Emergence of New Epidemiological Hepatitis B and C Profiles in High Risk Groups in Latin America Emergence of New Epidemiological Hepatitis B and C Profiles in High Risk Groups in Latin America

Latin America includes Mexico, the islands of the Caribbean and Central and South America, which possess a rich cultural and natural heritage. A narrative literature review was made to determine epidemiological hepatitis B and C profiles in high risk groups in Latin America, such as, drug users, hemophiliacs, and chronic kidney disease (CKD), human immunodeficiency virus (HIV) infected individuals. Using data from international databases that disseminate published quality studies. All studies with desired information regarding site and study population were included. It was observed that HBV prevalence diminished in several groups, probably due to implementation of HBV vaccination in var ious Latin America Countries (LACs). On the other hand, HCV prevalence is high among high risk groups compared to general population, but different values were observed in LAC, probably due to different access to education programs, assays evaluated, popula - tion size and type of recruitment. Due to chronicity of HBV and HCV, it is important to increase access to diagnosis, HBV vaccination and implementation of education programs to high risk groups to diminish burden of these infections.


Introduction
The Latin American and Caribbean region encloses the Spanish, Portuguese and Frenchspeaking countries of the American continent and covers almost 22,000,000 km 2 . It includes Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Cuba, El Salvador, Ecuador, Guatemala, Haiti, Honduras, Mexico, Nicaragua, Panama, Paraguay, Peru, Dominican Republic, Uruguay and Venezuela, which possess a rich cultural and natural heritage [1].
Clinical manifestation of hepatitis B and C virus infection varies in both acute and chronic disease. HBV acute phase could be subclinical or anicteric hepatitis to icteric hepatitis and in some cases fulminant hepatitis. Acute Hepatitis C is often asymptomatic and leads to chronic infection in about 75% of cases. During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations can occur in both acute and chronic infection. Pathophysiology is based on the inflammatory response to the virus that replicates in the hepatocyte [2][3][4].
Viral hepatitis is an important public health issue over the world, but there is still some gaps regarding the prevalence of these viruses in Latin America. Hepatitis B virus (HBV) infection has a heterogeneous distribution in Latin America and it is estimated at least 7-12 million people infected by virus [5]. Most of Latin American countries presented low seroprevalence (less than 2% of HBsAg positivity), including Mexico, Honduras, Nicaragua, Costa Rica, Panama, Cuba, Paraguay, Uruguay, Chile, Argentina, Peru and North Colombia. Intermediate seroprevalence (2.0-8.0% of HBsAg) are observed in Central America (Guatemala, Belize, El Salvador, Honduras, Haiti the Dominican Republic and Puerto Rico), Ecuador, Venezuela, Guyana, Surinam, French Guyana and South of Brazil. High seroprevalence (>8% of HBsAg presence) are observed in Peru, South Colombia, Northern Bolivia and Northern Brazil; however, these reports are primarily estimates [6][7][8][9].
Hepatitis C virus (HCV) infection prevalence varies from 1.2 to 1.6% in Peru, Mexico, Venezuela, Argentina and Brazil where almost 80% were viremic [9]. According the same study, genotype 1 was the most frequent detected, but genotype 1b was the most prevalent in all countries except in Peru where genotype 1a was the highest prevalent. Díez-Padrisa et al. [7] reported that Grenada, Bolivia, Haiti, Trinidad and Tobago and El Salvador have the highest prevalence (≥2.5%) in Latin America.
Epidemiological studies to determine HBV and HCV prevalence are important, principally among high risk population, such as human immunodeficiency virus (HIV) infected subjects, drug users, hemophiliacs and chronic kidney patients. HIV individuals coinfected with HBV or HCV could present clinical complications of liver disease and increased risk of developing cirrhosis. Individuals who are drug and alcohol abusers are at risk of becoming infected with HBV or HCV due to unprotected sexual practices that are common to these users besides the sharing of needles and syringes [10]. Chronic kidney disease (CKD) and coagulopathy patients are often exposed to blood, such as during hemodialysis or blood components transfusion where the risk of contracting viral infections is also very high [11]. and evidence-based care. This type of review gives comprehensive background for understanding current knowledge and highlighting the significance of new research in this area.

Methodology
A narrative review of the literature was done using SCIELO, LILACS and MEDLINE® database searches in an iterative manner during December to April 2018 to retrieve articles related to current and historical epidemiological profile of hepatitis B and C in the countries of Latin America and the Caribbean.
All authors independently read each article in full text, evaluated the relevance and quality of retrieved articles to include the data, and recorded the main findings of each study to include the relevant articles in Table 1. Primary and secondary studies were included in the review, but duplicate studies were removed.

Hepatitis B and C prevalence in patients infected by HIV
HIV infection can increase clinical complications of liver disease associated to HBV and HCV, such as increasing the risk of developing cirrhosis up to five times in those co-infected with HIV/HCV [12]. With antiretroviral therapy and a significant increase in the life expectancy of people living with HIV, liver disease in patients with HCV and/or HBV infection has become the leading cause of non-AIDS-related deaths in this population.
In Latin America and the Caribbean, the prevalence of HBV and HCV in people living with HIV is quite variable. Moreover, few data are available, unlike data for Europe and the United States [12]. Over the world, 10% of people infected with HIV are also coinfected with HBV [13], since both viruses has the parenteral and sexual pathways as a route of infection, coinfection of these two viruses are common [14].
All over the world, HIV/HCV coinfection is reported in 4% of HIV-infected people and probability of HCV infection is six times higher in people living with HIV than in the general population [23]. Recently, a systematic review reported prevalence of HIV/HCV co-infection in Latin America of 8% varying from 5 to almost 50% according countries [23]. In LAC, the estimated seroprevalence of HCV infection varied from 0.8 to 58.5% (mean 17.37; median 10.91), with the highest in Argentina (58.5%) and Brazil (53.5%) and the lowest in Venezuela (0.7%) and Colombia (0.8%) [12].
The differences in HCV prevalence observed in LAC were probably due to difference in assays used and characteristics of the population included. In addition, it was observed that HCV prevalence is higher in HIV infected individuals compared to general population in Latin America countries [12].
This high rate of coinfection among these viruses is probably due to the common transmission of these infections, especially among high risk individuals, such as injecting drug users (IDU) living with HIV. Health preventive measures for reducing HBV and HCV infection in these individuals could reduce the prevalence of hepatitis viruses in Latin America region.

HBV and HCV infection in illicit substance users
According to United Nations Office on Drugs and Crime (UNODC) [27], around 5% of the global adult population used illicit substance at least once in 2015 and 0.6% of global adult population suffer from drug use disorders [27]. The consumption of psychoactive substances is related to risks and damages of great social magnitude: unprotected sexual practices, sharing of syringes and needles, as well as exposure to sexually transmitted and parenteral infections, such as HBV [10]. Worldwide prevalence of HBV infection among injecting drug users (IDU) is estimated at 7.4%, suggesting that 880,000 IDU are infected with HBV [27].
In Latin America, the most consumed illicit substance by individuals at drug treatment is Cannabis (around 45%), followed by Cocaine (almost 40%). Recent systematic review demonstrated that HBsAg prevalence varies from 2 to 10% among people who inject drug (PWID) in Latin America countries [28]. In this review, studies published from 2011 to 2017 were included and most of PWID were young (aging less than 25 years), had history of arrest and incarceration, and use opioid.
Most of prevalence studies of HBV in illicit substance users (ISU) in Latin America were conducted in Brazil, followed by Argentina, Colombia, Mexico and Uruguay. In Northern Brazil, HBV prevalence (anti-HBc positivity) was 36.7% in ISU, genotypes A, D and F were found and risk factors were: (i) male gender, (ii) age above 35 years, (iii) anti-HIV positivity, (iv) tattoos, (v) the use of injected drugs, (vi) the use of illicit drugs for more than 3 years, (vii) sexual relations without protection, (viii) sexual relations with another DU, and (ix) more than 10 sexual partners in the past 24 months [29]. In Southeast Brazil, anti-HBc prevalence around 55% was found among IDU in 1999 and IDU living with HIV in 2007. It is important to observe that HBsAg prevalence drops from 7.8 to 3.4% in this region what could be the result of vaccination campaigns [30][31][32]. Occult HBV infection (OBI) of 12.7% was also documented in IDU from Central West region of Brazil demonstrating a high prevalence of OBI in this population [33].
HCV prevalence varies among ISU in Latin America. Degenhardt et al. [28] estimates prevalences less than 40% and higher than 80% among IDU in Latin America. A recent review included studies from 2000 to 2013 conducted in Argentina, Brazil, Colombia, Dominican Republic, Mexico, Panama, Peru, Puerto Rico, Uruguay and Venezuela [38]. Anti-HCV prevalence in ISU was below 7% in the majority of studies included in this review, but anti-HCV rates from 30 to 67% were found in ISU in Argentina and Brazil [39][40][41].

Hepatitis B and C prevalence in patients with chronic kidney disease patients under dialysis treatment
It is well known that patients undergoing dialysis treatment are at increased risk for contracting viral infections. The reasons may be their underlying impaired cellular immunity and the blood exposure to infectious materials through the extracorporeal circulation for a prolonged period. Moreover, hemodialysis patients may require blood transfusion, frequent hospitalizations and surgery, which increase opportunities for nosocomial infection exposure [11]. Most frequent viral infections reported hemodialysis units are HBV, HCV and HIV [54]. These infections influence negatively the survival of the hemodialysis patients and those undergoing renal transplant [55].
Worldwide, HCV prevalence among patients on hemodialysis varies from as low as 1 to up to 70% [56] and the dialysis-related risk of HCV infection development is estimated at 2% per year [54]. Anti-HCV prevalence is low in Latin America (about 1.23%) [57] and varies from country to country, between regions of the same country and even among hemodialysis patients [58]. High anti-HCV prevalence was found in hemodialysis patients in Peru (59%) and from them, 4.5% had mixed infection with hepatitis B (HBsAg positive) [59]. In Venezuela, a study conducted in four hemodialysis units found 71% of anti-HCV and 25% of HBsAg among hemodialysis patients [60].
In Argentina, a study demonstrated a drop in anti-HCV prevalence in a same hemodialysis unit showing prevalence of 41.5% in 1994; 26.9% in 1996; 12% in 1998 and 8.5% in 2000 [61]. According to the Chronic Dialysis Registry of Argentina, anti-HCV prevalence decreased from 2% in 2004 to 1% in 2011 and global HCV prevalence was 4.9% in 2011 [62,63].
In Brazil, some studies have been performed to evaluate HCV prevalence in different hemodialysis units. In 2006, among 70 patients of the south region undergoing hemodialysis, seven (10%) presented HCV infection [72]. Still in 2006, but in Salvador city (Northeast Brazil), the anti-HCV prevalence among hemodialysis patients was 10.5% with detectable HCV RNA in 73.6% of them. In this study, the most frequent HCV genotype was genotype 1 followed by genotypes 3 and 2 [73]. In North region, anti-HCV prevalences from 4 to 14% were found in 7 dialysis center in Para State in 2013. In this study, HCV RNA was detected in 5.3% of the patients and genotype 1 was the most frequent, followed by genotypes 2 and 3 [74]. Recently, Barbosa-Ribeiro et al. [17] found 12.6% of anti-HCV prevalence in Hemodialysis patients at Northeast Brazil. In Southeast region, anti-HCV prevalence of 13 and 14.8% was found in 2008 and 2010 years [75,76].
HBV prevalence varies in CKD patients in Latin America. In Mexico [77] found 7.1% of HBsAg prevalence in 10 hemodialysis units at 2010 and two of them were co-infected with HCV (0.5%) [77]. In Uruguay, HBsAg prevalence of 1% was found in hemodialysis patients probably due to mandatory screening of blood donors and patients for HBsAg since 1981 [71].
Among patients undergoing hemodialysis, it is relatively common to observe occult hepatitis B cases due to vial of transmission and prolonged vascular access [83]. In Brazil, prevalence of OBI of 1.5, 3 and 15% was found in Northeast and Southeast region of Brazil [83][84][85]. HBV genotype A was the most prevalent in these studies.

HBV and HCV infection among coagulopathy patients
Hereditary coagulopathies are hemorrhagic diseases resulting from deficiency of one or more plasma coagulation proteins, implying a reduction in the formation of thrombin which is a key factor for blood clotting. Among hereditary hemorrhagic disorders, hemophilia (type A and B) and von Willebrand's disease (VWD) are the most common [86]. Hemophilia A and B are X-linked hemorrhagic disorders caused by mutations in the factor VIII and factor IX genes, affecting almost exclusively male individuals. Both factors play a role in the intrinsic pathway of blood clotting and the affected individuals present severe, moderate and mild forms of disease defined by plasma coagulation factor levels [87]. While VWD is caused by a decreased or dysfunction of the protein called Von Willebrand Factor (VWF) and affects both genders. The diversity of mutations leads to the appearance of several clinical manifestations, manifesting with platelet dysfunction associated with the decrease of serum levels of factor VIII [88].
Worldwide, it is estimated that hemophilia affects 1 in 5000 newborns while VWD reaches from 0.8 to 2% of the population. According to the 2015 global annual report of the World Federation of Hemophilia, which included data from more than 304,000 people with hereditary coagulopathy from 111 countries, 49.7% of the cases were from hemophilia A, 9.9% from hemophilia B, 24.6% of DVW and 13.9% of other coagulopathies [86].
The treatment of coagulopathies is based on the replacement of the deficient coagulation factor, when there are hemorrhagic manifestations or as primary prophylaxis. This therapy increases the survival of these patients and their success in preventing the different hemorrhagic manifestations [89,90]. On the other hand, due to multiple blood transfusions and use of cryoprecipitate, elaborated from a pool of frozen human plasma, these individuals are at risk for transmission of infectious agents, such as hepatitis B and C viruses [91,92].
Most of viral infections occurred before 1985, when inactivation techniques were introduced in clotting factor concentrates. Thus, countries in Latin America, as well as other regions of the world, suffer the impact of these viral infections, which have evolved into chronic cases of the disease.
Regarding anti-HCV prevalence in coagulopathy patients, a universal screening in 1995 identified 51.6% of anti-HCV in hemophiliac patients from Cuba [95]. In 2007 to 2010, anti-HCV prevalence was 39.03% in this group in Cuba [99]. While in Colombia, patients from the cities of Bogotá and Medellin in 2003 presented 32.2% of anti-HCV [74]. In Peru, a study with multi-transfused patients from the seven largest hospitals in the country revealed 56.6% of anti-HCV prevalence [97]. In Honduras, 8 hospitals in the cities of Tegucigalpa and San Pedro Sula identified anti-HCV prevalence of 26.9% [94]. In Mexico, 46.3% of anti-HCV prevalence was found in hemophiliacs at 2008 [93]. In Argentina, 42.7% of anti-HCV positivity was found in hemophiliacs from 2002 to 2004 [100]. As the same was found for HBV, Ferreira et al. [98] observed a decrease in anti-HCV prevalence from 24.2% in 2007 to 4.7% in 2012. However, recent study in coagulopathy patients from Northeast Brazil found 47% of anti-HCV prevalence [17].

Conclusion(s)
In Latin America countries, HBV and HCV infection are still great public health problem in individuals infected by HIV, CKD patients, coagulopathy patients, illicit substance abusers.
Prevalences of these infections are higher in these individuals compared to general population and different patterns of epidemiology were found between and within countries probably due to differences in access to diagnosis and treatment in these regions. A fall in the prevalence of HBV and HCV infection has been observed in these groups due to HBV immunization and HCV screening especially among CKD and coagulopathy patients. However, outbreaks still happen in these groups showing the importance of education programs to prevent the transmission of these viruses.
The recommendations for each group are: among CKD and coagulopathy individuals, it is important to provide access to sensitive methods of diagnosis, screening of blood products and equipment and HBV vaccination. Among ISUs and HIV infected individuals, it is important to provide access to diagnosis, increase prevention and education campaigns to reduce the risk of acquiring HBV and HCV due to risky sexual behavior or sharing of needles and syringes. Vaccination against HBV should also be a priority in these groups. All these recommendations must be made in all countries of Latin America since epidemiological differences between HBV and HCV infection among countries is based on the different investments made in health, especially those related to diagnosis and prevention.