Global and Indian distribution of hepatitis B virus (HBV) genotypes/sub-genotypes 

References

1. Europe A2, D1-D4 Pourkarim MR et al., 22 Thijssen M et al. 23 & Olinger CM et al. 24 North America 1a, 1b, 2a, 2b, 2c and 3a Olinger CM et al. 24 South America A1, A2,, F4, F1, F2,F2a, D3 Reuter et al., 19 Wolf JM et al. 25 & Araujo NM et al. 26 Asia A1, B2-5, B7, B9,C1, C2, C3, C4, C5-16, D1,D2,D3,D4 Potter BI et al., 20 Lin Set al., 21 Kyaw et al. 27 & A.A.AI-Qahtani et al. 28 Africa A1-A7, D1, D2-D4, D7-D8 Kafeero et al., 17 Thijssen M et al. 23 & Hannachi N et al. 29 Oceania C4, D4 Liu Z et al. 13
2. HBV Epidemiology in India South Asia, including India faced significant fatality rates every year due to several infectious diseases. Millions of people in India are at a risk from chronic hepatitis B, HIV and tuberculosis. Now India ranks second globally in terms of population affected by HIV infection and AIDS, indicating a rapid shift in the virus epidemiology of transmitted through prenatal or sexual routes. 30 These illnesses are quite common in many South Asian countries are attributed to factors such as poverty, unhygienic living conditions, illiteracy, unsafe blood supplies, and inadequate hospitality, multiple use of same needles/syringes, risky sexual behaviours, and frequent intravenous drug use. 31 The World Health Organization's report on hepatitis B virus (HBV) prevention in India indicates that the prevalence of HBsAg in the general population ranges from 0.1% to
3. 7%, with the majority of studies demonstrating frequencies in between the 2%–8% range, but the HBsAg prevalence among the blood donors varies from 1% to
4. 7%. 32 Although, some North Eastern states exhibit higher positivity around 7%, other parts of India show no substantial geographical change. Approximately, 50 million HBV carriers are thought to exist in India with an average of 5%, representing nearly 15% global pool of HBV carrier and making it the second highest populated country among chronic HBV infections globally. 33 Conservative approach suggested that over 9 million people in India will acquire HBV infection at some point in their lifetime, around 1.5 million developed chronic HBV infection and nearly 2 million died from acute or chronic HBV-related complications. 34 Few primitive tribes in Andaman and Nicobar Islands have shown unusual high positivity rates of HBsAg in contrast to mainland India. According to studies, there is a hyperendemic of HBV infection; the Nicobarese have a carrier HBsAg of 23.3% followed by Shompen 37.8%, the Karen 11.6%, and the Jarawa tribe has a 65%. The highest documented prevalence rates of HBsAg worldwide are seen in the Jarawa tribe. 35-37 India's vast and diverse population comprises various racial communities with distinct cultures, ethnicities, dietary habits, and lifestyles, which leads to a wide range of infectious and chronic disease patterns. India’s geographical location revealed different HBV genotype variations between West, Central and East Asian countries. The Indian population has significant genetic, geographic, and sociocultural variety as a result of historical anthropological migrations. Additionally, the distribution of HBV genotypes may be significantly impacted epidemiologically by India's more than 200 years of colonial rule. 1 The different distribution of HBV genotypes in the different regions of the countries reflects this multi-ethnic background (Figure 1). Furthermore, recent increases in trade, drug and international travel has been significantly impact the epidemiology of HBV and other perinatal transmission of infections in India, particularly in the eastern and north-eastern regions. 39 Gaur et al. / Indian Journal of Microbiology Research 2025;12(3):287–294 291 Figure 1: Geographical Distribution of HBV genotypes/subgenotypes in India 15,16,40-42 In Uttar Pradesh, North India HBV genotype D is the most prevalent which covers around 78-80% among HBV infections leads to chronic hepatitis while genotype A reported only in 20-22% cases. Although there is insufficient data to determine the precise prevalence of its genotypes and sub-genotypes in the eastern region of Uttar Pradesh, it has been reported in many Indian research that genotypes A and D are the most prevalent among all variations. According to a study by Sibnarayan Datta, northern India has an equal prevalence of genotypes A and D. 42 In another study conducted by Salman Khan et al. from Meerut, Uttar Pradesh, India found that the genotype B and genotype A were found to be 68.8% and 31.25%, respectively. 43 The studies conducted so far has revealed genotype D as predominant genotype over genotype A. 44 Till now, very limited research has been conducted to investigate the epidemiology and genetic diversity of HBV in eastern and other regions of Uttar Pradesh.
5. HBV Gene Mutation Mechanism for Diversity A significant factor that makes HBV incurable is the complex form of HBV mutation. High mutational rate found in HBV in comparison with other DNA viruses, it was calculated at
6. 4 × 10-5 to 3.2 × 10-5 nucleotides per site per year. In addition to a number of other reasons including the virus's inherent traits, host immunological pressure, and selective pressure from antiviral therapies, HBV is a highly variable virus whose evolution and variation follow theory of natural selection and random drift leads to a wide range of genetic variations which includes different genotypes, subgenotypes, and quasispecies. The main cause of HBV diversity is the reverse transcription process that occurs during HBV replication, which gives its trait comparable to RNA viruses. 45 292 Gaur et al. / Indian Journal of Microbiology Research 2025;12(3):287–294
7. Factors influence genetic diversity There are several important factors responsible for genetic diversity of HBV. Some of these are listed below as: 46
8. Dominant and resistant gene can become advantage for a patient.
9. Drug-resistant mutations may arise as a result from antiviral therapies. Genotype and subgenotype variations can influence disease severity and response to treatment.
10. The host's immune system can also drive the evolution of HBV, favouring variants that evade immune clearance.
11. The existence of different HBV genotypes (A-H) across the world contributes to the overall genetic diversity.
12. Exchange of genetic information between HBV genotypes due to recombination and this is also the cause of diversity.
13. Methods to Detect Genetic Mutation There are various methods and techniques to detect viral mutations and quantification for the comprehensive analysis of genetic mutation and diversity of gene variants. Recent techniques like sequencing methods (Direct and Next Generation sequence) have made it easier to detect HBV DNA mutations. Many other sensitive and high throughput techniques can be used to detect genomic mutations in HBV. Allele-specific oligonucleotide hybridization (ASOH), Amplification refractory mutation system (ARMS), clone- based sequencingand multiple real time Polymerase chain reaction (RT-PCR) amplification techniques enabling detection of mutations even at low frequencies of viral quasispecies. Restriction Fragment Length Polymorphism (RFLP) uses restriction enzymes to cut DNA at specific sites, allowing for detection of mutations that alter the restriction sites. 47
14. Effects of HBV Genotypes and Sub-Genotypes on Clinical Practice High replication rates and the capacity to evade immune clearance, HBV genotypes may influence the prevalence by affecting replication rates. HBeAg is more prevalent in individuals with genotype C than in those with genotype B, indicating that HBeAg clears more rapidly in genotype B patients. 48 A relationship has been identified in between abnormal liver enzymes level and HBV genotype, which are less common in hepatitis B carriers with genotype B than in those with genotype C. 49 However, several studies has been observed the linkage between HBV genotype B and HCCto be more strongly at an earlier stage but this observation hasn't been confirmed in other studies. 50 In Saudi Arabia, where genotype D is predominant, HBV associated liver cancer ranks as the second most common cancer among men, pointing to a significant correlation between HBV genotype D and liver cancer. 51 Various factors such as age, male gender, frequent severe acute exacerbations, nucleotide mutation frequency, and HBV reactivation after HBeAg sero- conversion increase the risk of advanced liver diseases in CHB patients. 52 A study conducted by C Fernandes da Silva et al. highlighted the uncertainty over which genotypes and subgenotypes pose the greatest risk for liver cancer and cirrhosis; however, his study suggested that HBV/C presents a greater risk. 53 The A2 subgenotype is often linked with high viral loads, leading to acute infection via horizontal transmission, while chronic and occult infections are due to subgenotypes D1 and D3 respectively. 11,54 Yen–Hsuan Ni et al. demonstrated in their study that genotype B accounts for over 70% of chronic HBV infections in Taiwan, with delayed HBeAg sero-conversion noted in those with HBV genotype C. 55 Further changes and mixtures of genotypes appear only in individuals who experienced HBeAg sero-conversion during childhood HBV chronic infection. Genotype B remains predominant among the pediatric age group, making up the majority of HBsAg carrier children. 56
15. Conclusion The HBV genotypes and its variants may be used to predict the progression of the liver disease, which will help clinicians in developing effective therapeutic strategies and customize antiviral treatment. This study highlights genetic changes over the time and geographical location versus different geographical distributions of genotypes and sub-genotypes, which play pivotal role in disease progression, helping to devise necessary preventive measures to mitigate the onset of new infections and the spread of emerging genotypes across the globe and in India. The emergence of genotypes or subgenotypes and its significant mutation plays a critical role in determining early clinical outcomes in different geographical areas. Delayed HBeAg sero-conversion was observed in patients with genotypes C and D in comparison to patients infected with genotypes A and B. Furthermore, those with C and D genotypes are more likely to experience worse clinical outcomes due to the quick progression of the disease and sometimes it may lead to HCC. In contrast to individual with genotypes C and D, those with genotypes A and B often respond therapies based on interferon. The efficacy of nucleotide analogue treatments and HBV genotype do not significantly correlate.
16. Source of Funding None.
17. Conflict of Interest None. Gaur et al. / Indian Journal of Microbiology Research 2025;12(3):287–294 293 References
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