Viral hepatitis update: Progress and perspectives

Table 1 Features of different types of hepatitis virus

	HAV	HBV	HCV	HDV	HEV
Family	Picornaviridae	Hepadnaviridae	Flaviviridae	Undefined1	Hepeviridae
Genus	Hepatovirus	Orthohepadnavirus	Hepacivirus	Deltavirus	Orthohepevirus
Genome	Positive single-stranded linear RNA	Double stranded gapped DNA	Positive single-stranded linear RNA	Negative single-stranded circular RNA	Positive single-stranded linear RNA
Genome length (kb)	7.5	3.2	9.6	1.7	7.2
Genotype	6 genotypes: I, II and III infect humans, and IV, V and VI infect non-human primates	10 genotypes (A to J)	8 (1 to 8)	8 (1 to 8)	8 (1 to 8)
Transmission	Fecal-oral	Parenteral, sexual, and perinatal	Exposure to infected blood	Exposure to infected blood and body fluids	Fecal-oral; zoonotic; blood transfusion
Treatment	None. In case of severe hepatitis, treatment of symptoms	Pegylated interferon-alpha and nucleoside/nucleotide analogues	DAA	Pegylated interferon-alpha	Ribavirin (in chronic HEV infection)
Prophylaxis	Yes (inactivated vaccine)	Yes (recombinant vaccine)	No	Yes (HBV vaccine)	No2
Clinical outcome of infection	Self-limited	Self-limited and chronic	Self-limited and chronic	Self-limited and chronic	Self-limited
Chronic infection rate	No	Depends on the age of acquisition of the infection. Birth or in infancy 90%, 1 yr and 5 yr of age 30%-50%, adulthood 5%. Hemodialysis patients 40%. Immune deficient patients 20%	80%	More frequent in HBV/HDV superinfection than coinfection	Acute infection in most of the cases. Chronic infection in immunosuppressed populations

¹It is not defined yet in any of the established viral families.

²There is only one vaccine, approved and used only in China. HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HDV: Hepatitis D virus; HEV: Hepatitis E virus; DAA: Direct antiviral agents.

Table 2 Hepatitis A virus highlights

	Hepatitis A virus
1	The risk of HAV infection is associated with the lack of safe water and poor and sanitation
2	Due to the vaccine introduction in childhood, young adults are becoming more susceptible to HAV infections
3	In countries where waterborne transmission is rare, outbreaks occur among men who have sex with men, injecting drug users and contaminated food
4	Since molecular detection is not routinely performed for diagnosis, surveillance programs, including viral amplification and sequencing, are needed to know the strains that circulate in a certain place
5	One of the greatest challenges for HAV is to increase vaccination coverage globally, still implementing the single-dose schedule, to decrease the new infections, and, in the long term, to achieve its eradication

HAV: Hepatitis A virus.

Table 3 Hepatitis B virus highlights

	Hepatitis B virus
1	Several host factors, such as male gender, alcohol intake, and obesity have been associated to worse disease progression. Current challenge implies finding genetic markers to predict the course of HBV infection. In this line, different SNPs associated with the outcome of HBV infection have been recently identified
2	In the last years, new diagnostic assays have been developed in the framework of the diagnosis of HBV infection. The implementation of quantitative HBsAg, HBcAg, and HBV-RNA in routine clinical practice could probably improve the management of patients with CHB
3	Current antiviral treatments have some shortcomings, such as poor SVR or prolonged schedules. Direct antiviral agents against different HBV targets, including HBV cccDNA, are under evaluation. Moreover, immunemodulatory therapies to overcome host immune impairment observed in chronic infections are being investigated
4	Although a safe and cost-effective vaccine is available since the 1980s, an inadequate response is achieved in particular settings. New and more potent adjuvants, as well as formulations that include alternative viral antigens could improve the response rate vaccination
5	The development of new antiviral therapies that enables achieving functional cure as well as accurate diagnostic methods and more effective vaccines will contribute with the purpose of the WHO to eliminate by 2030 hepatitis as a global health problem

HBV: Hepatitis B virus; SNP: Single nucleotide polymorphisms; HBsAg: Hepatitis B surface antigen; HBcAg: Hepatitis B core Antigen; CHB: Chronic hepatitis B; SVR: Sustained virological response; WHO: World Health Organization.

Table 4 Hepatitis C virus highlights

	Hepatitis C virus
1	WHO global hepatitis elimination strategy aims to reduce 90% of new HCV incidence, 65% of mortality and treat at least 80% of patients
2	DAA treatment leads to regression of clinical symptoms and liver disease complications even in those patients with other comorbidities, co-infections, or advanced liver disease
3	The immune response plays a central role in viral elimination. The understanding of the relationship between achieving protection and activation of immune responses is mandatory for the development of an effective prophylactic vaccine
4	Immune response restoration after DAA treatment is also under debate, certain immune features are reinvigorated, but many immune exhaustion signs may persist
5	SVR after DAA rates higher than 97% are usually attained, but still, a minor group of patients (4%-5%) fails to eradicate HCV due to resistance-associated variants, some of them arising after treatment but others naturally occurring in treatment naïve individuals
6	DAA efficacy impacts on transplantation from HCV-infected donors into infected or uninfected recipients; however, early outcome data are encouraging, experience is limited, and many issues remain under debate
7	HCC risk after DAA treatment has been extensively discussed; however, recent seminal reports support the notion of a reduced rate for occurrence or recurrence of HCC after DAA SVR
9	There are numerous HCV vaccine approaches including a few candidates who accomplished phase I trials, but a prophylactic HCV vaccine that can contribute to the eradication goal remains a pending issue

DAA: Direct antiviral agents; SVR: Sustained virological response; WHO: World Health Organization; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma.

Table 5 Hepatitis D virus highlights

	Hepatitis D virus
1	The natural course and outcome of acute hepatitis D differ according to HBV and HDV co-infection or superinfection
2	HDV and HBV genotypes in addition to host factors influence the course of chronic hepatitis
3	The implications on liver disease of HVD, HBV, and innate immunity interplay remain to be understood
4	Chronic setting leads to more severe hepatitis associated with higher rates of HCC and a faster progression to cirrhosis compared with HBV monoinfection. HDV pathologic changes are limited to the liver with histopathologic features that are not specific for it
5	HDV remains difficult to treat with the current available therapies, and although, several promising new therapies have been described treatment is still the greatest challenge in HDV infection

HDV: Hepatitis D virus; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma.

Table 6 Hepatitis E virus highlights

	Hepatitis E virus
1	HEV is transmitted by the fecal-oral route (involving contaminated waters) and also as a zoonosis
2	In the last years, many studies have focused on HEV detection in environmental and food matrices, and blood products as alternative sources of infection
3	A new etiological agent of human hepatitis E, Orthohepevirus C, previously known to infect rats, has been recently described
4	Although most cases of HEV infection produce acute hepatitis, chronic infections seem to be an increasing problem, particularly in Europe
5	Complications and extrahepatic manifestations are also increasingly recognized
6	Only one vaccine for HEV has been licensed in China, with little known data, which limits its use

HEV: Hepatitis E virus.