclusion of different HBV genotypes. However, we cannot exclude that other factors, such as the type of immunosuppressive regimen, and serological status of HBV infection before reactivation, can influence the patterns of mutations detected during HBV reactivation.…”

Section: Discussioncontrasting

confidence: 70%

“…19 This mutation has been also described in a case of corticosteroid-induced reactivation of latent HBV infection in an HIV-positive patient. 12 Within the 139-149 segment, we also observed an enrichment of variability at the S-HBsAg position 145, known to abrogate the production of, as well as reduce the HBsAg affinity for, neutralizing Abs. 16,20 Mutations at position 145 as well as at positions 100, 109, 118, 134, 144, and 154 have been also detected during HBV reactivation in previous studies (based on clinical case description or lower number of patients).…”

Section: Discussionmentioning

confidence: 69%

“…Drug Resistance in Patients With HBV Reactivation Despite LMV Prophylaxis. In our study, 9 patients developed HBV reactivation despite LMV prophylaxis (median [IQR] duration: 12 [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] months). The primary LMV resistance mutations, rtM204V or rtM204I, were detected in 3 patients at reactivation.…”

Section: Resultsmentioning

confidence: 99%

“…8 Anecdotic clinical case descriptions have highlighted a high degree of genetic variability in the S gene in patients developing HBV reactivation. [9][10][11][12][13][14] The S gene is composed of the pre-S1, pre-S2, and S region, coding for the three forms of HBV surface glycoproteins: the small-sized HBV surface antigen (S-HBsAg) as well as the medium-(pre-S21S) and large-sized surface antigen (pre-S11pre-S21S). An in-depth characterization of the extent of genetic variability throughout the entire S gene in patients undergoing immunosuppression-related HBV reactivation is still missing.…”

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confidence: 99%

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Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression

et al. 2015

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Hepatitis B virus (HBV) reactivation during immunosuppression can lead to severe acute hepatitis, fulminant liver failure, and death. Here, we investigated hepatitis B surface antigen (HBsAg) genetic features underlying this phenomenon by analyzing 93 patients: 29 developing HBV reactivation and 64 consecutive patients with chronic HBV infection (as control). HBsAg genetic diversity was analyzed by population-based and ultradeep sequencing (UDS). Before HBV reactivation, 51.7% of patients were isolated hepatitis B core antibody (anti-HBc) positive, 31.0% inactive carriers, 6.9% anti-HBc/anti-HBs (hepatitis B surface antibody) positive, 6.9% isolated anti-HBs positive, and 3.4% had an overt HBV infection. Of HBV-reactivated patients, 51.7% were treated with rituximab, 34.5% with different chemotherapeutics, and 13.8% with corticosteroids only for inflammatory diseases. In total, 75.9% of HBV-reactivated patients (vs. 3.1% of control patients; P < 0.001) carried HBsAg mutations localized in immune-active HBsAg regions. Of the 13 HBsAg mutations found in these patients, 8 of 13 (M103I-L109I-T118K-P120A-Y134H-S143L-D144E-S171F) reside in a major hydrophilic loop (target of neutralizing antibodies [Abs]); some of them are already known to hamper HBsAg recognition by humoral response. The remaining five (C48G-V96A-L175S-G185E-V190A) are localized in class I/ II-restricted T-cell epitopes, suggesting a role in HBV escape from T-cell-mediated responses. By UDS, these mutations occurred in HBV-reactivated patients with a median intrapatient prevalence of 73.3% (range, 27.6%-100%) supporting their fixation in the viral population as a predominant species. In control patients carrying such mutations, their median intrapatient prevalence was 4.6% (range, 2.5%-11.3%; P < 0.001). Finally, additional N-linked glycosylation (NLG) sites within the major hydrophilic loop were found in 24.1% of HBV-reactivated patients (vs. 0% of chronic patients; P < 0.001); 5 of 7 patients carrying these sites remained HBsAg negative despite HBV reactivation. NLG can mask immunogenic epitopes, abrogating HBsAg recognition by Abs. Conclusion: HBV reactivation occurs in a wide variety of clinical settings requiring immune-suppressive therapy, and correlates with HBsAg mutations endowed with enhanced capability to evade immune response. This highlights the need for careful patient monitoring in all immunosuppressive settings at reactivation risk and of establishing a prompt therapy to prevent HBV-related clinical complications. (HEPATOLOGY 2015;61:823-833)

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression

et al. 2015

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“…HBV is associated with a global burden of about 600,000 deaths a year 1. HBV causes an acute hepatitis that becomes chronic in a percentage that is highly dependent on age of acquisition of the infection 5–7. In fact, the rate of chronicity is about 90% in infants infected at birth or during the first year of life, 30%–50% in children aged 1–6 years, and 5%–10% in children above 6 years of age and in adults 1,2.…”

Section: Introductionmentioning

confidence: 99%

Vertical transmission of hepatitis B virus: challenges and solutions

Gentile¹,

Borgia²

2014

IJWH

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More than 240 million people worldwide are chronically infected with hepatitis B virus (HBV). Mother-to-child transmission remains the most important mechanism of infection in countries with a high prevalence of HBV. Universal screening of all pregnant women, at-birth prophylaxis with specific anti-HBV immune globulin, as well as HBV vaccination for newborns of infected mothers are effective in reducing the risk of vertical transmission. However, in cases of a high viral load and hepatitis B e antigen positivity, there is a residual risk of HBV transmission to the newborn despite prophylaxis. This review focuses on the above-indicated strategies and on the efficacy and safety of antiviral drugs administered during the third trimester of pregnancy.

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Molecular epidemiology of hepatitis B virus genotypes circulating in acute hepatitis B patients in the Campania region

Sagnelli

Ciccozzi²,

Pisaturo

et al. 2014

J. Med. Virol.

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Fifty-three HBV-DNA-positive patients with symptomatic acute hepatitis B were enrolled from 1999 to 2010 to evaluate molecular and phylogenetic changes in HBV in southern Italy. HBV polymerase region was evaluated by direct sequencing in plasma samples obtained at first observation. Different data sets were aligned and a phylogenetic tree was inferred using PhyML program. Statistical robustness was confirmed with a bootstrap analysis. A Bayesian Markov chain Monte Carlo method and a Bayesian skyline plot were used to estimate the evolution of our samples. The dN/dS rate (ω) was estimated by the maximum likelihood approach to investigate the presence of codons under positive selection. The MacClade program was used to test viral gene out/in flow only among HBV-D3 subgenotype patients with different risk factors. Of the 53 patients, 83% were born in Italy and 17% were foreigners. HBV genotype D was prevalent (64.1%), followed by genotype A (26.4%), E (3.8%), and F (5.7%). The prevalent subgenotype was D3 (70.6%). The Bayesian tree of the 24 D3 subgenotypes showed two main clades both dated 1994; 40% of viral gene flow observed was from intravenous drugs users and heterosexual patients. Phylogenetic analysis of HBV isolates showed that HBV-D3 remains the prevalent genotype, but also subgenotype A2 has become frequent in southern Italy. This may be of clinical relevance in years to come, since patients with HBV-genotype-A chronic infection less frequently than those with genotype D develop HBeAg-negative chronic hepatitis and respond more frequently to alfa-interferon treatment.

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HBV transmission from an occult carrier with five mutations in the major hydrophilic region of HBsAg to an immunosuppressed plasma recipient

Cited by 33 publications

References 13 publications

Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression

Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression

Vertical transmission of hepatitis B virus: challenges and solutions

Molecular epidemiology of hepatitis B virus genotypes circulating in acute hepatitis B patients in the Campania region

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