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Hepatitis B Update (reflection)

ReFlections Vol 44, May 4, 2018. RGA (Reinsurance Group of America, Incorporated®)

Author : Akhilesh Pandey Senior Underwriter, Research and Manual Development. RGA India.

Abstract :

Hepatitis B is one of the world’s most prevalent infectious diseases  today. The disease has been recognized for millennia, but the first actual breakthrough in understanding its etiology came more than 50 years  ago, when it was discovered that the serum protein Australia Antigen  (first discovered in Australian Aborigines) was in fact the surface antigen (HBsAg) of the hepatitis B virus (HBV). This discovery enabled the development of a successful hepatitis B vaccine in 1981.1

Although the HBV vaccine has been administered routinely at birth in the U.S. since 1991 and despite ongoing population education and awareness efforts, HBV infection remains a global health hazard. It is frequently asymptomatic, so many acutely and chronically infected patients may be unaware they have this disease and so can be the cause of significant mortality and morbidity.

The aim of this article is to update readers on advances in the understanding, treatment, and prognoses for this condition, as well as the underwriting and claims implications for life and health insurers.

About HBV: Epidemiology

The hepatitis B virus (HBV) is a DNA virus belonging to the hepadnaviridae family. It is considered to be the most complex of the five known forms of viral hepatitis (A, B, C, D, and E). HBV is also a global disease: the World Health Organization (WHO) in 2017 estimated that 325 million individuals worldwide are living with the disease’s chronic form, a 25% increase from 2015’s 260 million estimate. In addition, the Centers for Disease Control and Prevention (U.S.) recently stated that approximately 600,000 individuals worldwide die annually as a direct or indirect consequence of HBV infection. 

The disease’s highest prevalence (just over 7%) is in the Western Pacific region (including China and Taiwan) and in Africa. Eastern and Southern Europe, Southeast Asia and Japan have intermediate prevalence levels (2% to 7%), and North America has extremely low prevalence (<2%)2 which is not surprising, as the HBV vaccine has routinely been administered to U.S. newborns for nearly three decades. 

The main forms of transmission are via bodily fluids such as blood, semen, and saliva. In areas where HBV is endemic, vertical transmission (i.e., prenatal or perinatal transmission) is its dominant mode of spread. The chances of infection becoming chronic is close to 90% among infected infants, presumably because infant immune systems are immature (immune tolerance phase) whereas among older children and adults, chronicity may vary between <1% to 10%.3 In areas of lower prevalence, the main routes for HBV transmission are unprotected sexual intercourse, intravenous drug use or, for health care workers, direct contact with bodily fluids of infected persons.3

Clinical Manifestations

HBV infections start out as acute and progress either to resolution or to chronicity. The acute phase lasts from one to six months. During this time, infected individuals generally do not have symptoms, but are able to pass the infection to others. However, when symptomatic, individuals with acute hepatitis B can experience anorexia, nausea, low-grade fever, myalgia, changes in the ability to smell or taste, jaundice (icterus), and mild to moderate pain in the right upper quadrant of the abdomen. In rare cases (<3%) fulminant hepatitis B can develop,5 leading to rapid liver failure, encephalopathy, coma, and death.

Those whose hepatitis B has neither spontaneously cleared in six months nor has progressed to fulminant hepatitis are considered to have progressed to chronic hepatitis B (CHB). As noted earlier, risks of chronicity will differ among infants, older children, and adults due to immune response displayed by the host and the virus’s route of transmission. 

Patients with chronic infection may remain infected for the rest of their lives. They are generally asymptomatic unless the infection progresses to hepatocellular carcinoma (HCC) or there is a transition from compensated cirrhosis to decompensated cirrhosis. In decompensated cirrhosis, patients may have symptoms including jaundice, ascites, edema, encephalopathy, and variceal hemorrhage.
 

Extrahepatic Manifestations

Extrahepatic manifestations of hepatitis B can appear both in the acute and chronic stages. They can have significant mortality and morbidity implications, but clinical prevalence of these is generally low compared to hepatic symptoms. Notable extrahepatic manifestations include:6 

  • Polyarteritis nodosa (PAN) and other vasculitides
  • Glomerulonephritis
  • Hemolytic anemia
  • Dermatological manifestations (e.g., purpura, oral lichen planus, urticaria, pitted keratolysis)
  • Serum sickness
  • Polyarthritis and polyarthralgia
  • Graves’ disease

Phases of Chronic Infection 

HBV is not static but a very dynamic virus, hence it keeps fluctuating between different phases once chronic HBV has developed. The course of a chronic HBV infection has four phases7: 

  • Immune tolerant phase. This is characterized by the presence of the hepatitis B e antigen (HBeAg), high serum HBV DNA levels (>20,000 IU/ml), normal or minimally elevated ALT (alanine aminotransferase) levels, and no or minimal liver fibrosis on biopsy.
  • Immune clearance (also known as immune active or immune reactive HBeAg-positive) phase. During this phase, the immune system is actively attacking infected liver cells. The patient is HBeAg-positive and is experiencing intermittent or persistent elevation of ALT levels and high HBV DNA levels (although not high in comparison with those seen in the immune tolerant phase). The phase can last from weeks to years and ideally ends with HBeAg seroconversion, signaling entry into the next phase.
  • Immune control/inactive carrier phase. This phase is characterized by a lack of HBeAg, the presence of HBsAg, persistent normal ALT levels at least three times over 12 months, and low (<2,000 IU/ml) to undetectable levels of HBV DNA.
  • Reactive/HBeAg-negative CHB (immune escape) phase. There is always the possibility that the disease might reactivate due to mutation of the genes in the pre-core or core promoter regions of the HBV genome. In this phase, HBV DNA levels are rising despite the patient having seroconverted to anti-HBe positive (e.g., the presence of HBeAg antibodies), elevated ALT levels, viral loads of ≥2,000 IU/ml), and moderate to severe liver inflammation and fibrosis levels. In these patents, the virus is active and chronic and risk of cirrhosis rises.

The HBV Genome and Its Mutations

The HBV is a small, circular, partially double-stranded DNA genome, containing four partially overlapping open reading frames (ORFs): 

  • the viral core protein (C) (HBcAg)
  • the polymerase/reverse transcriptase (P) (DNA polymerase)
  • the surface proteins (S) (HBsAg)
  • the hepatitis B virus X protein (HBx)
The general function of the X protein is not yet clearly understood, but it appears to be associated with an increased risk of developing liver cancer.8

The HBV genome is unique among human viral pathogens in that it replicates via a protein-primed reverse transcriptase of an RNA intermediate (i.e., pre-genomic RNA). The reverse transcriptase also lacks proofreading activity, which may explain why HBV has a reported mutation rate 10 times higher than that of other DNA viruses and why its genetic variation is so wide.
 
During the replication process, translation at the pre-core region results in HBeAg, and at the core region, in HBcAg. HBeAg levels are used clinically as an index for infectivity, viral replication, severity of disease and response to treatment. HBcAg, the core antigen, indicates active viral replication (meaning the person is infectious). Mutations at these sites are considered the main causes of HBeAg-negative (Phase 4) hepatitis, as most infected individuals who are HBeAg-negative harbor mutated variants in the pre-core and core promoter regions of their HBV genome.
 
The most frequent mutation of the gene (e.g., mutations of the core promoter’s basal core promoter section) results in an HBeAg-negative phenotype due to termination of translation, which reduces HBeAg secretion with consequent increase in viral replication. Further pre-core promoter mutation causes elimination of HBeAg production, resulting in HBeAg-negative disease.9,10 It has also been suggested that HBeAg proteins might modulate the patient’s immune response as a tolerogen (an antigen that induces immune tolerance), thereby promoting chronicity of the HBV infection.

Additionally, there is mounting evidence that detection of such pre-core and core mutations may confirm whether a patient with no or low levels of HBeAg has HBeAg-negative disease due to the mutation is actually responding to treatment.11, 12, 13, 14 

 
Many other mutations of this genome have been recognized, including several within the HBV polymerase ORF leading to antiviral drug resistance, those associated with vaccine failure (HBsAg escape mutant), or loss of HBV detection by diagnostic assays due to altered HBsAg. 
 
Rapid diagnostic testing (RDT) for HBsAg has specificity close to 100% and is more convenient and is easier to perform outside of a laboratory than conventional enzyme-linked immunosorbent assays.15

A greater understanding of HBV genome mutations is likely to contribute to improved diagnostic testing and therapeutic protocols. 
 

Diagnosis, Antiviral Therapy, Recent Advancements

Since the discovery of the Australia antigen there has been continuous improvement in HBV-related virological tools, which has made a considerable impact on the ability to screen for and diagnose HBV.

  • Rapid diagnostic testing (RDT) for HBsAg has specificity close to 100% and is more convenient and is easier to perform outside of a laboratory than conventional enzyme-linked immunosorbent assays.15
  • HBsAg assays can accurately quantify HBsAg levels which have several possible indications in clinical practice and can be used as an alternative parameter for monitoring treatment response.16
  • Commercially available advanced molecular diagnostic tools such as real-time transcription-mediated amplification-based assays can accurately quantify HBV DNA levels, which are essential for the diagnosis and prognosis of HBV infection.17

Unlike in hepatitis C, complete clearance of HBV is highly unlikely due to its high mutation rate and extremely low rate of viral replication. Therefore, the goal of treatment is prevention of progressive liver disease or the development of hepatocellular carcinoma (HCC). The incidence of the latter is 15 to 20 times higher in those with chronic HBV compared with control populations.18, 19

Treatment guidelines are based on the recommendations of major professional organizations that are focused on the study, prevention, and cure for liver disease such as the EASL (European Association for the Study of the Liver) and the AASLD (American Association for the Study of Liver Diseases).

Treatment options focused on mutation of the genome depend on how the virus is replicating, the phase, and the patient’s immune response. Current options include: 20 

  • Nucleoside analogues such as lamivudine, entecavir, and telbivudine
  • Nucleotide analogues such as adefovir and tenofovir disoproxil
  • Pegylated interferon

Data suggests that maintained suppression of HBV replication using nucleoside and/or nucleotide analogues may reduce the worsening of liver fibrosis, thereby reducing the risk of developing cirrhosis, and prevent further disease progression (including HCC) in patients with advanced liver fibrosis or cirrhosis.21, 22 

The main challenge with antiviral drug treatment is the emergence of drug resistance and resumption of HBV viral replication. This issue, however, may be overcome by using adjuvant therapy with low-resistance drugs (e.g., combination therapy with tenofovir and entecavir).23

Therefore, the approval of new treatments is largely dependent on their impact on the following surrogate markers:24

  • Biochemical: ALT/AST levels
  • Virological: HBV DNA levels, HBeAg serostatus, HBsAg serostatus
  • Histological: using various histological scoring models such as the METAVIR score, which assesses the liver’s level of inflammation and fibrosis, the Knodell score/HAI (histology activity index), which measures liver inflammation and scarring, or the Ishak score (a modified Knodell score)

Since the development of HBsAg loss is, as noted earlier, a rare event, it is relatively difficult to determine the therapeutic endpoint while treating HBV infection. However, the biochemical, virological, and histological surrogate markers listed above can be useful ways to measure the need for or efficacy of antiviral treatment. 

Co-infection with HIV or HCV

As HIV and HBV can share similar transmission routes, up to 14% of patients with HIV are co-infected with HBV. The highest prevalence of this is in sub-Saharan Africa and Asia.25 Mortality in these co-infected patients is 50% higher than for mono-infected individuals. 26 

Approximately 2% to 15% of HBV patients are co-infected with hepatitis C. In these patients, the hepatitis C virus can become dominant if untreated, reducing HBV levels  to nearly undetectable, but once the hepatitis C has been treated and is resolved, HBV replication can increase. This co-infection can lead to more severe liver disease and an increased risk for progression to HCC.27

An Insurance Medicine Analysis – Mortality and Morbidity

The long-term mortality and morbidity implications of chronic HBV infection in otherwise healthy Chinese insurance applicants was reviewed in an article by Pokorski, et al. Mortality ratios of 150% to 175% and 125% to 150% were estimated for men and women respectively, suggesting that the majority of HBV cases are within insurable range. However, risk varied based on factors such as seropositivity, ALT levels, circulating HBV DNA viral loads, and degree of fibrosis or cirrhosis.28 

In terms of morbidity, there is a significant risk of both hepatic and extrahepatic cancer, HR 2.34 (95% CI: 2.15-2.55), even after the exclusion of any co-infected patients.29

Although the impact of chronic HBV on the incidence of coronary artery disease or atherosclerosis appears to be insignificant, it remains under investigation.

 

Implications for Life Insurance and Living Benefits Risk

The continuous evolution of diagnostic tools and treatment modalities means the risk profile of those with chronic HBV infection is improving. This will provide several benefits for life insurance and living benefits applicants as well as insurance carriers.

For life insurance: 

  • More applicants will be insurable based only on full blood profile (e.g. serum albumin, alpha fetoprotein level, LFTs, HBV DNA viral loads).
  • Non-invasive diagnostic technologies such as liver scans (e.g. Fibroscan®) can lead to earlier treatment initiation, thus improving long-term prognoses.
  • Liver biopsy will continue to be an important way to assess the degree of fibrosis and the subsequent initiation of treatment. The use of biopsy in general, however, is now limited to more complex cases and therefore simpler non-invasive techniques such as Fibroscan®, USG, and others, are gaining more popularity.
  • Antiviral therapy could provide more beneficial outcomes if access to these treatments was more readily available, particular in areas where chronic hepatitis B disease is endemic.
In summary, acute hepatitis B can become a chronic infection. Frequent and long-term monitoring has been shown to have a favorable impact on prognosis, thus improving insurers’ ability to insure these lives.
 
For living benefits: 

  • When there is adequate treatment, fewer claims may be experienced for critical illness policies, hospital cash benefits, total and permanent disability products, and long-term care products.
  • The effective prevention or early diagnosis of HBV will result in a substantial reduction in economic cost and burden on health-related services by the alleviation of chronic HBV-related disease(s).

Summary

Advances in the diagnosis and treatment of chronic HBV infection have resulted in more favorable outcomes. Although both mortality and morbidity risk may still vary, risk factors such as serostatus, circulating serum HBV DNA, and degree of fibrosis should to be taken into consideration when assessing any particular profile. Second, the cost-effectiveness of antiviral treatments and programs such as universal HBV vaccination, in adulthood as well as at birth, may have an important role in deciding the actual benefit of these advances. Hepatitis B infection, once it reaches chronicity, is less likely to resolve, but its management has improved over the past decade due to advances in diagnosis and treatment, which has resulted in significant suppression of virus activity. For those individuals with access to these advanced measures, the prognosis will be significantly improved, and will reduce its risk for both life and living benefits.

References

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2. MacLachlan JH, et al. Hepatitis B Virus Epidemiology. Cold Spring Harbor Perspectives in Medicine. 2015; 5:a021410. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448582/pdf/cshperspectmed-HEP-a021410.pdf

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17. Chevaliez S, et al. The New Aptima HBV Quant Real-Time TMA Assay Accurately Quantifies Hepatitis B Virus DNA from Genotypes A to F. Journal of Clinical Microbiology. 2017 Feb 15; 55(4):1211-9. http://jcm. asm.org/content/55/4/1211.

 
18. Amin J, et al. Cancer incidence in people with hepatitis B or C infection: a large community-based linkage study. Journal of Hepatology. 2006 Aug; 45(2): 197-203. https://www.sciencedirect.com/ science/article/pii/S016882780600167X

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21. Zhang QQ, et al. Long-Term Nucleos(t)ide Analogues Therapy for Adults With Chronic Hepatitis B Reduces the Risk of Long-Term Complications: A MetaAnalysis. Virology Journal. 2011; 8(1): 72. https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC3046930/

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23. Lim YS. Management of Antiviral Resistance in Chronic Hepatitis B. Gut and Liver. 2017 Mar 15; 11(2): 189-95. https://www.ncbi.nlm.nih.gov/ pubmed/28183162 

 
24. Feld JJ, et al. Endpoints of therapy in chronic hepatitis B. Hepatology. 2009 May; 49(5 Suppl): S96-S102. https://www.ncbi.nlm.nih.gov/ pubmed/19399800

25. Askari A, et al. Prevalence of Hepatitis B Co-Infection Among HIV Positive Patients: Narrative Review Article. Iranian Journal of Public Health. 2014 Jun; 43(6): 705-12. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC4475589/

26. Van Griensven J, et al. Hepatitis B and C Co-Infection Among HIV-Infected Adults While on Antiretroviral Treatment: Long-Term Survival, CD4 Cell Count Recovery and Antiretroviral Toxicity in Cambodia. PLoS One. 2014 Feb 12; 9(2). http://journals.plos.org/ plosone/article?id=10.1371/journal.pone.0088552

27. Konstantinou D, et al. The spectrum of HBV/HCV coinfection: epidemiology, clinical characteristics, viral interactions and management. Annals of Gastroenterology. 2015 Apr-Jun; 28(2): 221-8. https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4367211/

28. Pokorski RJ, Ohlmer U. Long-Term Morbidity and Mortality in Chinese Insurance Applicants Infected With the Hepatitis B Virus. Journal of Insurance Medicine. 2001;33(2): 143-64. https://www.ncbi.nlm. nih.gov/pubmed/11510512

29. Kamiza AB, Su FH, Wang WC, et al. Chronic Hepatitis Infection is Associated with Extrahepatic Cancer Development: A Nationwide PopulationBased Study in Taiwan. BMC Cancer. 2016; 16(1): 861. https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC5100218/ 

 
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