Hepatitis B Virus Genotypes and Human Populations: Comparison
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Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Arturo Panduro.

Hepatitis B virus (HBV) is a challenge for global health services, affecting millions and leading thousands to end-stage liver disease each year. HBV is classified into ten genotypes (A to J) and more than 40 sub-genotypes based on a genomic divergence of 8% and 4% (intra-genotype variation), respectively.

  • hepatitis B virus
  • genotypes

1. Introduction

Hepatitis B virus (HBV) infection remains a significant challenge for healthcare services worldwide. In 2019, over 296 million people had chronic hepatitis B, and 820,000 died due to hepatitis B complications. [1]. HBV is highly infectious and can be transmitted vertically from mother to child, and horizontally by sexual contact or contaminated materials [2]. While most HBV infections are asymptomatic, almost 90% of children infected and 5% of adults infected may develop chronic hepatitis B [2]. Without proper management, HBV infection can lead to serious liver complications, such as liver cirrhosis and hepatocellular carcinoma (HCC) [3].
In contrast to chronic hepatitis B, acute hepatitis B occurs within six months of exposure to the virus and refers to the initial phase of HBV infection [4]. Symptoms of acute hepatitis B include loss of appetite, fatigue, abdominal pain, jaundice, nausea, vomiting, fever, and dark urine [4]. While most individuals with acute HBV infection recover fully within a few months due to an efficient immune response that clears the virus [4], others may experience symptoms ranging from moderate to severe.
Fulminant hepatitis B is the most severe form of acute hepatitis B, affecting roughly 1–2% of patients with hepatitis B [5[5][6],6], and when it occurs, it can progress rapidly to life-threatening liver failure. Common complications include encephalopathy, coagulopathy, and multiorgan failure [7], attributed to the host’s exaggerated immune response that rapidly impairs the liver’s primary functions, such as detoxification, protein synthesis, and metabolism [7,8][7][8]. Dysfunction of these cellular processes can affect other organs (kidney, lung, heart, and brain), leading to abnormal personality changes, confusion, abnormal bleeding, easy bruising, prolonged bleeding time, and, in severe cases, coma [7,8][7][8]. Without specialized medical care, the survival rate of patients with fulminant hepatitis B is poor (~25%), and liver transplantation could be the best hope for survival [8].
On the other hand, occult hepatitis B infection (OBI) is characterized by the presence of low levels of HBV DNA in the liver or peripheral blood of people who test negative for hepatitis B surface antigen (HBsAg) [9]. In OBI, the virus can pass undetected within cells without causing significant liver damage [10]. This characteristic favors the long-term survival of both the host and HBV. However, under certain circumstances, such as immune suppression or chemotherapy, OBI can reactivate, leading to acute hepatitis B [11].

2. Hepatitis B Virus Genotypes and Human Populations

HBV is classified into ten genotypes (A to J) and more than 40 sub-genotypes based on a genomic divergence of 8% and 4% (intra-genotype variation), respectively [12,13][12][13]. HBV sub-genotypes are typically designated using a combination of letters and numbers (for example, A1, A2, B1, B2, etc.). The classification of HBV in genotypes and sub-genotypes has important clinical implications, including their association with disease progression, response to antiviral therapy, and global distribution [12,13,14,15,16,17,18,19,20,21,22,23,24,25][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. HBV genotypes A, B, C, and D were discovered simultaneously in 1988, and four years later, genotypes E and F were proposed [12,13][12][13]. Subsequently, genotypes G and H were discovered in 2000 and 2002, respectively [14,15][14][15]. In 2000, an aberrant genotype with evidence of recombination between genotypes A and C was identified [17]. These HBV sequences were classified as genotype I in 2008 [18]. Finally, genotype J was identified in an 88-year-old patient diagnosed with HCC in 2009 [19]. With the discovery of all HBV genotypes, it was possible to identify that each has a different geographical distribution and show a close relationship with its host populations [20,21][20][21]. Genotype A is prevalent in Europe and Eastern–Southern Africa. Sub-genotype A1 is found in southeastern Africa, Brazil, and South Asia. Meanwhile, A2, or Ae, is distributed in Europe and American countries with European ancestry. On the other hand, A3 is prevalent in central African countries near the Atlantic Ocean [26]. Genotypes B and C are commonly found in Asia, including China, Japan, Korea, and Australia. The greatest diversity of sub-genotypes B1–B9 is found in ethnic groups of the Indonesian archipelago. Interestingly, B6 in the North American Arctic suggests a complex evolutionary history [27]. Regarding the sub-genotypes C (C1–C5), most of them are distributed in Southeast Asia. However, C1 and C2 can also be detected in smaller proportions in Canada, the United States, and Northwestern Europe [26]. A study involving over 1000 genomes of HBV genotype D identified 11 sub-genotypes (D1–D11). The primary sub-genotypes are D1–D4. D1 predominates in the Mediterranean, Arab countries, India, Russia, Australia, and New Zealand. D2 prevails in Northern Europe, Eastern Europe, Southeast Asia, and North America, whereas D3 is detected in Europe, South Africa, the Caribbean Islands, and South America. D4 has been reported mainly in the Caribbean Islands with African ancestry [20,21,28][20][21][28]. Genotype E is predominant in West–Central Africa, while genotype F is widespread in Central and South America. [23]. The main F sub-genotypes are F1-F4, with F1 being predominant in countries near the Pacific Ocean, while F2 is detected in Brazil and Venezuela. F3 prevails in Colombia and Venezuela, and F4 is common in Argentina and Bolivia [23]. Genotype G is mainly detected in the risk group of men who have sex with men (MSM) from Mexico, the United States, France, and the Netherlands [23,24][23][24]. Genotype H is endemic mainly to Mexico [25]. Genotypes I and J have also been reported in Southeast Asia [18,19][18][19].
According to the region, HBV genotypes have been linked to several distinct clinical outcomes. In Spain, genotype A has a low antiviral response, while genotypes B and C have been associated with HCC in Asia [27,28][27][28]. In Native Alaskan populations, the sub-genotype F1 increased the risk of HCC 12-fold compared with genotypes B and D [29]. In Europe and Asia, genotype D has been linked with the worst rates of acute, fulminate, and chronic liver disease compared with genotype A [30]. In Mexico, patients infected with the genotype A2 were more susceptible to drug resistance mutations than non-A genotypes [31]. In a small population residing in the Brazilian Amazon, individuals with genotype D exhibited a 7.44-fold higher risk of developing advanced liver disease than individuals with genotypes A and F [32]. In contrast, most people are asymptomatic to the infection caused by genotype F1b in the Colombian Amazon region [33]. In Mexico, genotype H infection is often asymptomatic without significant clinical or laboratory manifestations of liver disease. Also, genotype H has been associated with low viral loads and OBI, particularly in the indigenous people of Mexico [10,23][10][23]. HCC is rare among Mexican patients with genotype H [34], but when found in another region, for example, in Japan [35], it is linked to HCC, suggesting that genotype H has sustained a closer adaptative relationship with the Mexican population. On the other hand, the clinical outcomes and diversity of HBV genotypes could be affected by the recombination and mixing of HBV genotypes [36,37][36][37]. Recombination occurs when two distinct HBV genotypes or sub-genotypes infect the same host cell, exchanging genetic material during replication [36]. Meanwhile, HBV mixture refers to the individual presence of more than one HBV genotype in the same host, which can occur due to co-infection or super-infection. Both recombination and HBV mixtures have been associated with several clinical outcomes, such as the development of liver fibrosis and hepatocellular carcinoma [37,38][37][38]. In patients with human immunodeficiency virus (HIV), mixtures of three HBV genotypes increased the risk of significant liver fibrosis 15-fold compared with dual-mixtures or single-genotype infection [39]. In addition, it was found that chronic patients with very high viral loads (>1 million IU/mL) are typical in the presence of HBV genotype mixtures [39]. High viral load levels may be due to the interaction between viral proteins and the genome of different HBV genotypes. A study showed that genotype G can use the core protein of genotype A2 to enhance its viral replication [40].

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