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. 2014 Dec;88(24):13971-80.
doi: 10.1128/JVI.01594-14. Epub 2014 Sep 3.

Recent population expansions of hepatitis B virus in the United States

Sumathi Ramachandran  1 , Michael A Purdy  2 , Guo-liang Xia  2 , David S Campo  2 , Zoya E Dimitrova  2 , Eyasu H Teshale  2 , Chong Gee Teo  2 , Yury E Khudyakov  2
Affiliations

Recent population expansions of hepatitis B virus in the United States

Sumathi Ramachandran et al. J Virol. 2014 Dec.

Abstract

The recent epidemic history of hepatitis B virus (HBV) infections in the United States is complex, as indicated by current disparity in HBV genotype distribution between acute and chronic hepatitis B cases and the rapid decline in hepatitis B incidence since the 1990s. We report temporal changes in the genetic composition of the HBV population using whole-genome sequences (n = 179) from acute hepatitis B cases (n = 1,206) identified through the Sentinel County Surveillance for Acute Hepatitis (1998 to 2006). HBV belonged mainly to subtypes A2 (75%) and D3 (18%), with times of their most recent common ancestors being 1979 and 1987, respectively. A2 underwent rapid population expansions in ca. 1995 and ca. 2002, coinciding with transient rises in acute hepatitis B notification rates among adults; D3 underwent expansion in ca. 1998. A2 strains from cases identified after 2002, compared to those before 2002, tended to cluster phylogenetically, indicating selective expansion of specific strains, and were significantly reduced in genetic diversity (P = 0.001) and frequency of drug resistance mutations (P = 0.001). The expansion of genetically close HBV A2 strains was associated with risk of infection among male homosexuals (P = 0.03). Incident HBV strains circulating in the United States were recent in origin and restricted in genetic diversity. Disparate transmission dynamics among phylogenetic lineages affected the genetic composition of HBV populations and their capacity to maintain drug resistance mutations. The tendency of selectively expanding HBV strains to be transmitted among male homosexuals highlights the need to improve hepatitis B vaccination coverage among at-risk adults.

Importance: Hepatitis B virus (HBV) remains an important cause of acute and chronic liver disease globally and in the United States. Genetic analysis of HBV whole genomes from cases of acute hepatitis B identified from 1998 to 2006 in the United States showed dominance of genotype A2 (75%), followed by D3 (18%). Strains of both subtypes were recent in origin and underwent rapid population expansions from 1995 to 2000, indicating increase in transmission rate for certain HBV strains during a period of decline in the reported incidence of acute hepatitis B in the United States. HBV A2 strains from a particular cluster that experienced the most recent population expansion were more commonly detected among men who have sex with men. Vaccination needs to be stepped up to protect persons who remain at risk of HBV infection.

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Figures

FIG 1
FIG 1
Phylogenetic maximum-likelihood tree constructed using HBV S gene sequences (378 bp) (a) and WG sequences (3.2 kb) (b) from genotypes A and D. The frequencies of the S gene sequences are color-coded, with the color scale shown in the vertical bar for each phylogenetic tree. Red circles in panel b represent sequences that have the most common variant of the S gene found in 76 WGs. Each white circle represents a WG sequence in which S gene is unique.
FIG 2
FIG 2
Phylogenetic analysis of WG sequences belonging to genotypes A and D, color-coded according to county and year of sampling. The sentinel Counties are Jefferson County, AL; Pinellas County, FL; Pierce County, WA; Multnomah County, OR; San Francisco County, CA; and Denver County, CO.
FIG 3
FIG 3
Bayesian skyline plot showing HBV epidemic history in the United States. Middle line represents mean estimate of effective population size, plotted as the log Neτ, and blue lines shows the 95% highest posterior density (HPD) intervals for this estimate. The time scale encompasses a lower limit of 95% HPD for time of the most recent common ancestor (tMRCA) to the time of collection for the most recent specimens.
FIG 4
FIG 4
(a) Phylogenetic analysis of WG (genotype A2) color-coded according to year of diagnosis. The bootstrap values are marked on the figure. Cluster 1 sequences (highlighted in yellow) represent most heterogeneous lineage of sequences compared to cluster 2 (not highlighted). (b) Skyline plot for the A2 cluster 1. The middle black line represents the estimated mean of the effective population size (logarithmic scale). The blue lines show the limits of the 95% HPD for this estimate. The vertical dotted line represents the lower 95% HPD for tMRCA. (c) Skyline plot for A2 cluster 2.
FIG 5
FIG 5
(a) Nucleotide diversity of the entire HBV genome, color-coded based according to the year of diagnosis. Each point is an average over a window of 301 nt, with a step of 1. The diagram at the bottom of the figure depicts the HBV genetic map in alignment with the nucleotide numbering on the x axis. (b) Frequency distribution of nucleotide distances among WG from A2 and D3 isolates, color-coded according to the year of diagnosis.
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