Preface

#### **Hepatitis B:**

Viral hepatitides are important public health problems in humans. The etiologic agents were not identified until 1965, when Baruch S. Blumberg found the relationship of an Australia antigen to serum hepatitis. The antigen was found to be the surface antigen of the hepatitis B virus (HBV). This observation launched a new era in the diagnosis, prevention, and treatment of hepatitis B. Over 15 to 20 years, the natural history of HBV infection was elucidated, and more importantly, an effective vaccine became available. The routes of transmission were also made clear, rendering effective interruption in the transmission. The vaccine, together with effective interruption of the transmission, contributed greatly to the control of HBV infection. However, these measures do very little for those who have already been chronically infected. Fortunately, specific therapies against chronic hepatitis B started to appear about 10–15 years before, and the treatments have improved substantially in the last few years.

Nevertheless, hepatitis B virus infection remains a major problem for public health worldwide and represents a challenging disease for practicing physicians. Of the 2 billion people who have been infected with the hepatitis B virus, more than 350 million have chronic infections. Roughly, around 30% of the world's population show serological evidence of current or past infection. These chronically infected individuals are at high risk of death from cirrhosis and liver cancer. The use of new antiviral drugs, such us nucleotide analogues, offers hope in the prognosis of patients suffering from chronic hepatitis B.

The hepatitis B virus is a partly double-stranded DNA virus, with several serological markers: HBsAg and anti-HBs, HBeAg and anti-HBe, and anti-HBc IgM and IgG. It is transmitted through contact with infected blood and semen. A safe and effective vaccine has been available since 1981, and although variable, the implementation of universal vaccination in infants has resulted in a sharp decline in prevalence.

Hepatitis B virus is not cytopathic; both liver damage and viral control, and therefore clinical outcomes depend on the complex interplay between virus replication and host immune response. Overall, as much as 40% of men and 15% of women, with perinatally acquired hepatitis B virus infection, will die of liver cirrhosis or hepatocellular carcinoma. In addition to decreasing hepatic inflammation, longterm antiviral treatment can reverse cirrhosis and reduce hepatocellular carcinoma. Development of new therapies that can improve HBsAg clearance and virological cure is warranted.

The diffusion of HBV infection is still wide in several low-income countries, where the prevention, management, and treatment of HBV infection are a heavy burden for the governments and healthcare authorities. Of note, the information on the HBV epidemiology is minimal in numerous eastern European and Latin-American countries. The studies on molecular epidemiology performed in some countries provide an important contribution for a more comprehensive knowledge of HBV

epidemiology, and phylogenetic studies provide information on the impact of recent and older migratory flows.

Occult hepatitis B virus (HBV) infection (OBI) is characterized by the persistence of HBV DNA in the liver tissue, in individuals negative for the HBV surface antigen. The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world, the different assays utilized in the studies, and the different populations studied. Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals. The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.

Although far from perfect, effective means to treat those who are chronically infected now exist. In Taiwan, acute and chronic liver diseases were rampant as early as the beginning of the last century. Studies around 1975 showed an extremely high prevalence of chronic hepatitis B infection in the general population (15–20%), and 80–90% of the chronic liver diseases and hepatocellular carcinoma were caused by chronic infection with the HBV. This important health problem caught the attention of the government in the late 1970s, and a government-sponsored control program was finalized in 1981. Accordingly, a mass vaccination program against hepatitis B, primarily aiming at immunizing newborn infants, was launched on July 1, 1984. Twenty years after implementation of the program, the hepatitis B carrier rate in children covered by the program decreased by 85%, from ~15% to <1%. Most importantly, the deadly sequela of hepatocellular carcinoma in the vaccinees was also found to decrease in parallel. This is the first time that a human cancer was prevented by vaccination. Despite the success, there are still some who were born after implementation of the program but were not prevented from developing chronic hepatitis B infection and hepatocellular carcinoma. Non-compliance to the vaccination schedule, breakthrough infection, and intrauterine infection are the causes of the failure. At present, we have effective measures for immunizing susceptible individuals, interrupting the routes of transmission, and treating the chronically infected. The time for considering the elimination or even the eradication of HBV infection has come. This is especially true for countries where hepatitis B infection is not endemic. Nevertheless, with the admirable results achieved in the past, Taiwan should also think about elimination/eradication of hepatitis B, even though it will certainly be much more difficult than in the non-endemic countries.

#### **Hepatitis C:**

Hepatitis C virus (HCV) infection is a major health problem worldwide. Approximately 170–200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma, and even liver failure. Cloning of the hepatitis C virus was reported in 1989. By now, the entire viral genome has been sequenced. It consists of a single-stranded positive RNA, with relationship to the Flaviviridae. The envelope region shows considerable variability. Six major genotypes have been described. HCV is transmitted via the parenteral route, mainly blood, rarely by sexual contact. Hepatitis C occurs worldwide and is found in 0.01 to 1.5% of blood donors. The immune response is unable to clear the virus in 80% of infected subjects, probably because of the hypervariability. In the acute phase the hepatitis has only mild symptoms and the chronic hepatitis usually also runs a mild course. After many years, liver cirrhosis may develop in 20% of cases; in these subjects there is a high

incidence of hepatocellular carcinoma. The diagnosis can be made by detection of anti-HCV antibodies in the blood and an immunoblot confirmation test. The viral genome can be detected by the HCV-RNA (PCR) test. Immunization against hepatitis C is not possible yet.

Infection with the hepatitis C virus is an example of translational research success. The reciprocal interactions between clinicians and scientists have allowed in 30 years the initiation of empirical treatments by interferon, the discovery of the virus, the development of serological and virological tools for diagnosis but also for prognosis (the non-invasive biochemical or morphological fibrosis tests, the predictors of the specific immune response including genetic IL28B polymorphisms). Finally, welltolerated and effective treatments with oral antivirals inhibiting HCV non-structural viral proteins involved in viral replication have been marketed this last decade, allowing for the cure of all infected subjects. HCV chronic infection, which is a public health issue, is a hepatic disease, which may lead to cirrhosis and hepatocellular carcinoma (HCC) but also a systemic disease with extra-hepatic manifestations either associated with a cryoglobulinemic vasculitis or chronic inflammation. The HCV infection is the only chronic viral infection that may be cured: the so-called sustained virologic response, defined by undetectable HCV RNA 12 weeks after the end of the treatment, significantly reduces the risk of morbidity and mortality associated with hepatic and extra-hepatic manifestations, which are mainly reversible. The history of HCV ends with the pangenotypic efficacy of multiple combinations, easy to use for 8–12 weeks with one to three pills per day and minimal intolerance issues. This explains the short 30 years from the virus discovery to the viral hepatitis elimination policy proposed by the World Health Organization (WHO) in 2016.

A complete eradication of the virus is one of the most important treatment goals for antiviral research. In 2011, the first-generation protease inhibitors boceprevir (BOC) telaprevir (TVR) was approved by FDA as the direct-acting antiviral agents. A number of promising new direct-acting antiviral agents (DAAs) have been developed in the past few years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs are in use for patients with chronic HCV and cirrhosis. In this review, we will discuss the results of clinical trials of several DAAs and the approved combinations, including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. A number of drugs, including Sovaldi®, Harvoni®, Viekira Pak®, Epclusa®, Zepatier® have been approved by FDA in the last years.

Hepatitis C virus infection is a significant health problem worldwide, and is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation in the United States. The management of HCV has changed significantly over the last 5 years, as treatments have become simpler and more efficacious. Medication efficacy is now greater than 90%, with a high barrier to resistance and fewer side effects. This review is a collaboration between primary care and hepatology providers to explore all aspects of HCV management: acute versus chronic HCV infection, transmission and testing, and diagnosis and treatment. Specific medications for the treatment of HCV infection are considered, and patient and medication factors including genotype, liver disease status, and comorbidities affecting medication choice are discussed. This is a new era for the management of HCV infection, and interested primary care physicians, family doctors, and general internists can be at the forefront of diagnosis, management, and treatment of HCV.

DAAs have transformed traditional treatment options for hepatitis C virus infection. DAA combinations have been shown to be highly effective in reducing the burden of

**IV**

**Hepatitis C:**

epidemiology, and phylogenetic studies provide information on the impact of

Although far from perfect, effective means to treat those who are chronically infected now exist. In Taiwan, acute and chronic liver diseases were rampant as early as the beginning of the last century. Studies around 1975 showed an extremely high prevalence of chronic hepatitis B infection in the general population (15–20%), and 80–90% of the chronic liver diseases and hepatocellular carcinoma were caused by chronic infection with the HBV. This important health problem caught the attention of the government in the late 1970s, and a government-sponsored control program was finalized in 1981. Accordingly, a mass vaccination program against hepatitis B, primarily aiming at immunizing newborn infants, was launched on July 1, 1984. Twenty years after implementation of the program, the hepatitis B carrier rate in children covered by the program decreased by 85%, from ~15% to <1%. Most importantly, the deadly sequela of hepatocellular carcinoma in the vaccinees was also found to decrease in parallel. This is the first time that a human cancer was prevented by vaccination. Despite the success, there are still some who were born after implementation of the program but were not prevented from developing chronic hepatitis B infection and hepatocellular carcinoma. Non-compliance to the vaccination schedule, breakthrough infection, and intrauterine infection are the causes of the failure. At present, we have effective measures for immunizing susceptible individuals, interrupting the routes of transmission, and treating the chronically infected. The time for considering the elimination or even the eradication of HBV infection has come. This is especially true for countries where hepatitis B infection is not endemic. Nevertheless, with the admirable results achieved in the past, Taiwan should also think about elimination/eradication of hepatitis B, even though it will certainly be much more difficult than in the non-endemic countries.

Hepatitis C virus (HCV) infection is a major health problem worldwide.

Approximately 170–200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma, and even liver failure. Cloning of the hepatitis C virus was reported in 1989. By now, the entire viral genome has been sequenced. It consists of a single-stranded positive RNA, with relationship to the Flaviviridae. The envelope region shows considerable variability. Six major genotypes have been described. HCV is transmitted via the parenteral route, mainly blood, rarely by sexual contact. Hepatitis C occurs worldwide and is found in 0.01 to 1.5% of blood donors. The immune response is unable to clear the virus in 80% of infected subjects, probably because of the hypervariability. In the acute phase the hepatitis has only mild symptoms and the chronic hepatitis usually also runs a mild course. After many years, liver cirrhosis may develop in 20% of cases; in these subjects there is a high

Occult hepatitis B virus (HBV) infection (OBI) is characterized by the persistence of HBV DNA in the liver tissue, in individuals negative for the HBV surface antigen. The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world, the different assays utilized in the studies, and the different populations studied. Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals. The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without

recent and older migratory flows.

liver disease.

chronic HCV infection in clinical trials and have been recommended by the European Association for the Study of the Liver (EASL) treatment guidelines. Second generation DAAs (sofosbuvir plus daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, sofosbuvir plus velpatasvir, glecaprevir plus pibrentasvir, grazoprevir plus elbasvir) have very high sustained viral response (SVR) rates and good safety profiles, higher resistance barriers, and are more convenient. Real-world data in all 3 genotypes generally support the EASL guidelines and high overall sustained virological response rates are reported with recommended regimens. However, real-world data are only available for sofosbuvir plus daclatasvir, sofosbuvir/ ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir. Furthermore, because of the existing level of evidence, it is difficult to define optimal regimens based on real-world data (ie, treatment duration, when to include ribavirin, and options for patients with cirrhosis). The real-life challenges of managing HIV-coinfected patients are also discussed showing the additional burden of avoiding drug-drug interactions between DAAs and antiretrovirals.

The elimination of HCV has been made possible through the availability of new antiviral drugs that may now be administered to all patients with HCV infection, even those with decompensated cirrhosis. The goal of the WHO is to reduce the incidence of chronic hepatitis infection from the current 6–10 million to 0.9 million cases of chronic infections by 2030, and annual deaths from 1.4 million to fewer than 0.5 million. Achieving these targets will require full implementation of epidemiological knowledge of HCV infection, screening and testing practices, and strategies to link HCV patients to care.

> **Prof. Luis Rodrigo, MD** Emeritus Professor of Medicine, University of Oviedo, Oviedo, Spain

Section 1 Hepatitis B

#### **Chapter 1**

## Molecular Variants for HBsAg: Surface and Subtype

*Johra Khan*

#### **Abstract**

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one-third of the global population has been infected with this virus; approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Hepatitis B virus (HBV) belongs to the hepadnavirus family of enveloped DNA viruses containing a partially double-stranded genome of 3182 ± 3221 bp depending on the genotype that encodes four overlapping open reading frames. HBV is classified into eight genotypes (A–H) that are geographically dispersed. Genotype A is predominant in North America, Western Europe, and Africa; genotypes B and C in Asia; genotype D in Southern Europe, Africa, and India; genotype E in West Africa; genotype F in Central and South America and Alaska; genotype G has been found in the United States, France, and Germany; and genotype H in Central America. Genotypes A, B, C, and D predominate in the United States, while the other genotypes are less common. Further detailed analysis of these HBsAg variants would provide further understanding of the antigenic structure of HBV.

**Keywords:** genotypes, subtypes, surface antigen, hydrophilic region, HBsAg variants

#### **1. Introduction**

A report by Blumberg in 1965 led to the discovery of hepatitis B surface antigen (HBsAg) which is also known as Australian antigen and its related antibody which is hepatitis B surface antibody or HBsAb [1]. After a gap of 5 years, in 1970, another scientist, Dane, visualized the hepatitis B (HBV). Since that time, a significant development has been made about the epidemiology, virology, natural history, and the treatment of this hepatotropic virus. It is the smallest of the DNA viruses that infect man and cause acute hepatitis of varying severity. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. It can survive when stored for 25 years at −20°C, for 24 months at −80°C, for 6 months at room temperatures, and for 7 days at 44°C [2].

Hepatitis B is a global healthcare problem, especially found in developing countries. As per an estimate, one third of the world population has been infected with this virus which is around 350 million people are enduring carriers and only 2% of them are spontaneously seroconvert yearly [3]. Many current vaccination programs seem to be promising in the effort to reduce the incidence of this disease [4]. HBV is transmitted through hematological and sexual means. The consequence of this infection is a complex viral-host interaction which results in either as an

acute disease with symptoms or an asymptomatic disease. Patients may develop an immunity to HBV or it may enter a chronic carrier state (**Figure 1**). The later consequences of this infection are cirrhosis and then development of hepatocellular carcinoma (HCC) [5]. Hepatitis B virus (HBV) belongs to the hepadnavirus family of enveloped DNA viruses containing a partially double-stranded genome of 3182 ± 3221 bp depending on the genotype which encodes four overlapping and open reading frames which are as follows:

The genome is read in all three reading frames, and viral regulatory elements are all within coding regions which introduce constraints on the ability of the virus to accept mutations and remain viable [6]. Nevertheless, heterogeneity among the strains of HBV circulating globally is 10%-fold greater than that in the majority of DNA viral genomes. This is explained, at least partially, by the fact that hepadnavirus replication takes place via an RNA intermediate, and reverse transcriptase is known to have a high error rate 16. A nucleotide exchange rate of between 0–1 and 0–7 per year [7] has been estimated for the HBV [8] and woodchuck hepatitis virus (WHV) [9]; genomes, respectively, which is similar

*Molecular Variants for HBsAg: Surface and Subtype DOI: http://dx.doi.org/10.5772/intechopen.85282*

to the most slowly evolving gene of retroviruses, the gag gene, and one to two orders of magnitude lower than the mutation rates previously calculated for the positive- and negative-strand RNA viruses [10]. The virus persists in 2–10% of adult patients and approximately 90% of infected infants leading to chronic liver disease. In highly endemic areas, infection is predominantly acquired during the perinatal neonatal period or by horizontal transmission in the first few years of life [10, 11] which results in a high prevalence of long-term HBV carriers with a low average age at infection [12], the virus has a long time span in which to evolve within its host.

#### **1.1 Natural history**

Acute infection with HBV in adulthood is rarely associated with the development of potentially fatal fulminant liver failure. Chronic infection, whether acquired in childhood or in adulthood, is associated with progressive liver disease, risk of cirrhosis, liver failure, and HCC and rarely with extrahepatic manifestations. Chronic HBV infection is characterized by four distinct phases: immune tolerance, immune clearance, inactive carrier state, and reactivation [13]. The immune tolerance phase is characterized by detectable HBeAg, high levels of HBV DNA (>105 copies/ml), and normal ALT levels. The immune clearance phase, also called CHB, is characterized by detectable or undetectable HBeAg, undetectable or detectable anti-HBe antibodies, lower or fluctuating levels of HBV DNA, high or fluctuating ALT levels, and active inflammation as seen on liver biopsy. The inactive HBsAg carrier state is characterized by detectable HBsAg, undetectable HBeAg, detectable anti-HBe antibodies, low levels of HBV DNA (<104 copies/ml), and normal ALT levels. Later in the carrier phase, HBsAg may become undetectable, and anti-HBs antibodies may appear [13], although reactivation can occur in inactive HBV carriers (**Figure 2**).

#### **Figure 2.**

*Different stages of HBV infection. https: //www.123rf.com/photo\_83543016\_stock-illustration-liver-diseaseprogression-in-hepatitis-c-virus-infection-3d-illustration.html.*

#### **2. The surface gene and variants**

HBV is classified into eight genotypes (A–H) that are geographically dispersed. Genotype A is predominant in North America, Western Europe, and Africa; genotypes B and C in Asia; genotype D in Southern Europe, Africa, and India; genotype E in West Africa; genotype F in Central and South America and Alaska; genotype G has been found in the United States, France, and Germany; and genotype H in Central America. Genotypes A, B, C, and D predominate in the United States, while the other genotypes are less common. 31 Genotype B is associated with less active disease, slower progression, and lower incidence of hepatocellular carcinoma (HCC) than genotype C. Genotypes A and B generally respond better to treatment with interferon than do genotypes C and D. No relation between HBV genotypes and response to nucleos(t)ide analogue-based therapies has been demonstrated 31.

Originally, four genotypic groups of HBV (A–D) were defined, based on an inter-genotypic divergence score of 8 ± 5–10 ± 0% between 18 complete genomes, as compared to a score of 1 ± 1–2 ± 7% between isolates within the same genotype [14]. This genotypic classification was extended to six genotypes (A–F) by phylogenetic analysis of 122 surface antigen (HBsAg) genes [15]. The genotypic groups are geographically arranged [16] with genotypes B and C confined to Asia, while genotype A predominates in Northern Europe giving way to genotype D as one moves toward the Mediterranean region. Genotype E is mainly found in parts of East, Central, and West Africa, and genotype F is only found in the New World and the Pacific which is also home to the Cq—subgroup of genotype C [17]. Two subgroups of genotype A, subgroups A and A, were found in approximately equal amounts in an urban population from South Africa together with 10% of genotype D [17].

In the recent advances in molecular diagnostic techniques, it was found that HBV envelop is made of host-derived bilayer of phospholipids encoded by S gene. c1.

#### **3. The surface gene variants**

The mutation in HBV depends on the high rate of replication of this virus which in turn depends on RNA- dependent DNA polymerase. In highly variant individuals, the mutation of genome can be up to 1010 per day. Whereas most of the variants produced are defective, some of them can cause infection or reason for treatment failure.

#### **3.1 HBsAg variants**

In the structure of virus, the coat of the outer surface is made up of hepatitis B surface proteins which are made in larger amounts than needed by the virus to its reproduction process. The excess amount of these surface proteins clusters together into some spherical units of size between 17 and 25 nm of diameter, and sometimes it also forms rods of different lengths. It is found that in some studied cases, these units condense as a core particle to produce a whole and infectious virus unit that passes into the blood stream and can also infect many other healthy liver cells. All the different structures like extra spheres, rodlike and also sometimes complete viral particles easily move in the blood stream in large amount and can be easily detected; only it takes little long time for these protein particles to appear in blood.

The incubation time for this hepatitis B Virus (hepatitis B) can be between 6 and 25 weeks. It was found that after infection for up to 1 to 6 weeks before symptoms start occurring, HBsAg appears. To confirm the presence of hepatitis B infection, the positive result for the presence of hepatitis B surface protein (HBsAg) is the

available standard test to indicate current infection. If the hepatitis B surface protein (HBsAg) remains present for a time of more than 6 months, it is generally considered as an indicator for chronic infection.

It is reported that if excess of HBs proteins is produced, it may allow infectious hepatitis B virus particles to leak the immune system by mopping some low levels of surface antibodies that may be produced by the immune system due to its 145 amino acid which is glycine that changes to arginine (G145R) [18].

#### **3.2 Hepatitis B core protein (HBcAg)**

The HBc proteins link together to form the hepatitis B core that encapsulates HBV DNA and DNA polymerase; this core is in turn encapsulated by HBs proteins.

The core protein (HBc) is not detectable in the bloodstream; however it can be detected in the sample of liver cells taken after a liver biopsy.

#### **3.3 HBe protein (HBeAg or "e" antigen)**

The Hepatitis B "e" antigen (HBeAg) is a peptide and normally detectable in the bloodstream when the hepatitis B virus is actively reproducing; this in turn leads to the person being much more infectious and at a greater risk of progression to liver disease. The exact function of this nonstructural protein is unknown; however it is thought that HBe may be influential in suppressing the immune system response to HBV infection. HBeAg is generally detectable at the same time as HBsAg and disappears before HBsAg disappears. The presence of HBeAg in chronic infection is generally taken to indicate that HBV is actively reproducing and there is a higher probability of liver damage. In acute infection HBeAg is generally only transiently present [19].

However mutant strains of HBV exist that replicate without producing HBeAg. In many cases infection with these mutant strains is more aggressive than HBe producing strains [20].

#### **4. Variants associated with antiviral therapy**

Polymerase variants are another class of variants detected during therapy with nucleoside analogues which become the reason for drug resistance. The most recognized mutation affecting lamivudine drug is due to change in 204 amino acid from methionine to valine or isoleucine (M204 V/I) which sometimes occurs with another change at 180 amino acid position (L180 M). This change helps in replication and healthy survival of the mutant.

In HBV-infected patients during liver transplant therapy, antiviral prophylaxis is combined with HBIG drug as the polymerase gene and surface gene in HBV have the same regions of the genome; although read in a different frame, the mutation in one can force the other for it. This could lead to complications in selection of mutants for both HBsAg and HBV polymerase [21].

#### **4.1 HBV variants associated with active immunization**

Active immunization is the most effective way to control the prominent cause of hepatitis, human hepatitis B virus (HBV). The highly antigenic hepatitis B surface antigen (HBsAg) is directly related to induce the humoral immune response, which on the other hand provides immunity against HBV infection. Neutralizing B cell epitopes are believed to be due to changes in position 124 to 147 of HBsAg, defined as the "a" determinant [22].

In recent years, HBV variants with mutations on the "a" determinant have been recognized following vaccination. These mutants are proficient in independent replication and lead to active infection [23–25]. These mutations have been identified at various positions on the "a" determinant, the most often identified being the glycine-to-arginine change at position 145 (G145R) of HBsAg [25–31].

The most important is that some of the mutants existed before the vaccination program is introduced. These include changes of amino acids at positions 126, 129, 133, and 145 [29, 31]. Some of these are naturally occurring HBsAg variants which are transmissible and are able to infect even the vaccinated population [29, 31]. HBsAg variants have recently been recognized on the major hydrophilic loop of HBsAg (aa 100–160) but outside the conventional "a" determinant [32]. These new mutants can occur in both the vaccinated and unvaccinated individuals in a population and are not able to be neutralized by the presently available antibodies.

#### **5. HBsAg in liver transplantation**

The patients suffering with chronic HBV contagion are having high risk of developing cirrhosis and hepatic liver failure and having hepatocellular carcinoma. The well-known orthotopic liver transplantation (OLT) procedure is a well-established treatment for liver failure and other hepatocellular carcinoma patients. The occurrence of HBV infection creates many exceptional issues with patients undergoing orthotopic liver transplantation treatment. The inability to get treatment and HBV reinfection occurs in almost 75–80% of persons who undergo OLT treatment. Recurrence of HBV infection even after OLT repeatedly followed by aggressive clinical treatments and also related with a major decrease in successful graft and the rate of patient recovery. In recent times some new antiviral therapies and prophylactic schemes using hepatitis B immune globulin (HBIG) have been established to decrease the risk of recurrence of HBV infection in OLT patients.

#### **5.1 Liver transplantation after treatment of HBV infection**

There are numerous aims of providing antiviral therapy to patients with cirrhosis which is secondary to prolonged HBV infection. The patients who have with compensated cirrhosis, they can get antiviral therapy which can inhibit development to decompensated cirrhosis and eradicate the possible requirement for OLT treatment. The antiviral therapy can effectively decrease the risk of advancement to hepatocellular carcinoma.

For patients having decompensated cirrhosis, antiviral therapy can improve liver function which can also delay the need for transplantation. If the patient's condition progresses to the point that transplantation is needed, the aim of antiviral therapy is to minimize the HBV risk at the time of transplantation, thereby controlling the risk of recurrence of HBV infection after OLT.

#### *5.1.1 Major therapies for minimizing HBV infection or recurrence*

**IFN-α**: Before starting treatment with IFN-α, the hazards and uses related to IFN-α therapy must be carefully assessed in patients having cirrhosis with chronic HBV infections. IFN-α treatment is related with a burst in serum aminotransferases in 35–55% of already treated patients. For patients having progressive liver disease, IFN-α rehabilitation may increase the hepatic breakdown, so it has to be avoided. IFN-α treatment can aggravate cytopenia and additional intensification the risk of severe bacterial toxicities. IFN-α treatment can be provided safely by keeping

#### *Molecular Variants for HBsAg: Surface and Subtype DOI: http://dx.doi.org/10.5772/intechopen.85282*

close monitoring system for the patients having compensated cirrhosis [33]. Some researchers prove that up to 31% of the cirrhotic HBV patients cured using IFN-α-2b had showed seroconversion of antibody related to hepatitis B antigen, and they lose of measureable HBV DNA, in response rates which are similar to that of the non-cirrhotic patients. Various studies had shown that the cirrhotic patients who have lost HBeAg show superior up to 10 years of survival rate in comparison to the patients who had shown no response to IFN-α therapy [34]. Some of the researchers had shown in there research that the rate of incidence of hepatocellular carcinoma may be lesser in patients who had received treatment using IFN-α, generally in the subcategory of patients who had cleared HBV DNA from their blood serum [35, 36]. Generally, the risks related to IFN-α treatment and the occurrence of harmless and well-tolerated oral antiviral therapies have reduced the usefulness of IFN-α treatment in patients having cirrhosis. Pegylated IFN-α-2a was newly accepted by the US Food and Drug Administration to be used for the treatment of chronic hepatitis B. A few related data is presently available showing the use of pegylated IFN-α in relation to cirrhotic patients having hepatitis B.

**Lamivudine**: It is based on nucleoside analogue which is an effective inhibitor of HBV DNA replication process. It was one of the first accepted orally administered medications to be used for the treatment of patients having chronic HBV infection. It has also confirmed an exceptional safety picture in both the compensated and uncompensated patients of cirrhosis. In patients suffering from decompensated cirrhosis because of HBV infection, lamivudine is shown to be a safe and effective drug therapy. Previous researches having uncontrolled case studies show the conflicted results for lamivudine treatment which was shown to delay advancement to death or toward liver transplantation [37, 38]. Liaw et al. [39] stated the results related to a large, potential, multicenter randomized trial based on the study of 651 patients who had chronic hepatitis B, and bridging fibrosis was randomized to obtain any of the lamivudine or placebo. The basic points of this research was time essential for the disease development, which is also known as hepatic compensation, hepatocellular carcinoma, spontaneous bacterial peritonitis, variceal bleeding, or death associated with liver disease. After they receive a treatment for a period of 32.4 months which can range from 0 to 42 months in which a substantially larger percentage of patients in the placebo group in contrast to the lamivudine group developed disease advancement (17.7% vs. 7.8%; Pp. 001), because of which the study was finished early. Moreover, hepatocellular carcinoma arose in a less percentage of patients in the lamivudine-treated individual than in the placebo group (3.9% vs. 7.4%, Pp .047). The results show that based on lamivudine is more effective in reducing the occurrence of hepatic decompensation and hepatocellular carcinoma in patients who have chronic HBV infection and also progressive fibrosis or cirrhosis. The main aspect reducing the use of lamivudine is that it causes the increase of mutations in the YMDD motif of the HBV DNA polymerase gene, which develops resistance against lamivudine. YMDD mutations are emerging with a rate of ∼20% every year against lamivudine treatment which are related to the return of active viral replication [40]. The findings of lamivudine resistance in clinical setting vary according to the rigorousness of underlying liver damage. The initial sign related to resistance usually occurs as a recoil in the HBV DNA level, lacking any other irregular biochemical or clinical results. However, advanced liver failure has been defined in connotation with the occurrence of YMDD mutations.

So, patients with cirrhosis need closely observing during their receiving prolonged lamivudine therapy.

**Adefovir dipivoxil:** An oral prodrug of adefovir which is a nucleotide analogue of adenosine monophosphate that inhibits HBV DNA polymerase. Many studies show that adefovir has tremendous activity against wild-type as well as lamivudine-resistant HBV strains. Researchers evaluated the safety and efficacy of adefovir dipivoxil (10 mg daily) in 128 patients having lamivudine-resistant HBV and are waiting for liver transplantation. Treatment for a period of 48 weeks managed to cause an average decrease in HBV DNA titer of 4.1 log10 copies/ml, where as in non-detectable HBV DNA (by PCR; lower limit of detection, 400 copies/ml), it was in 81% and showed better Child-Pugh score which is up to 92%. Adefovir dipivoxil treatment can generally be accepted very finely with an increase in their serum creatinine level up to 10.5 mg/dL from baseline in around 12% of the patients. No patient is required to stop adefovir dipivoxil therapy due to nephrotoxicity. The survival rate after 48 weeks was 84% which is significantly better than the rate for historical control subjects.

**Other oral agents**: Entecavir a new guanosine nucleoside analogue which was recently accepted by the US Food and Drug Administration for the treatment of chronic hepatitis B. Although no publication is done, but a huge phase III research has proven that HBeAg-positive patients provided with entecavir (0.5 mg daily for 48 weeks) showed a mean change in HBV DNA titer of \_6.98 log10 copies/ml, which was considerably better than that was found with lamivudine [33]. Entecavir has also revealed activity against lamivudine- and adefovir dipivoxil-resistant HBV strains. Still there are no exact data available on the use of entecavir in patients with decompensated cirrhosis or in association with liver transplantation.

#### **6. Conclusion**

HBsAg variants with changes outside the "a" identification of these new HBsAg variants and their functional analysis may provide further understanding of the antigenic structure of HBV; also liver transplantation for hepatitis B is having complication of the risk of recurring HBV infection. It significantly reduces the rates of graft success and patient survival after transplantation. Effective therapy with OLT recipient patients having chronic HBV infection involves management of antiviral therapy before OLT to reduce the hepatitis B viral titer at the time of transplantation.

#### **Acknowledgements**

I am grateful to Deanship of Scientific Research, Majmaah University, Al Majmaah 11952, Saudi Arabia, for providing support for this research.

### **Conflict of interest**

I declare that there is no conflict of interest with any or all the above writing.

*Molecular Variants for HBsAg: Surface and Subtype DOI: http://dx.doi.org/10.5772/intechopen.85282*

#### **Author details**

Johra Khan College of Applied Medical Sciences, Department of Medical Laboratories, Majmaah University, Al Majmaah, Saudi Arabia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[16] Satapathy SK, Garg S, Chauhan R, Malhotra V, Sakhuja P, Sharma BC, et al. Profile of chronic hepatitis B virus in children in India: Experience with 116 children. Journal of Gastroenterology and Hepatology. 2006;**21**(7):1170-1176

[17] Nayak NC, Dhar A, Sachdeva R, et al. Association of human hepatocellular carcinoma and cirrhosis *Molecular Variants for HBsAg: Surface and Subtype DOI: http://dx.doi.org/10.5772/intechopen.85282*

with hepatitis B virus surface and core antigens in the liver. International Journal of Cancer. 1977;**20**:643-654

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[40] Carman WF, Trautwein C, Van Deursen FJ, et al. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis. Hepatology. 1996;**24**:489-493

#### **Chapter 2**

## Hepatitis B Genotyping and Clinical Implication

*Damodar Paudel and Sushma Suvedi*

#### **Abstract**

Hepatitis B is one of the killer diseases and distributed globally. Nepal sandwiched between India and China. China is the country with high prevalence of hepatitis B surface antigen (HBsAg) account 30% of the world's HBsAg carriers, and India which has intermediate HBsAg prevalence accounts 10% of the world's carriers. Nepal has a low prevalence (around 1%) of hepatitis B virus (HBV) infection in general population. A and D genotypes are more prevalent in India, while band C is in China. The survey done in 2012 elaborated the common genes that are A and D and recombinant C/D in Nepal, but the clinical consequences are unclear. The prevalence of hepatitis B is low in Nepal, but it is widely common in intravenous drug users, PLHA, and HCV positive. The implication of HBV genotyping has clinical implication for the treatment. Basically, response of peginterféron, and antiviral drugs (adefovir, lamivudine, telbivudine) in hepatitis B.

**Keywords:** hepatitis B, genotyping, distribution, clinical implication, management

#### **1. Introduction**

About 257 million people were infected chronically with hepatitis B (HBsAg positive), and 887,000 deaths were recorded in 2015 due to hepatitis B virus (HBV) related liver diseases, mostly from complication with cirrhosis and hepatocellular carcinoma (HCC) indicating an urgent necessity for better ways to prevent such complication of HBV [1]. HBV infection is the tenth leading cause of death and main contributor of HCC, which is ranked the fifth leading cause of cancer in man [2, 3]. HBV can be differentiated from other hepatitis viruses by genotype and subgenotype. HBV sequence differs by >8% form other genotypes and 4–8% nucleotide differences for subgenotypes. Including newly identified genotypes I and J, there are 10 genotypes A–J. Some HBV genotypes are further classified into subgenotypes.

About 30 subgenotypes are available till date. Many studies have reported that different genotypes and subgenotypes show different geographical distribution and are related to disease progression, clinical progression, response to antiviral treatment, and prognosis [4].

As shown in **Figure 1**, genotype A is widespread in sub-Saharan Africa, Northern Europe, and Western Africa; genotypes B and C are common in Asia; genotype C is primarily observed in Southeast Asia and China; genotype D is dominant in Africa, Europe, Mediterranean countries, and India including Nepal. Genotype E is dominant in South Africa. As a minor genotype, genotype G is reported in France, Germany, and the United States; and genotype H is commonly encountered in

**Figure 1.** *Global distribution of HBV genotype.*

Central and South America and genotype I in Vietnam and Laos. The newest HBV genotype, genotype J, has been identified in the Ryukyu Islands in Japan [5].

However, geographical distribution is still incomplete as data was based on very small numbers of patients and from only few countries.

Nepal is sandwiched between India and China, two countries with high prevalence of hepatitis B surface antigen (HBsAg) positive cases; 30% of the world's HBsAg carriers are in China and 10% in India. Nevertheless, Nepal has a low prevalence (around 1%) of hepatitis B virus (HBV) infection in general population [6]. Hepatitis virus A and D genotypes are dominant in India, while Band C is dominant in China. The prevalence of HBV infection is low in Nepal, but still it is widely common among intravenous drug users, PLHA, and HCV-positive populations. Although our previous study revealed only A, D, and C/D recombinant genotype [8], in the locality of Nepal, all four common genotypes (A, B, C, and D) were reported in the previous study [7].

Phylogenetic tree (**Figure 2**) was obtained from the aligned sequences combining with all human hepatitis B subgenotypes. The Nepal 10 strain was a C/D recombinant genotype, and it is differed from the genotypes A and D or other Nepalese strains. Genotype A1 in Nepal was more similar to that of Bangladesh and the Philippines, while A2 was more similar to the genotype A2 of Japan, Germany, Canada, and Russia. Genotype A1 (Nepal 31, 41, 24, 64, 50, 6, 9, 7, 47 strains) is similar to the A1 genotype of the Philippines, while strain 36, 16, and 18 are more similar to Bangladesh A1 strain. Almost all A1 strains of Nepal showed 88% similarity with Malawi A1 strain. Basically, HBV E genotype of Ghana and Sweden is nearby the genotype D of Nepal. Even some sequences from Germany and Italy are similar to the genotype D of Nepal.

Among genotype D, Nepal 12 and 55 isolates are similar with German D genotype isolates, while Nepal 60 and 57 isolates are more similar with D isolates of Italy and France and Russian isolates of D genotype. These isolates are 93% similar with Nepal 21 f isolates from where the strain Nepal 28 was evolved. Nepal 28 isolates of D genotype is evolved to more similar isolates 22, 32, and 14. Nepal isolates 40, 38

*Hepatitis B Genotyping and Clinical Implication DOI: http://dx.doi.org/10.5772/intechopen.82492*

**Figure 2.** *Phylogenetic tree of Nepal study 2012.*

1, 53, 11, 42, and 73 are more similar. Nepal 73 is more similar with 81, 79, and 72, while Nepal 81 and 79 is 88% similar with Nepal 72 isolates [8].

#### **2. Clinical importance of HBV genotypes**

As different regions have different serotypes and different clinical spectrum and different molecular epidemiological patterns, different HBV genotypes, but not different rashes, may influence clinical outcome, HBeAg seroconversion rate, mutational patterns in the precore and core promoter regions, and response to interferon therapy [9].

Determination of genotypes: detection of the sequence differences in pre-S or S gene can be done by several methods, e.g., direct sequencing, restriction fragment length polymorphism, line probe assay, genotype-specific PCR, and mass spectrometry.

#### **3. Treatment: noncirrhotic patients**

Cirrhosis is defined as distortion of the hepatic architecture and the formation of regenerative nodules. It is generally irreversible in its late stage. It can progress even to hepatocellular carcinoma (HCC). The recommendation for the treatment initiation for cirrhotic patients are available as three different guidelines (EASL 2017, Asia pacific 2015, AASLD 2018) shown in **Table 1** [4, 10, 11].

All patients with compensated cirrhosis HBeAg positive and HBV DNA level >20,000 U/ml with increased ALT twice higher than the normal limit are recommended to be treated by all three regional guidelines. However, AASLD guideline recommends different upper limit of normal (ULN) of ALT in male and female, i.e., 35 and 25, respectively, although EASL and APSL guidelines recommend 40 as ULN of ALT. HBeAg-negative patients with cirrhosis and HBV DNA > 2000 U/ml and the ALT twice higher than normal or the family history of cirrhosis and HCC are also recommended for treatment. EASL recommended to treat patients if fibrosis is present [10–12]. Different guideline recommendations are shown in **Table 1**.

**Table 1.**

*Comparison of the recommendation of different guideline treatments of noncirrhotic HBV patients.*

#### **4. Treatment: cirrhotic patients**

Patients with compensated cirrhosis and HBV DNA level >2000 U/ml are treated per recommendations for immune-active chronic hepatitis B (CHB). All three guidelines recommend to treat patients with decompensated cirrhosis and detectable viral load. In cases of compensated cirrhosis, there is discrepancy among the guidelines. In cases of HBV DNA <2000 copy/ml, AASLD and EASL both recommend to treat irrespective to ALT, whereas APSL recommended to such cases to treat only when ALT is above normal [10–12]. Treatment guideline is shown in **Table 2**.

#### **Table 2.**

*Comparison of the recommendation of treatment of different guideline of cirrhotic HBV patients.*

### **5. Clinical characteristics of different genotype are important**

Genotype B is a common genotype in Asia. Some characteristics of genotype B are as follows [13–16]:

Genotype C is also a common genotype in Southeast Asia and China. Characteristics of genotype care are as follows [13–16]:

Genotype A is distributed worldwide. Characteristics of genotype A are as follows [13–16]:

#### **Table 3.** *Clinical characteristics of different genotypes of HBV.*

#### *Hepatitis B Genotyping and Clinical Implication DOI: http://dx.doi.org/10.5772/intechopen.82492*

Genotype D also has worldwide distribution. Characteristics of genotype D are as follows [13–16].

Different HBV genotype clinical characteristics are compared in **Table 3**.

#### **6. Antiviral treatment**

The goal of therapy

Long-term goal is to reduce the risk of HCC and chronic liver diseases.

Peg-IFN alfa-2a or alfa-2b is recommended before starting peg-IFN therapy to HBeAg-positive patients; good responders should be identified; i.e., low viral load, HBV genotypes A and B, high serum ALT levels (above 2–5 times ULN) and high activity scores on liver biopsy are the predictors for better responding patients.

As the baseline predictor of response for the therapy to HBeAg-negative patient, HBV genotype, HBV DNA, ALT, HBsAg levels, and age are the crucial factors [17].

When to terminate Peg-IFN therapy: if low probability of response for HBeAg positive.

Or

No decline of HBsAg level for HBV genotype A and D at week 12 of treatment.

#### **6.1 HBeAg loss**

HBeAg loss with HBV DNA <2000 IU/ml for 6 months after treatment. Genotype D HBeAg-negative patient decreasing <2log decline in HBV DNA at week 12 of peg-IFN therapy [18].

Either entecavir or tenefovir is recommended for HIV

#### **6.2 No response**

HBeAg-positive patient with HBsAg level >20,000 IU/ml predicted no response after treatment. HIV positive, TNF + entecavir (lamivudine) + EFV is recommended. Other drugs are recommended as the second-line therapy if the first-line drug treatment is failed (if HBV DNA > log10 IU/ml in 3-month period [19].

#### **6.3 Response to lamivudine**

Genotype B has sustain responsiveness to lamivudine followed by genotype C. Genotype A is more resistant than genotype D so that virological responses to the drug are better in genotype D than genotype A. Pediatric patients have good tolerance to lamivudine. The younger the age at diagnosis, the longer consolidation treatment period [20].

#### **6.4 Response to adefovirdipivoxil**

Patients infected with genotypes A and D equally respond to 48-week treatment of adefovirdipivoxil, but there could be the adefovir resistance in patients having genotype D.

#### **6.5 Response to entecavir or telbivudine**

The relationship of HBV genotypes on drug resistance to entecavir was evaluated in lamivudine-refractory patients. Two-year therapy of telbivudine showed that HBeAg seroconversion, ALT normalization, and HBV negativity were comparable among different genotypes. Entecavir treatment has a chance of HBsAg seroloss in genotypes A and D, and the efficacy is better in Caucasian than in Asian population [20].

#### **6.6 Tenefovir (TDF)**

HBsAg loss in genotype A patient followed by genotype D (20 and 10%, respectively) was reported after completion of 144 weeks of treatment of TDF. The therapeutic effect was less in genotypes B and C [20].

#### **Table 4.**

*Antiviral treatment doses and period of recommendation by different guidelines.*

#### **6.7 Management of incomplete responder**

Incomplete responder should be checked for the drug adherence.

Patients who have previous exposure to lamivudine should be considered for entecavir resistance.

EASL recommend to switch to NA or combination therapy if detectable HBV DNA in 12 weeks of therapy. Combination of TDF + ETV has resulted in undetectable DNA even after 4 years, which is better than TDF alone [21]. Most of the study and the guideline do not recommend peg-IFN + nucleot(s)ide therapy, but recommend to use peg-IFN after NA therapy. Antiviral drugs and their continuation recommended by different guideline are illustrated in **Table 4**.

### **7. Conclusion**

HBV genotyping is important for the proper management of chronic HBV patients. Clinical characteristics may be helpful to estimate the genotype and initiate antiviral therapy.

### **Author details**

Damodar Paudel1 \* and Sushma Suvedi<sup>2</sup>

1 Department of Medicine, Internal Medicine Unit, National Academy of Health Science, Nepal Police Hospital, Kathmandu, Nepal

2 Department of Microbiology, Nepalgunj Medical College, Nepalgunj, Nepal

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] WHO, WHO Key facts; 2018

[2] Zamor PJ, deLemos AS, Russo MW. Viral hepatitis and hepatocellular carcinoma: Etiology and management. Journal of Gastrointestinal Oncology. 2017;**8**(2):229-242

[3] Raihan R et al. Hepatocellular carcinoma in Malaysia and its changing trend. Euroasian Journal of Hepato-Gastroenterology. 2018;**8**(1):54-56

[4] Lin CL, Kao JH. Hepatitis B virus genotypes and variants. Cold Spring Harbor Perspectives in Medicine. 2015;**5**(5):a021436

[5] Sunbul M. Hepatitis B virus genotypes: Global distribution and clinical importance. World Journal of Gastroenterology. 2014;**20**(18):5427-5434

[6] Shrestha SM, Shrestha S. Chronic hepatitis B in Nepal: An Asian country with low prevalence of HBV infection. Tropical Gastroenterology. 2012;**33**(2):95-101

[7] Huy TT et al. High prevalence of hepatitis B virus pre-s mutant in countries where it is endemic and its relationship with genotype and chronicity. Journal of Clinical Microbiology. 2003;**41**(12):5449-5455

[8] Paudel D et al. Diversity of hepatitis B genotypes in Nepal and updated phylogenetic tree: A pilot survey in 2012. JNMA; Journal of the Nepal Medical Association. 2014;**52**(196):982-991

[9] Furusyo N et al. Relationship of genotype rather than race to hepatitis B virus pathogenicity: A study of Japanese and Solomon islanders. The American Journal of Tropical Medicine and Hygiene. 2004;**70**(5):571-575

[10] Association, E. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. Journal of Hepatology. 2017;**67**(2):370-398

[11] Terrault NA et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;**67**(4):1560-1599

[12] Sarin SK et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update. Hepatology International. 2016;**10**(1):1-98

[13] Kramvis A. The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics. Reviews in Medical Virology. 2016;**26**(4):285-303

[14] Liaw YF. HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B. Hepatology International. 2009;**3**(3):425-433

[15] Kmet Lunacek N, Poljak M, Maticic M. Distribution of hepatitis B virus genotypes in Europe and clinical implications: A review. Acta Dermatovenerologica Alpina Pannonica et Adriatica. 2018;**27**(3):141-146

[16] Lin CL, Kao JH. The clinical implications of hepatitis B virus genotype: Recent advances. Journal of Gastroenterology and Hepatology. 2011;**26**(Suppl 1):123-130

[17] Liu LZ et al. Improvements in the management of chronic hepatitis B virus infection. Expert Review of Gastroenterology & Hepatology. 2018;**12**(11):1-14

[18] Rijckborst V et al. Early on-treatment prediction of response to peginterferon alfa-2a for HBeAgnegative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology. 2010;**52**(2):454-461

*Hepatitis B Genotyping and Clinical Implication DOI: http://dx.doi.org/10.5772/intechopen.82492*

[19] WHO. Guidelines for the Prevention Care and Treatment of Persons with Chronic Hepatitis B Infection; 2015. Available in https://www.who.int/hiv/ pub/hepatitis/hepatitis-b-guidelines/ en/

[20] Man Cho S, Choe BH. Treatment strategies according to genotype for chronic hepatitis B in children. Annals of Translational Medicine. 2016;**4**(18):336

[21] Chan HLY et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014;**146**(5):1240-1248

Section 2 Hepatitis C

#### **Chapter 3**

## Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art

*Alexandra Porras-Ramírez and Alejandro Rico-Mendoza*

#### **Abstract**

Infection with the human immunodeficiency virus (HIV) modifies the course of infection by the virus of hepatitis B (HBV) by several mechanisms: the rate of chronicity, prolonging viremia by HBV, and increase in morbidity related to liver disease. The treatment for both infections should be done in a coordinated manner, to avoid the emergence of resistance in HIV, HBV or both, as well as major alterations in the hepatic enzymes. Monotherapies with lamivudine or emtricitabine select, rapidly, mutant strains of the HBV and HIV. Monotherapy with adefovir has moderate effects in coinfected patients as they already have mutations. If the treatment of HBV can defer until the combination antiretroviral therapy of HIV is necessary, these patients should receive a combination of tenofovir plus lamivudine (or emtricitabine), since this provides a powerful therapy against HBV and establishes a good central axis for antiretroviral therapy. In addition, it would prevent the selection of HBV variant resistance. The influence of HIV in the HCV infection. Increase in load HIV-driven viral hepatitis exacerbates hepatic lesions and influences transmission of the HCV. The risk of sexual transmission increases when HIV is present in the carrier. Coinfection modifies the evolution of fibrosis in patients with HIV, with higher speed in those who have low CD4 counts, so that the onset of cirrhosis occurs before, and the risk of liver decompensation is also more frequent. The consequence of this situation is an increase in liver-related morbidity and mortality.

**Keywords:** hepatitis B, HIV coinfection, hepatitis C

#### **1. Introduction**

The hepatitis B virus is one of the most pathogenic and prevalent in the world. In some places, up to 95% of those infected with HIV have also been infected with hepatitis B, and 10–15% will develop chronic hepatitis B. However, there is a great variation for both infections according to the geographical region and the risk group. In the USA, it is estimated that 100,000 HIV-infected patients suffer from chronic HBV. We do not have data for our country. In patients coinfected with HIV and HBV, HBV is less likely to be eliminated. The infection with primary HBV leads to chronic hepatitis in 2–5% of immunocompetent adults, while patients infected with HIV can become chronic about 5 times more (15–23%). One possible reason is the T-cell defect associated with HIV infection.

HBV and HIV have several characteristics in common even though HBV is a double-stranded DNA virus. After entering the hepatocyte, viral DNA is integrated into the host genome and the viral RNA is translated by the HBV inverse polymerase in new viral DNA and transcribed to viral proteins. The reverse transcription can be inhibited by nucleic acid (t) transcriptase inhibitors reverse. The integration of the virus into the host's genome in hepatocytes and CD4+ T cells prevents its eradication.

Finally, the mechanisms used to develop resistance are very similar in both viruses. All HIV patients should be screened for HBV and HCV. Screening of HIVinfected patients for HBV must start with the HBsAg application, anti-HBs, and anti-HBc. If a positive HBsAg is found, you must complete the study with HBeAg, anti-HBe, and HBV DNA. On the other hand, for all patients diagnosed with HBV infection, you should have an ELISA for HIV to rule out coinfection.

Like patients monoinfected with HBV with chronic hepatitis B, those coinfected with HIV should be evaluated every 6–12 months for hepatocellular carcinoma, by measuring alpha-fetus protein and performing an ultrasound of the liver. This recommendation is regardless of whether the patient has apparent cirrhosis or not.

The improvement of survival in infected patients by the human immunodeficiency virus (HIV), resulting from the introduction of the therapy powerful antiretroviral ("HAART"), has caused chronic liver infections will become important causes of hospitalization and mortality in patients infected with HIV (HIV+) [1].

Liver diseases and their consequences represent between 30 and 55% of the causes of death in these patients [2]. Frequently, the infection by the viruses of the hepatitis B (HBV) and hepatitis C (HCV) is a cause of chronic liver disease in patients who are HIV+, which can be attributed to the means of transmission and the epidemiological factors among the three viruses [3].

Although the impact of HBV is still not well known in the progression of HIV disease, you have to be very clear about the interference of infection by HIV in the natural history of HBV infection. Coinfected patients have viral loads of HBV that are higher than monoinfected, with a greater risk and a shorter time of evolution to cirrhosis [4].

The presence of HIV modifies the natural history of HCV infection, accelerating the progression of hepatic disease in coinfected people. Of people infected with HCV, between 8 and 24% contract cirrhosis in the first 10–20 years after their HCV infection [5]. The annual incidence of hepatocellular carcinoma of cirrhosis is between 1 and 4% [5].

Works carried out in different countries have shown that the prevalence of HIV/ HBV coinfection ranges between 4.8 and 15% [6–8]. In Brazil, according to previous studies in various urban areas, the prevalence of chronic hepatitis B in patients who are HIV+ ranged between 5.3 and 19.2% [9–12]. Studies conducted in several countries reveal that the frequency in the presence of anti-HCV in patients who are HIV+ varies between 0 and 42.5% [6–8].

#### **2. Coinfection with hepatitis B in patients with HIV**

Hepatitis B, caused by the hepatitis virus B (HBV), is an important problem of public health and it is the most serious kind of viral hepatitis. It can cause chronic liver disease and carries a high risk of death for cirrhosis and liver cancer. It is estimated that in the world there are 2 billion people infected with HBV and more than 350 million with chronic liver infection [13].

Coinfection of HBV with the human immunodeficiency virus (HIV) is common since they have the same transmission routes.

#### *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

In Western Europe and in the United States, it has been found that 7–10% of HIV patients have a chronic infection by HBV, with men who have sex with other men being the group with the highest prevalence [14–16]. Patients coinfected with HBV and HIV have an increased risk of liver cirrhosis, terminal liver disease and death by hepatic pathology, especially in patients with low CD4 lymphocyte counts and concomitant use of alcohol [15]. There is a greater risk of hepatocarcinoma and adverse hepatotoxic effects in patients using therapy with highly effective antiretroviral drugs (TARAE) coinfected with hepatitis B [16].

Ninety-five percent of HBV infections in adults who are healthy are self-limiting with an elimination of HBV blood and lasting immunity against the reinfection. Chronic infection happens in less than 5% of patients older than 5 years [14, 17]. Immunosuppressed patients such as patients with HIV, who are in substitution therapy for kidney and diabetics, present a greater risk of chronicity of HBV infection [18–20]. Approximately 15% of patients with chronic infection older than 5 years can evolve into cirrhosis and hepatic cancer, remaining asymptomatic until the appearance of the clinical manifestations of said complications [21]. It is estimated that 20% of HIV-positive patients infected with HBV will develop chronic hepatitis by this agent [18].

The antigens and antibodies associated with the infection of hepatitis B virus are as follows:

The infection hidden by HBV may be present in 10–45% of HIV-positive patients [24, 25]. Therefore, it is recommended that in all HIV-positive patients the following exams for HBV screening are done: HBs Ag, total anti-HBc or anticore IgG and

anti-HBs. If the patient has an isolated positive IgG anticore, it is a must to perform the viral load of HBV DNA. If a patient has anticore IgG positive in isolation and the viral load for HBV is negative, this patient should be vaccinated against hepatitis B and he or she could have an anamnestic or primary response [26, 27].

In patients infected with HIV, atypical serological patterns may appear. More frequent is the isolated presence of anti-HBc (**Table 1**), indicative of hepatitis B cured with loss of antibodies. Exceptionally, it may be hepatitis hidden B, defined by the presence of HBV DNA in liver and serum (viremia will usually be <103 copies/ml and may be intermittent) in patients with negative HBsAg. In the hidden hepatitis B, the markers usually detected are anti-HBc, anti-HBs, and anti-HBe, although these markers can be negative (hepatitis B hid seronegative) 4 in most patients with hidden hepatitis B, the HbeAg is negative4 (**Table 1**).

#### **2.1 The course of concurrent hepatitis B and HIV infection**

In HIV-positive patients, chronic hepatitis B has an unfavorable evolution compared with patients infected only with HBV, and the associated mortality risk with hepatopathy is significantly increased. In the MACS study (multicenter AIDS cohort study), coinfected patients had an associated mortality to liver disease 8 times higher than HIV-positive patients HBsAg negative and 15 times greater than patients negative for both infections. Mortality associated with hepatopathy due to hepatitis B has increased, significantly, since the introduction of the highly active antiretroviral therapy (HAART).

In addition to increased mortality, in coinfected patients, HIV accelerates the progression of hepatitis B and increases the risk of cirrhosis significantly. It is important that the clinician is not fooled by the apparent benign course of hepatitis B in HIV patients since this is due to its cellular immunological compromise. Frequently, these patients have only one slight increase in transaminases. However,

#### **Table 1.**

*Serologic markers of HBV and clinical interpretation.*

#### *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

if HBV-DNA is measured, as a marker of viral replication, this is higher in HIV patients than in patients who are immunocompetent.

There is a direct correlation between the degree of immunosuppression and control of HBV replication in the coinfected patients. Patients with AIDS usually show, more frequently, signs of active viral replication. Even in cases with hepatitis B, apparently resolved, progressive deterioration of the immune system can lead to re-activation of an HBV infection. Most studies on the influence of hepatitis B in the evolution of HIV infection have not demonstrated a shortening in survival. The infection with HBV does not lead to a faster reduction of cells CD4+ or increase the frequency of defining diseases of AIDS. However, some interactions do occur. For example, the hepatotoxicity associated with antiretroviral drugs is three times more in patients with chronic HBV hepatitis.

#### **2.2 Prevention**

All HIV-infected patients who are serologically negative for HBV should be vaccinated; this should be done despite the fact that the vaccine may be less effective in them. Approximately 30% of patients who are HIV positive are primarily nonresponsive to the vaccine, against 2.5% of immunocompetent individuals. This is especially true for individuals with minor CD4 of 500 cells/mm3 . Therefore, for these patients, a standard vaccination schedule is recommended. If the patient has less than 350 CD4 cells, it is advised to postpone vaccination until after antiretroviral therapy, and patients should be educated in strategies to prevent the progression of liver diseases, such as suppressing consumption of alcohol and tobacco and not using herbal supplement (many of which are hepatotoxic).

Standard vaccination against HBV is less effective in infected patients for HIV. The administration of four doses of 40 μg (months 0, 1, 2, and 6) improves significantly the serological response, and it is the recommended guideline [28].

The consumption of alcohol has an additive effect in terms of progression to fulminant hepatitis, development of aggressive chronic liver disease, and development of hepatocellular carcinoma. Hepatotoxic drugs must be used very carefully and under strict surveillance [29].

#### **2.3 Treatment**

HBV-HCV and HBV-HCV-HDV infections are associated with further progression of rapid liver fibrosis [30]. The treatment indications for patients coinfected with HBV-HCV are the 16, same as for each of the infections separately. In patients with multiple infections, there is a predominance of replication (VHD > HCV > HBV) that conditions the detection of viral loads of HBV and HCV lower than in patients without multiple infections [31].

The suppression of HIV replication and immunological improvement secondary to initiation of antiretroviral treatment (ART) is associated with a lower progression of liver disease, even in patients with decompensated cirrhosis [32].

Therefore, ART is a priority in the care of these patients. In those with preserved liver function, any of the drugs recommended in the therapeutic guidelines can be used since the risk of severe hepatotoxicity is low. In child B/C stages, protease inhibitors (PIs) and raltegravir (RAL) are more secure than NEV or EFV [33].

Dolutegravir [34], etravirine [35], and rilpivirine [36] can be used as there is no need to adjust the dose in patients with moderate hepatic insufficiency (child A/B), and in advanced stages, some centers monitor the plasma concentrations of the drugs and adjust their doses. RAL has demonstrated adequate serum levels without the need for dose adjustment and a good tolerance in child [37] stage C patients.

In coinfected patients with HBV/HIV, tenofovir (TDF) suppresses HBV replication in most patients and should be part of the ART, and if there are no contraindications, whenever possible, it will be added as second nucleoside analog (t) gone [33] TC or FTC.

It must be taken into account that simeprevir (SMV) increases TDF levels and, potentially, the risk of nephrotoxicity. In an observational study in patients infected with HIV and coinfected with HBV/HDV, the addition of interferon for 48 weeks to treatment with TDF (n = 4) was associated with a greater decrease in VHD-RNA compared to TDF (n = 13). However, the guideline optimal treatment and response monitoring are not well determined and the clinical relevance of the decrease in VHD-RNA due to IFN is unknown [38].

#### **3. Coinfection with hepatitis C in patients with HIV**

The influence of HIV in the HCV infection. Increase in load HIV-driven viral hepatitis exacerbates Hepatic lesions and influences transmission of the HCV. The risk of sexual transmission increases when HIV is present in the carrier. This situation is more evident in the case of homosexual men with multiple sexual contacts without using a preservative [39, 40].

In the case of mother-to-child transmission, the risk of transmission to the fetus in coinfected women for HIV is between 2 and 5 times higher than in mothers monoinfected by HCV and it is between 5 and 25% [41].

Hepatitis C behaves differently in people with HIV, since HIV accelerates the evolution of hepatitis C (even so, many people have lived for many years with a coinfection for HIV and HCV, often without knowing they were coinfected). The risk of significant damage to the liver is greater in people with HIV who have a CD4 count below 200 cells/mm3 . HCV can be treated, regardless of whether the person is or is not infected with HIV. Antiretroviral therapy has reduced notably the number of deaths caused by HIV. Currently, liver disease in the terminal stage produced by coinfection with HCV has become one of the causes of death rates among people living with HIV in certain areas of the United States and Western Europe. In part, this is because HCV infection can go undiagnosed until there has already been serious liver damage.

Coinfection modifies the evolution of fibrosis in patients with HIV, with higher speed in those who have low CD4 counts, so that the onset of cirrhosis occurs before, and the risk of liver decompensation is also more frequent. The consequence of this situation is an increase in liver-related morbidity and mortality [42, 43].

It is confirmed that coinfection by the HIV alters the natural history of HCV, that increases the risk of can become chronic of HCV, accelerates the progression of liver fibrosis associated with VHC [44], increases the risk of decompensation of cirrhosis and decreases survival after the first episode of decompensation. On the contrary, contradictory data have been published about the impact that HCV can have in the natural history of HIV, although does not seem to influence the progression of clinical events defining AIDS or in mortality [45, 46].

The progression of fibrosis is variable and depends on factors related to the causative agent and factors related to the host. Among these factors, consumption of alcohol, age at acquisition of infection, race, viral coinfections like the concomitant infection with HIV, time of infection, body mass index, and various genetic factors have been described [22]. Among these, the studies in animals have identified some determinant genetic progression of fibrosis; as well in humans, we have tried to identify polymorphism genetics to predict the degree of progression in hepatitis C and in steatosis of a nonalcoholic liver [47]. Therefore, there are a number of factors that you can modify to prevent the progression of liver fibrosis, including alcohol

#### *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

intake and other toxins, the normalization of the index of body mass, and the prevention of infections for other hepatotropic viruses.

Hepatitis C does not make HIV worse, but it can complicate your treatment, since many drugs to treat HIV metabolize in the liver. Coinfected people have more risk of developing hepatotoxicity associated with the antiretroviral treatment than those who only have HIV. In any case, the benefits of HIV treatment outweigh the risk of hepatic toxicity [48].

HCV screening tests are recommended to all people with HIV. Even if you have already been diagnosed with coinfection with HIV and HCV, it is important to know how HCV is diagnosed and controlled. Unlike HIV, a positive result in the HCV antibody test does not always mean that the person has a chronic infection [48].

HCV screening tests consist of two stages. As usual, first, a test for the detection of antibodies against HCV is carried out. If the result is positive, this means that you have been infected by hepatitis C before and possibly still have. People who eliminated hepatitis C spontaneously without treatment still have the antibodies for many years afterwards. On the other hand, in some cases, the results of the antibodies screening tests are negative even when the person has a chronic infection of hepatitis C. This can happen if [48]:

An HCV RNA (viral load) screening test is needed to confirm the existence of a chronic infection (by HCV). The test of viral load searches for genetic material of HCV in the same way that HIV viral load test is used to detect this virus. If the quantity of HCV RNA in the bloodstream is detectable, it means that is currently infected with HCV. If on the other hand it is undetectable, a second test must be performed after 6 months. Yes, if the viral load is not detected in two successive tests, it means that the person has eliminated HCV from the body (**Table 2**) [48].

#### **3.1 Prophylaxis**

Serology should be performed against HAV and HBV to all adult patients infected with HIV, and even more so if infection coexists with HCV in order to vaccinate, if appropriate, after having carried out the immunological study. In patients with susceptible HIV, the vaccine against hepatitis A will be administered in a two-dose

#### **Table 2.**

*Diagnosis of HCV and clinical interpretation.*

schedule separated by 6 months at patients presenting figures > 200 CD4/ml. With those who are in a degree of older immunosuppression, you should wait until your CD4 numbers increase above the 200 cells/ml. There are no recommendations about when to perform the revaccination.

The standard vaccination guideline against HBV is three doses intramuscularly in the deltoids at 0, 1, and 6 months, which produce immunity greater than 90%. The answers are worse particularly among those with lower CD4 [49]. It has been postulated that doubling the standard doses or administering another dose could produce more adequate protection titles [50]. Patients with CD4 < 200 will proceed to vaccination when the figure has increased.

Immunization with the vaccine is lost with time, so controls must be carried out later to check the protection. Controls will be carried out between 4 and 12 weeks after finishing the vaccination, and more lately once a year.

#### **3.2 Treatment for genotype 1 of hepatitis C**

The evidence supports that the beginning of the antiretroviral therapy and, therefore, controlling early replication of HIV and maintaining a good immunological situation are the first measures to adopt in the coinfected patients. Existing data indicate that antiretroviral treatment can slow down the progression of chronic HCV liver disease in the coinfected patient, even in the carriers of liver disease, increasing their survival [51, 52].

Studies based on liver biopsies have demonstrated a relationship between the management of antiretroviral treatment, immunological improvement, and the presence of lower grades of hepatic fibrosis [53, 54].

#### *3.2.1 Boceprevir or telaprevir + PR*

In patients coinfected with HIV and HCV genotype 1 and without previous treatment for HCV SVR after treatment with Boceprevir (BOC) or telaprevir (TVR) was higher (63–74%) than in those treated with PR (29–45%) [55, 56].

Efficacy and side effects with both triple patterns were similar to those observed in monoinfected patients. The dose of RBV was 800 mg/d in almost all patients. Although significant pharmacokinetic interactions have been described, the coadministration of lopinavir/r, atazanavir/r, and darunavir/r, allowed in the study with PR/BOC, did not affect efficacy [55].

The results of the Unite 115 study support the dosage of TVR every 12 h in coinfected patients and ART based on IP/r or raltegravir, as well as the possibility of shortening the duration to 24 weeks (T12 + PR24) in patients without cirrhosis with HCV-RNA undetectable in S4 and S12.

In pretreated coinfected patients, the results of observational studies are similar to those obtained in clinical trials with monoinfected patients. The efficacy of these guidelines is insufficient in cirrhotic patients or patients with previous response to partial or null P/R. Due to its limited efficacy and high toxicity, treatment with BOC and TVR should be considered for exceptional use, in patients with genotype 1, without treatment or with recurrence prior to PR, when the guidelines considered preferred are not available or alternatives:

*Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

#### *3.2.2 Sofosbuvir (SOF) + PR*

In the study NEUTRINO [57], 291 patients infected with HCV, genotype 1, without prior treatment, received treatment with SOF + PegIFN alpha-2a + RBV (1000–1200 mg/d) during 12 weeks. Overall, 89% of patients with genotype 1 reached RVS12: subtype 1a, 92% (207/225); subtype 1b, 82% (54/66). The RVS12s was lower in cirrhotic patients (80%) than in noncirrhotic patients (92%).

In a multinational observational study (HCV-TARGET) [58], two thousand and sixty-three patients were analyzed treated with guidelines based on SOF, in combination with PR or with SMV±RBV (in patients with genotype 1) or in combination with RBV (in patients with genotypes 2 or 3); 48% were cirrhotic, 52% pretreated, and 18% with failure prior to triple treatment with PR + IP. Overall, 5.7% of patients had serious side effects (12 patients died and 9 of them were cirrhotic).

In this study, 85% (140/164) of patients with genotype 1 (45% pretreated; 27% pretreated with PR + IP) treated for 12 weeks with SOF + PR obtained an RVS4. SVR4 was higher in noncirrhotic patients (90%) than in cirrhotic patients (70%).

In the observational study TRIO [59] (n = 295, with genotype 1), the SVR 12 s global in patients without previous treatment (analysis by an intention of treatment) was 77%, without differences between cirrhotic patients (81%; 112/138) or not (81%, 25/31). In patients with previous failure (RN: 36%), RVS12 was 72% (90/125): 76% in noncirrhotic patients (n = 39) and 62% in cirrhotic patients (n = 85). Based on the previous regimen, RVS12 was 73% in patients with failure prior to IP + PR (n = 40) and 67% in patients with failure prior to PR (n = 36). Two percent of the patients abandoned the treatment because of side effects.

#### *3.2.3 Simeprevir (SMV) + PR*

In the QUEST-1 [60] clinical trials and QUEST-2 [61], the efficacy and safety of SMV (150 mg/d) + PR versus placebo + PR for 24 or 48 weeks (according to criteria of TGR) in patients monoinfected by HCV genotype 1 without previous treatment, the RVS24s overall was 80–81% for SMV + PR and 50% for PBO + P/R. SVR in patients infected with HCV subtype 1a with and without the Q80K polymorphism in the protease was 58% and 84%, respectively. The SVR obtained by patients with subtype 1b was 85% (228/267) globally and 90% (172/192) in the subgroup of European patients included in both studies. Depending on the degree of basal fibrosis, they reached SVR 84% (317/378) of the patients with fibrosis F0-F2, 73% (60/82) with F3, and 60% of the patients with cirrhosis.

A remarkable aspect is the predictive value of the response obtained with this guideline in week 4 of treatment. Of the 521 patients who started treatment with SMV in the QUEST studies, 78% (404/521) showed an RVR, and of them, 90% (362/404) reached RVS12.

In the study TMC435-C212 [62], 106 patients coinfected with HIV/HCV were analyzed treated with SMV/PR, with overall RVS12s of 74%; without previous treatment (n = 53): 79%; previous relapse (n = 15): 87%; RP (n = 10): 70%; RN (n = 28): 57%. Eighty-nine percent of patients without previous treatment or with recurrence, he obtained an RVR and of this 89%, he reached RVS12s. Treatment with SMV + PR was generally well tolerated, with a tolerability profile and safety similar to those shown in monoinfected patients.

In the PROMISE [63] study, patients monoinfected by HCV with recurrence were randomized previously after P/R, to treatment with SMV (n = 260) versus placebo (n = 133) during 12 weeks, with P/R (24–48 weeks). The RVS12s was 86% (128/149) in patients with subtype 1b and 70% (78/111) in those with subtype 1a (78% and 47% in patients without and with the Q80K polymorphism, respectively). Ninety-three percent obtained an RVRe and shortened the total duration of treatment at 24 weeks.

In the ATTAIN study [64], the noninferiority of SMV versus TVR was demonstrated, in combination with PR, in infected or monoinfected patients with partial or no response to RP. Based on the previous response, the SVR obtained was: patients with previous RP, 70% (163/234) with SMV versus 68.5% (163/238) with TVR; patients with previous RN, 44% (63/145) with SMV versus 47% (67/146) with TVR10. The risk of anemia was 3 times smaller in those treated with SMV, being also of a milder character than that that occurred in the TVR group.

#### **3.3 Treatment for genotypes 2 and 3 of hepatitis C**

#### *3.3.1 PEGIFN + RBV*

In patients coinfected with HIV/HCV genotypes 2/3, the probability of reaching an SVR with pegIFN-alpha-2a (180 μg/week) or alpha-2b (1.5 μg g/kg/week) and adjusted RBV weight (800–1200 mg/d) for 48 weeks is 62–71% [65, 66].

Patients without cirrhosis who achieve an RVR can be treated for 24 weeks without reduction of response rates [67, 68]. In patients with genotype 2 or 3, without previous treatment, due to the lower efficacy and toxicity associated with prolonged administration, treatment with PR should be considered for exceptional use, when the guidelines considered are not available preferred or alternative:

PR × 48 s (BI). In patients with RVR, PR × 24 s, in the absence of cirrhosis (BII).

#### *3.3.2 SOF + RBV*

In four clinical studies, phase III, with monoinfected patients with genotype 2, treated with SOF/RBV for 12 weeks, the SVR ranged between 86 and 97% [57, 60, 69]. Also, in the PHOTON 1 [70] studio in patients without prior treatment coinfected with genotype 2, the treatment with SOF/RBV for 12 weeks showed an RVS12 of 88% (23/26); in patients pretreated, the SVR after 24 weeks of treatment was 92%.

Although the data are inconclusive, pretreated cirrhotic patients could benefit from a treatment of more than 12 weeks. In the FUSION study, in patients, the SVR was pretreated 60% (6/10) in cirrhotic patients treated for 12 weeks and 78% (7/9) in those treated for 16 weeks [60].

#### *3.3.3 SOF + DCV*

In study AI444-040 89% (16/18) of the monoinfected with genotype 3, without treatment previous, non-cirrhotic, treated with SOF (400 mg**/**d) + DCV (60 mg**/**d) ± RBV during 24 weeks, he obtained an SVR, with no apparent impact of the inclusion or not of RBV in the effectiveness [70].

In the ALLY 3 study, 152 patients infected with HCV genotype 3 were treated with SOF 400 mg**/**d + DCV 60 mg**/**d for 12 weeks. Overall, they obtained an RVS12 on 90% (91/101) of patients without previous treatment: cirrhotic: 58% (11/19); without cirrhosis: 97% (73/75). Eighty-six percent (44/51) of the pretreated reached RVS12: cirrhotic, 69% (9/13); noncirrhotic, 94% (32/34) [71].

#### **3.4 Treatment for genotype 4 of hepatitis C**

#### *3.4.1 PEGIFN ALFA + RBV*

Overall, the probability of SVR of patients coinfected with genotype 4 to standard treatment with PR is less than 30% (**Table 1**) 1–5, although it is higher in patients with IL28B CC [32].

#### *3.4.2 SOF + PR*

We do not have information with the new direct antivirals in patients coinfected. In patients monoinfected with HCV, the analysis of patients with genotype 4 included in the Neutrino7 study showed an RVS12 of 96% (27/28) after 12 weeks of treatment with SOF + PR (1000–1200 mg/d).

#### *3.4.3 SOF + RBV*

In another study [72] in patients of Egyptian descent, the efficacy of SOF 400 mg/day + RBV (1000–1200 mg/day) for 24 weeks was greater than the 12-week schedule, in patients without previous treatment, 100% (14/14) versus 79% (11/14), as in pretreated, 93% (14/15) versus 59% (10/17).

In the Photon 2 [73] study, 84% (26/31) of patients coinfected with genotype 4, without pretreatment, treated with SOF + RBV for 24 weeks obtained an SVR: noncirrhotic 83% (19/23); cirrhotic 88% (7/8).

#### *3.4.4 Interactions between medications*

Boceprevir is a potent CYP3A4/5 cytochrome inhibitor. Exposure to medicinal products metabolized by CYP3A4/5 may increase when administered with BOC, which could increase or prolong its therapeutic effects and adverse reactions. BOC is partially metabolized by CYP3A4/5. The joint administration of BOC with drugs that induce or inhibit activity of CYP3A4/5 could increase or decrease exposure to Boceprevir [74]. Boceprevir is contraindicated when co-administered with drugs whose elimination is highly dependent on CYP3A4/5 and in which the elevation of plasma concentrations is associated with serious adverse events or they pose a vital risk. This is the case of midazolam, triazolam, bepridil, pimozide, lumefantrine, halofantrine, lovastatin, quetiapine, alfuzosin, silodosin, and derivatives ergotamines [74].

Telaprevir is partially metabolized by CYP3A and is a substrate of the glycoprotein-P (gp-P). Co-administration of Telaprevir with CYP3A-inducing drugs and/ or gp-P can reduce plasma concentrations of TVR. On the contrary, its co-administration with CYP3A inhibitor drugs and/or gp-P may increase plasma concentrations of Telaprevir. On the other hand, Telaprevir is an inhibitor potent of CYP3A4 and gp-P. This inhibition is time dependent and can be intensified during the first 2 weeks of treatment. At the end of the treatment, it may be necessary that approximately 1 week elapses for the inhibitory effect of Telaprevir to disappear. Telaprevir administration can increase the systemic exposure to drugs that are substrates of CYP3A or of gp-P, which may lead to an increase or prolongation of its effects and risk of adverse reactions [75].

Simeprevir is metabolized by CYP3A4. Therefore, the co-administration of Simeprevir with inhibitors of CYP3A4 can increase their plasma concentrations, and in contrast, co-administration of Simeprevir with CYP3A-inducing drugs can reduce plasma concentrations of Simeprevir [76]. Its use is not recommended combined with other nonanalog reverse transcriptase inhibitor nucleosides [76, 77]. The use of SMV with HIV protease inhibitors enhanced or not with ritonavir [77].

Sofosbuvir is a substrate of the gp-P. Therefore, drugs or products that are powerful inducers of gp-P (rifampicin, S Juan's herb, carbamazepine, and phenytoin) can reduce plasma concentrations of SOF and reduce its therapeutic effect. The interactions of Sofosbuvir with antiretroviral drugs have been investigated in a phase 1 clinical trial conducted in healthy volunteers [78]. Sofosbuvir modified the pharmacokinetics of antiretrovirals evaluated within the limits of the prespecified equivalency interval [79].

The interaction between Sofosbuvir and recent integrase inhibitors has not been evaluated; however, the existence of interactions has not foreseen significant differences between Sofosbuvir and these drugs [78].

Daclatasvir is a substrate of CYP3A4 and gp-P. Inducers of CYP3A4 and of gp-P can reduce plasma levels and the therapeutic effect of DCV. The co-administration with potent inducers of CYP3A4 and gp-P is contraindicated, while it is recommended to adjust your dose when used with moderate inductors. Inhibitors of CYP3A4 can increase plasma levels of DCV, so it is recommended to adjust their dose [80]. Daclatasvir has a scarce influence on cytochrome CYP3A4, so that its administration does not affect relevant to the metabolism of antiretroviral drugs and, therefore, adjustment of these is not required.

The administration of efavirenz induces the metabolism of daclatasvir reducing your AUC by approximately 50%. Therefore, it is necessary to increase the dose of daclatasvir at 90 mg/day in case of concomitant use with efavirenz. On the contrary, atazanavir/ritonavir increases the daclatasvir by 2.1 times and, consequently, it is required to reduce the dose of daclatasvir at 30 mg. Daclatasvir/ritonavir increases to a lesser extent the AUC of daclatasvir, by 40%, so it would not require dose adjustment of daclatasvir [81]. The dosage of daclatasvir is the same for ATV/r or DRV/r that for atazanavir or darunavir powered with cobicistat (COBI); that is, the doses of daclatasvir are 30 mg/day co-administered with atazanavir/cobicistat and 60 mg/day with daclatasvir/cobicistat [81]. No relevant interactions between tenofovir disoproxil fumarate and daclatasvir have been observed [80].

#### **4. Summary of hepatitis C treatment according to the genotype**

In **Table 3**, you can see the summary of hepatitis C treatment according to the genotype.

#### **5. Conclusions**

The influence of HIV in the HCV infection. Increase in load HIV-driven viral hepatitis exacerbates hepatic lesions and influences transmission of the HCV. The risk of sexual transmission increases when HIV is present in the carrier. This situation is more evident in the case of homosexual men with multiple sexual contacts without using a preservative [39, 40].

In the case of mother-to-child transmission, the risk of transmission to the fetus in coinfected women for HIV is between 2 and 5 times higher than in mothers monoinfected by HCV and it is between 5 and 25% [41].

Coinfection modifies the evolution of fibrosis in patients with HIV, with higher speed in those who have low CD4 counts, so that the onset of cirrhosis occurs before, and the risk of liver decompensation is also more frequent. The consequence of this situation is an increase in liver-related morbidity and mortality [42, 43].

#### *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

#### *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

**Table 3.** *Treatment of hepatitis C according to genotype.* *Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

### **Acknowledgements**

The authors acknowledge Universidad El Bosque for supporting the writing process of this chapter.

Alexandra Porras-Ramírez y Alejandro Rico-Mendoza express:

### **Conflict of interest**

The authors express no conflicts of interest.

#### **Acronyms and abbreviations**

*Hepatitis B and C*

#### **Author details**

Alexandra Porras-Ramírez\* and Alejandro Rico-Mendoza Grupo de Medicina Comunitaria y Salud Colectiva, Universidad El Bosque, Bogotá, Colombia

\*Address all correspondence to<EMAIL_ADDRESS>
© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Coinfection of Hepatitis B and C in HIV Patients: A Review of the State of the Art DOI: http://dx.doi.org/10.5772/intechopen.83704*

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## **Chapter 4** Hepatitis B and C Viruses

*Isaac Thom Shawa*

### **Abstract**

Hepatitis B and C viruses (HBV/HCV) are among the leading causes of liver disease. HBV is a partially double-stranded circular DNA virus whose genome is approximately 3200 bases with four overlapping open reading frames (ORFs) and belongs to *Hepadnaviridae* family. HBV prevalence varies worldwide, with high rates reported in low-income countries. Approximately 90% of HBV infections are acute, 10% progress to chronic infection among adult patients. Although HBV can be prevented by immunisation, there is no licenced HCV vaccine. HCV is a positivesense single-stranded RNA (+ssRNA) virus belonging to Flaviviridae family. The HCV global epidemiology varies, with high prevalence rates reported in low-income countries. Approximately 80% of acutely HCV-infected individuals develop chronic hepatitis disease, while 20% resolve spontaneously. Both HBV and HCV infections can result in both acute and chronic hepatitis, ranging in severity from asymptomatic to a life-threatening disease. The HBV and HCV are transmitted through contact with contaminated blood or its products. As compared with mono-infection, HBV/HCV co-infection has higher risk of liver damage. Thus, individuals who have active HBV and HCV infections are likely to be HCV-dominant with a high HCV viral load and low or undetectable HBV DNA levels.

**Keywords:** viral hepatitis, hepatitis B virus, hepatitis C virus, epidemiology, pathogenesis, natural history, diagnosis, genotype, treatment, natural history

### **1. Hepatitis B virus**

Hepatitis B virus (HBV) belongs to *Orthohepadnavirus* genus a member of the *Hepadnaviridae* family which includes other identified but less popular viruses such as *Pekin duck*, *woodchuck*, *Woolly monkey hepatitis B*, and *ground squirrel viruses*. There are some viral similarities in structure, size, nature, genetic replication, and ability to cause infection among these viruses, but HBV remains a major cause of chronic liver disease [1].

#### **1.1 Properties**

#### *1.1.1 Structure*

The HBV is a partially double stranded enveloped deoxyribonucleic acid (DNA) virus with an icosahedral symmetry that can be seen in three different forms and sizes [2]. The predominant form is a small, spherical particle (22 nm diameter), the other form has a diameter of 42 nm. Generally, the HBV virion is spherical, with a diameter of about 40–48 nm, and a length of about 3.2 kb [3]. Approximately 1014 HBV particles per millilitre can be present in the blood of an infected individual [4].

#### *1.1.2 HBV genome organisation*

The HBV genome is made up of a circular DNA which is partly single stranded and partly double stranded. The DNA is not fully double stranded; one strand is incomplete (short strand) whereas the other forms a full length strand (complete long strand). There are small molecules that are covalently linked to the 5′ end of each HBV DNA strand. The short strand is capped with a ribonucleic acid (RNA), whereas the complete long strand is linked to a viral DNA polymerase [5]. The HBV DNA forms a circular conformation, and the full length strand together with the double stands form a short sequence of triple-stranded at the 5′ ends. The HBV envelope comprises three proteins namely; small (S), medium (M), and large (L) that are expressed on the surface of the viral particle. The S protein is the most abundant of the three. The gene S encodes for the HBV surface antigen (HBsAg) [6].

#### *1.1.3 Genetic variation*

The HBV unique life cycle requires an error-prone reverse transcriptase for replication which results in genetic variation in the form of genotypes, sub-genotypes, and mutations. The relationship between HBV genetic variation and HBV-related pathogenesis has been described which determines the outcome of HBV exposure. The HBV genome has approximately 3200 bases with four overlapping open reading frames (ORFs) namely: pre-S/S (surface proteins), pre-C/C (pre-core/core), X (transcriptional co-activator) and P (DNA polymerase) [6, 7]. The pre-S/S ORF which encodes different structural envelope proteins (large, medium and small) is contained within the P ORF, the C ORF overlaps the P ORF by a quarter of its sequence length; whereas the X ORF overlap the P ORF by a third of its sequence length. From the above mentioned four ORFs, seven different proteins are translated [6].

#### *1.1.4 Replication cycle*

The HBV replication is initiated by the attachment of the viral particles to the target cells, in this instance, hepatocytes. A number of cellular receptors such as heparin sulfate proteoglycan (HSPG), and sodium taurocholate co-transporting polypeptide (NTCP) have been reported [8]. Following attachment to the hepatocytes, the viral particles fuse with the host cell's membrane and enter the cell through endocytosis. Following penetration into the cell, the virus uncoats releasing the genetic material (HBV DNA) into the cytoplasm, which is transferred into the nucleus through nuclear pores. In the nucleus, the genetic material is converted to a complete circular double stranded DNA (dsDNA) by the action of the host DNA polymerase. The dsDNA is then transformed into a covalently closed circular DNA (cccDNA) ring (an episomal viral genome) that serves as a template for transcription of five viral RNAs [6, 9, 10]. The dsDNA is very stable and can survive in the host nucleus for a long time. The cellular RNA polymerase transcribes the negative sense single stranded DNA (−ssDNA) to form a positive sense single stranded RNA (+ssRNA). The newly transcribed positive RNA strand leaves the nucleus and migrates to the cytoplasm for protein synthesis (translation). The reverse transcriptase enzyme converts the +ssRNA to form a −ssDNA (reverse transcription). The +ssRNA is flanked by a small fragment of DNA polymerase at the 5′ end which primes the reverse transcription of ¾ of the +ssRNA but unable to complete the transcription of the remaining third. This results in the formation of dsDNA viral particles containing one partially complete strand. The mature viral particles exit the cell through budding and invade other hepatocytes and repeat the replication cycle [11–13].

#### **1.2 Epidemiology**

The HBV prevalence varies worldwide, with high rates reported in low income countries. The World Health Organisation (WHO) estimates that 6.1% of the African population, and 6.2% of the Western Pacific region are infected with HBV [1]. The HBV endemicity is heterogeneous due to variable multiple factors such as child vaccination, injection drug use, poor sensitisation campaigns among others [14].

Approximately over 250 million people are infected with HBV globally [15]. The risks of infection vary widely due to different behaviours that determine the rate of exposure. Uninfected laboratory personnel and other health-care workers are at risk of HBV exposure from infected patients, but the degree of risk depends on several factors such as the strength of their immunity, and nature of work performed [16]. Likewise, patients are also at risk from hospital staff when there are conducting their duties such as surgery, haemodialysis, and dentistry procedures.

#### **1.3 HBV genotypes and their geographical distribution**

HBV genotype plays a significant role in the clinical outcome following viralhost interaction. There are 10 different genotypes of HBV (from A to J), that determine the liver disease clinical progression, prognosis, and the response to antiviral therapy. Genotypes A, B, C, D, and F are associated with rapid progression to cirrhosis and hepatocellular carcinoma. The HBV genotypes A and B are commonly isolated in acute HBV infected individuals [17].

The HBV genotypes geographical distribution varies from one genotype and subtype to the other. The variations in the HBV genotype distributions are related to mode and route of transmission, where vertical transmissions are associated with genotypes B and C [17]. The HBV genotype A is prevalent in Africa, and North Europe; genotypes B and C are widespread in Asia; genotype D is also common in Africa, some parts of Europe, and Asia; genotype E is predominantly in West and Central Africa; genotype F is common in America; genotype G is common in Western countries; genotype H is found in Central and South America; genotype I was reported in Vietnam and Laos; while genotype J was reported in Japan [7, 18].

#### **1.4 Transmission**