Antiviral Therapy

Viral hepatitis B, C and delta still remain a serious problem in Latin America. Data from the 1980s indicated that HBV and HDV infection are the main causes of chronic hepatitis. However, the spread of HBV infection could be controlled through the implementation of immunization programmes. Different countries from Mexico to Argentina display marked differences in terms of HBV genotype distribution. HBV genotype F has been identified as the most frequent in most Latin America countries, except for Mexico and Brazil, where genotypes H and A are the most frequent, respectively. In Latin America, the overall prevalence of HCV antibody is estimated to be 1.5%. Latin American countries have been very proactive in screening their blood supplies, thus minimizing risk of HCV transmission through transfusion. The number of diagnosed and treated patients is still low, thereby increasing the burden of complications such as liver cirrhosis or hepatocellular carcinoma. The most prevalent HCV genotype is 1, which is the genotype with the greatest worldwide spread, but it is a different genotype from other regions like Africa and Asia. HDV is present worldwide but its distribution pattern is not uniform. HDV was recently detected in novel geographic regions, reinforcing that it is a very serious health threat in under-developed countries. The main prevalence areas are the Mediterranean basin, the Middle East, central and northern Asia, western and central Africa, the Amazonian basin (Brazil, Peru, Venezuela and Colombia) and the Pacific islands. Novel strategies to increase HBV immunization in the Latin American population are needed to warrant thorough coverage in the rural areas.

The global hepatocellular carcinoma (HCC) incidence is widely variable, depending on geographic region and the prevalence of major risk factors. In Brazil, two large multicentre retrospective studies were performed to investigate clinical and epidemiological aspects of HCC. In the first study, performed in 1997, HCC was found in cirrhotic livers in 71% of cases. Chronic alcoholism was present in 36% of cases, chronic hepatitis B in 35% and hepatitis C in 25%. In a 2010 survey, cirrhosis was present in 98% of cases and HCV was the main aetiology (54%). Differences in HBV prevalence were found among regions. Selection of HCC treatment depends on tumour burden, liver function and performance status. Liver transplantation (LT) is the best available curative treatment for HCC in its early stage and with compromised liver function. After modifications in priority policy, the number of patients with early HCC submitted for LT has increased in the past 5 years in Brazil. Chemoembolization is the most common initial HCC therapy in early and intermediate stages of HCC in Brazil.

HCV-related liver disease is an important contributor to morbidity and mortality in the HIV-infected population. Successful treatment of HIV–HCV-coinfected patients is followed by favourable clinical outcomes. While the combination of pegylated interferon and ribavirin remains the mainstay in the treatment of non-1 HCV genotypes, the first generation of HCV protease inhibitors are being incorporated into existing HCV genotype-1 (HCV-1) treatment protocols. Although data are limited, the triple combination does improve the sustained virological response in HIV–HCV-1-coinfected subjects. However, with still very limited data in this setting, clinical decisions for triple therapy have to be individualized and made based on multiple considerations. Chronic HBV infection increases mortality in HIV-infected subjects. In the treatment of HIV–HBV coinfection, it is very important to coordinate HBV and HIV therapies. HBV-active HAART improves the outcome of patients with HIV–HBV coinfection and tenofovir has become a key component of the treatment for these patients, although a number of clinical situations require a case-by-case approach.

Approximately 2 billion people worldwide are infected with HBV, and 350 million people are chronic carriers. HBV is classified into nine genotypes (A to I). Genotype F is the most prevalent in the Spanish-speaking countries and in the Amerindian population in South America. HBV genotype F was primarily found in indigenous populations from South America and is divided into four subgenotypes (F1 to F4). Subgenotype F1 is further divided into F1a (found in Costa Rica and El Salvador) and F1b (found in in Alaska, Argentina and Chile). Subgenotypes F2 and F3 cocirculate in the north of South America: F2a is found in Brazil and Venezuela, F2b is described only in Venezuela, F3 is frequent in Colombia, Venezuela and Panama, and F4 is reported from the central and south areas of South America, including Bolivia, Argentina and southern Brazil. HBV genotypes and subgenotypes have distinct geographical distributions. It is currently under discussion whether they are associated with different prognoses, considering the patterns of severity of liver diseases in various populations. Furthermore, global human migrations affect the pattern of genotype distribution, introducing genotypes differing from those found in the original inhabitants.

The burden of viral hepatitis among indigenous populations of the United States, Canada and Greenland is greater than in non-indigenous populations. In particular, throughout the circumpolar Arctic regions, chronic hepatitis B infection is highly prevalent, although incidence rates have declined considerably in certain regions due to infant HBV vaccination. Unique HBV (sub)genotypes having distinct clinical outcomes and distribution patterns are also observed within this region. In conjunction with hepatitis B infection, hepatitis delta infection is also apparent within North American indigenous peoples, particularly with outbreaks in Greenlandic Inuit communities. Incidence rates for hepatitis C infection are higher for indigenous populations within the United States and Canada; however, some hepatitis C antibody-positive indigenous patients are more likely to be HCV RNA-negative compared to non-indigenous patients. Thus, an increased understanding of the epidemiology, clinical consequences and pathogenicity of viral hepatitis affecting the indigenous populations will help to address and balance the burden of infection.

The distribution of HBV genotypes is associated with populations of specific geographical regions of the world. We show data from the GenBank sequence database and medical reports, which indicate that HBV genotype H (HBV/H) is mainly distributed in Mexico, whereas HBV genotype F (HBV/F) is distributed in countries from Central America. The phylogenetic analysis and historical records suggest that HBV/H has been present in Mexico even before the arrival of the Spaniards. Interestingly, occult hepatitis B is a common finding in both natives and patients with chronic liver disease in Mexico. This suggests that an immunogenic background could be important during the natural history of liver diseases. The estimated large number of HBV/H-infected patients in Mexico does not correlate with the total number of patients with chronic liver disease and cirrhosis reported in the country. This may be because of the fact that HBV infection is often masked by alcoholic liver disease, HCV coinfection and/or obesity. Here, we analyse the data concerning the distribution of HBV/F and HBV/H genotypes in Central America and Mexico. Specifically, we focus on the effect of molecular epidemiology and pathogenesis of HBV/H. These recent findings reveal new areas of study with therapeutic potential in viral liver diseases.

The analysis of the HBV genome revealed the existence of 10 genotypes, named A–J. Evidence of the influence of the different genotypes in the natural history and treatment response to nucleoside/nucleotide analogues or interferon-based regimens is scant. HBV genotype F is one of the most prevalent circulating genotypes in South America and the Arctic Circle. Since most of the available information on HBV is from Asia, the US and Europe, it refects their predominant genotypes: A, B, C and D. To date, the evidence is not fully confirmed, but it appears that genotype F chronic hepatitis B is associated with a more aggressive course of liver disease, refected by higher histological indexes, a higher risk of development of hepatocellular carcinoma and a higher rate of liver-related mortality. In terms of treatment response, the available data is, unfortunately, even more limited; however, what data is available suggests acceptable and similar response rates to pegylated interferon-α2a in genotype F compared to genotype A. Response rates to nucleoside/nucleotide analogues is not influenced by genotype. The review of this limited data sheds light on the necessity to conduct further studies in South America and the Arctic Circle in order to better understand the different aspects of HBV genotype F, especially in relation to treatment response.

Many challenges exist for the study of HCV in the laboratory. Therapy using interferon (IFN) is expensive, not well tolerated and ineffective for many patients. HCV research has been hampered by the lack of a robust tissue culture system, but recent advances have made virus growth in culture possible. Cell culture systems using genetically engineered viruses have been reviewed extensively, but here we review recent advances made in the use of natural isolates and the molecular challenges that have been used to overcome the limitations in their growth. Six major genotypes have been identified for HCV that are further divided into numerous subtypes. Combination therapy utilizing IFN-α and ribavirin is the standard of care, but is successful in only one-half of patients. The reasons for IFN resistance may be viral- or host-related and may be due to multiple factors. Recently, telaprevir and boceprevir, together with IFN-α and ribavirin, have been added to the standard of care in patients infected with IFN-resistant genotypes. A major obstacle in the development of effective vaccines and improved therapeutics has been the lack of a reproducible and efficient tissue culture system for propagation of HCV. Many cell culture systems have used genetically-engineered viruses to gain growth in culture through the use of replicons, but recent advances using natural isolates may improve the outlook for progress in HCV research.

HBV and HCV are the only hepatotropic viruses capable of establishing chronic infections. More than 500 million people worldwide are estimated to have chronic infections with HBV and/or HCV, and they have an increased risk of developing liver complications, such as cirrhosis or hepatocellular carcinoma. During the past decade, several antiviral agents including immune-modulatory drugs and nucleoside/nucleotide analogues have been approved for the treatment of HBV and HCV infections. In recent years, the focus has been on the development of new and better therapeutic agents for management of chronic HCV infections. Bioinformatics has only been applied recently to the field of viral hepatitis research. In addition to the wide range of general tools freely available for identification of open reading frames, gene prediction, homology searching, sequence alignment, and motif and epitope recognition, several public database systems designed specifically for HBV and HCV research have now been developed. The focus of these databases ranged from being viral sequence repositories for the provision of bio-informatics tools for viral genome analysis, as well as HBV or HCV drug resistance prediction. This review provides an overview of these public databases, which have integrated bioinformatics tools for HBV and HCV research. Properly managed and developed, these databases have the potential to have a broad effect on hepatitis research and treatment strategies. However, the effect will depend on the comprehensive collection of not only molecular sequence data, but also anonymous patient clinical and treatment data.

Hepatitis delta is an inflammatory liver disease caused by infection with HDV. HDV is a single-stranded circular RNA pathogen with a diameter of 36 nm. HDV is classified in the genus Deltavirus and is still awaiting a final taxonomic classification up to the family level. HDV shares similarities with satellite RNA and viroids including a small circular single-stranded RNA with secondary structure that replicates through the ‘double rolling circle’ mechanism. The HDV RNA genome is capable of self-cleavage through a ribozyme and encodes only one structural protein, the hepatitis delta antigen (HDAg), from the antigenomic RNA. There are two forms of HDAg, a shorter (S; 22 kDa) and a longer (L; 24 kDa) form, the latter generated from an RNA editing mechanism. The S form is essential for viral genomic replication. The L form participates in the assembly and formation of HDV. For complete replication and transmission, HDV requires the hepatitis B surface antigen (HBsAg). Thus, HDV infection only occurs in HBsAg-positive individuals, either as acute coinfection in treatment-naive HBV-infected persons, or as superinfection in patients with pre-existing chronic hepatitis B (CHB). HDV is found throughout the world, but its prevalence, incidence, clinical features and epidemiological characteristics vary by geographic region. There are eight genotypes (1 to 8) distributed over different geographic areas: HDV-1 is distributed worldwide, whereas HDV-2 to 8 are seen more regionally. Levels of HDV viraemia change over the course of HDV infection, being significantly higher in patients with early chronic hepatitis than in cirrhosis. Chronic HDV infection leads to more severe liver disease than chronic HBV monoinfection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis. Current treatments include pegylated interferon-α and liver transplantation; the latter of which can be curative. Further studies are needed to develop better treatment strategies for this challenging disease.