Hepatitis C in Developing Countries: Current and Future Challenges

Hepatitis C in Developing Countries

Current and Future Challenges

Editor

Sanaa M. Kamal

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Introduction

Section 1. Hepatitis C Virus: Virology, Epidemiology, and Transmission

Chapter 1.1. Hepatitis C Virus: Virology and Genotypes

Introduction

Epidemiology of Hepatitis C Virus Genotypes and Genotypic Variations Around the World

Hepatitis C Virus Genotype Patterns in North Africa and the Middle East

Hepatitis C Virus Genotype Patterns in Sub-Saharan Africa

Hepatitis C Virus Genotype Patterns in Southeast Asia

Hepatitis C Virus Genotype Distribution in Eastern Europe

Hepatitis C Virus Genotype Patterns in the South America

Conclusions

Abbreviations

Chapter 1.2. Epidemiology and Modes of Transmission of HCV in Developing Countries

HCV Prevalence in Developing Countries

Age and Gender Distribution in Developing Countries

Modes of Transmission: Changing Patterns in the West and East

Section 2. The burden of Hepatitis C in Developing countries

Chapter 2.1. Public Health and Economic Burden of Hepatitis C Infection in Developing Countries

Introduction

Abbreviations

Chapter 2.2. Social, Cultural, and Political Factors Influencing HCV in Developing Countries

Introduction

Influence of Social Factors on HCV Transmission in Developing Countries

Lay Perspective of HCV in Developing Countries

Hepatitis C and Injecting Drug Use: The Realities of Stigmatization and Discrimination

Discrimination Toward People Living With Hepatitis C

Section 3. Hepatitis C Infection in Specific Geographic Regions

Chapter 3.1. Hepatitis C in Egypt

Introduction

Prevalence and Incidence of HCV in Egypt

Prevalence of HCV Among High-Risk Groups in Egypt

Acute Hepatitis C in Egypt

Modes of Transmission of HCV in Egypt

Impact of Immigration on HCV Transmission

Economic Burden of HCV in Egypt

Treatment of Hepatitis C in Egypt in the Era of Direct-Acting Antiviral Agents

Hepatitis C Prevention Strategies in Egypt

Abbreviations

Chapter 3.2. Hepatitis C in North Africa (Arabic Maghreb Region)

Introduction

The Status of HCV in Maghreb Region

Prevalence of HCV in Maghreb Countries

Factors Associated With HCV in Maghreb Region

Strategies to Prevent HCV in the Maghreb Region

Conclusion

Abbreviation

Chapter 3.3. Hepatitis C Virus in Sub-Saharan Africa

Introduction

Hepatitis C Virus Prevalence in Central Africa

HCV Prevalence in the West African Region

HIV/HCV Co-infection in Nigeria

HCV Genotypes in Nigeria

Modes of HCV Transmission in Nigeria

Chapter 3.4. Hepatitis C Virus Infection in the Indian Sub-Continent

Introduction

HCV in India

HCV in Pakistan

HCV in Myanmar

HCV in Afghanistan

HCV in Nepal

HCV in Bangladesh

HCV in Sri Lanka

HCV in Bhutan

HCV in Maldives

Chapter 3.5. Hepatitis C in Developing Countries in Southeast Asia

Epidemiology

Geographical Distribution of HCV Genotypes in Southeast Asia

HCV Genotype 6 in Southeast Asia

Hepatitis C and HIV in Southeast Asia

Hepatitis C in Vietnam

HCV in Myanmar

HCV in Indonesia

HCV in Philippines

HCV in Cambodia

Section 4. Hepatitis C Coinfections and Comorbidities in Developing Countries

Chapter 4.1. Hepatitis C and Schistosomiasis Coinfection

Introduction

Schistosoma Life Cycle and Modes of Transmission

Acute Schistosomiasis

Chronic Schistosomiasis

Immune Responses in Schistosomiasis

Immune Responses in Hepatitis C Infection

Concomitant Schistosomiasis and HCV Infection

Effect of Schistosomiasis on the Outcome of Acute Hepatitis C Infection

Effect of Schistosomiasis on the Progression of Chronic Hepatitis C

Chapter 4.2. Hepatitis C and Helminthic Infections

Introduction

Characteristics of Immune Response to Helminths

Concurrent Helminthic and Hepatitis C Infections

Effect of Helminths on Viral Infections

Concluding Remarks

Chapter 4.3. Hepatitis C and HIV Coinfection in Developing Countries

HIV in Developing Countries

HIV Epidemic in Sub-Saharan Africa

HIV in Developing Countries in Latin America and the Caribbean

Hepatitis C and HIV Coinfection

Impact of HIV Infection on Chronic HCV

Effect of ART on the Course of HCV

Treatment of HCV With Coexisting HIV Infection in the Era of Direct-Acting Antiviral Agents

Drug–Drug Interactions Between Antiretrovirals and DAAs

Conclusion

Abbreviations

Chapter 4.4. Hepatitis B and C Coinfection

Introduction

Epidemiology

Viral Interactions

Chapter 4.5. Hepatitis C Infection in Patients With Hemoglobinopathies

Introduction

Hemoglobinopathies in Developing Countries

Hepatitis C Infection in Patients with Hemoglobinopathies

Abbreviations

Chapter 4.6. Hepatitis C in Patients on Hemodialysis

Introduction

The Impact of HCV on Kidney Disease

Prevention of HCV Transmission in HD Units

Natural Course of HCV Infection in Patients With ESRD

Treatment of HCV in Patients with ESRD

Abbreviations

Chapter 5. Hepatitis C Screening and Diagnosis in Developing Countries

Screening of Hepatitis C virus Infection

Section 5. Evolution of Hepatitis C Treatment

Chapter 6. Hepatitis C Treatment in the Era of Direct-Acting Antiviral Agents: Challenges in Developing Countries

Introduction

Natural History and Outcome of HCV Infection

Evolution of HCV Therapy

Direct-Acting Antiviral Agents

Nonstructural Protein 5A Inhibitors

Ombitasvir–Paitaprevir– Ritonavir–Dasabuvir (Viekira Pak)

Patients with HCV and HIV Coinfection

Treatment of Patients With Decompensated Cirrhosis

Patients With HCV Recurrence After Liver Transplantation

Patients With HCV and Renal Impairment

Retreatment of Patients Who Failed Previous Therapy

Treatment of HCV and HBV Coinfection

DAA Resistance

Abbreviations

Appendix

Index

Copyright

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List of Contributors

Ahmed Abdel Aziz,     King Abdullah University for Science and Technology, Jeddah, Kingdom of Saudi Arabia

Sara A. Abdelhakam,     Ain Shams University, Cairo, Egypt

Othman Amin,     Al Khartoum University, Khartoum, Sudan

Ozlem Tastan Bishop,     Rhodes University, Grahamstown, South Africa

Mohamed A. Daw,     University of Tripoli, Tripoli, Libya

Thi Q. Doan,     Hanoi Medical University, Ho Chi Minh City, Vietnam

Ahmed M. Fouad,     American University of Lebanon, Beirut, Lebanon

Huda H. Gaafar,     Prince Sattam College of Medicine, Kharj, Kingdom of Saudi Arabia

Dahlia Ghoraba,     Ain Shams Faculty of Medicine, Cairo, Egypt

Tamer A. Hafez,     American University, Cairo, Egypt

Sanaa M. Kamal,     Ain Shams Faculty of Medicine, Cairo, Egypt

Khalifa S. Khalifa,     Ain Shams Faculty of Medicine, Cairo, Egypt

Osi Obadahn,     University of Lagos, Lagos, Nigeria

Mohamad A. Othman,     University of Gezira, Khartoum, Sudan

Shashi Shekhar,     Dar Al Uloom University College of Medicine, Riyadh, Kingdom of Saudi Arabia

Georgios Zacharakis

University of Nicosia, Nicosia, Republic of Cyprus

Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia

Introduction

Hepatitis C infection is a major public health issue worldwide [1–4]. The early stages of the infection are mostly asymptomatic and progress to chronic hepatitis, cirrhosis, or hepatocellular carcinoma (HCC). About 180  million people are infected worldwide with hepatitis C and most infected cases are in resource-limited countries [2,3]. The prevalence of hepatitis C virus (HCV) is much higher among at-risk populations (e.g., drug users, HIV-positive individuals, and prisoners) [4]. The deficient resources in such underprivileged regions pose significant barriers to containing the HCV epidemic in these countries. HCV prevalence can reach alarming levels, such as 60%–80% in injection drug users and more than 80% in HIV-coinfected individuals, particularly in developing countries where the number of injecting drug users is especially high [3,4]. The poor medical infrastructures, shortage of well-trained health-care workers, insufficient screening, abundance of risk factors for HCV transmission, and poor access to health care and treatment contribute to the huge burden of HCV in resource-limited countries [5]. Chronic HCV accounts for a substantial percentage of cirrhosis and HCC particularly in the endemic regions such as Egypt, sub-Saharan Africa, and South-East Asia.

The persistence and increased morbidity from HCV infection result from several factors including poor health education, poverty, inadequate prevention and screening strategies, frequent iatrogenic transmission, absence of insufficient medical insurance, prevalence of coinfection, stigma associated with the infection, and insufficient or even inexistent access to treatment [6]. In resource-limited countries, the inadequate infrastructures hamper the conduction of proper surveillance for collection of accurate data on the actual prevalence of HCV among the general population and vulnerable individuals. Despite the recent considerable strides in treatment and eradication of HCV in wealthy countries, reduction in transmission and morbidity from chronic HCV in poor countries remains a distant objective. Poverty and illiteracy are major factors that ignite HCV transmission in resource-limited countries. According to the World Health Organization, less than 50% of the blood supply in sub-Saharan Africa is screened for HCV, and 2–3  million people are infected each year through unsafe injections. Access to treatment is also a major obstacle to containing the epidemic in resource-limited countries.

The high burden of HCV in poor countries is not restricted to such regions. Recently, HCV spreads beyond its strongholds in Africa and South East Asia and posed a real threat to the health systems in Europe and North America. The recent mass migration waves introduced increasing numbers of documented or undocumented migrants or trafficked persons who come from countries with high HCV prevalence. Many migrants are not properly screened upon arrival to the host countries, and infected individuals may not have access to treatment. Furthermore, migrants in many countries are kept in camps where transmission of infections such as HIV, HBV, and HCV may be increased because of traditional and social behaviors. Thus, the increasing influx of refugees from highly endemic counties may change the disease burden in Western refugee-hosting countries. To date, WHO does not recommend obligatory screening of refugee and migrant populations for communicable diseases including HCV because there is no clear evidence of benefits (or cost-effectiveness); furthermore, it can cause anxiety in individual refugees and the wider community. Obligatory screening may deter migrants from asking for a medical check-up, thus jeopardizing identification of high-risk patients [7].

Taken together, the burden status of hepatitis C in resource-limited countries has been ignored and neglected for long intervals. Accurate estimates of the incidence and prevalence of HCV in developing countries are critical for designing effective strategies to combat the epidemic. Absence of a vaccine for HCV stresses the importance of strengthening preventive efforts and early identification and treatment of infected individuals. The advent of highly potent, new interferon-free antiviral drugs mandates serious collaborative efforts of health policy-makers, medical doctors, scientists, and governments to improve access to screening, care, and HCV treatment for patients living in resource-limited settings. To achieve this, it is crucial to conduct large clinical trials and national programs to adapt screening and treatment strategies to the local conditions of resource-poor settings, and cost-effectiveness studies should be carried out urgently as these are needed to demonstrate the feasibility, safety, and benefits of such therapeutic regimen for patients living in resource-poor HCV endemic countries.

This book explores the different aspects of the long-forgotten problem of hepatitis C infection in developing countries. The book chapters provide invaluable insight and up-to-date information about the HCV epidemiology and modes of transmission in different developing countries. The HCV genotypes, natural history, and treatment are analyzed. The impact of HCV on public health, economy, and social structure of affected countries is discussed.

Dr. Sanaa M. Kamal

References

[1] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011;17:107–115.

[2] World Health Organization. Hepatitis C. WHO fact sheet 164. Geneva, Switzerland: World Health Organization; 2000 Available from:. http://www.who.int/mediacentre/factsheets/fs164/en/.

[3] Lavanchy D. The global burden of hepatitis C. Liver Int. 2009;29(Suppl. 1):74–81. 

[4] Shepard C.W, Finelli L, Alter M.J. Global epidemiology of hepatitis C virus infection. Lancet Infect Dis. 2005;5:558–567.

[5] Lemoine M, Thursz M. Hepatitis C, a global issue: access to care and new therapeutic and preventive approaches in resource-constrained areas. Semin Liver Dis. 2014;34:89–97.

[6] Lemoine M, Eholie S, Lacombe K. Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach. J Hepatol. 2015;62:469–476.

[7] Assessing the burden of key infectious diseases affecting migrant populations in the EU/EEA, European Centre of Disease Prevention and Control. 2014 [Internet] at:. http://www.europarl.europa.eu/RegData/etudes/BRIE/2016/573908/EPRS_BRI(2016)573908_EN.pdf.

Section 1

Hepatitis C Virus: Virology, Epidemiology, and Transmission

Outline

Chapter 1.1. Hepatitis C Virus: Virology and Genotypes

Chapter 1.2. Epidemiology and Modes of Transmission of HCV in Developing Countries

Chapter 1.1

Hepatitis C Virus

Virology and Genotypes

Ahmed Abdel Aziz     King Abdullah University for Science and Technology, Jeddah, Kingdom of Saudi Arabia

Abstract

Hepatitis C virus (HCV) is a major causative agent of chronic liver disease worldwide. HCV is characterized by genetic heterogeneity, with at least six genotypes identified. The geographic distribution of genotypes has shown variations in different parts of the world over the past decade because of variations in population structure, immigration, and routes of transmission. Genotype differences are of epidemiologic interest and help the study of viral transmission dynamics to trace the source of HCV infection in a given population. HCV genotypes are also of considerable clinical importance because they affect response to antiviral therapy and represent a challenging obstacle for vaccine development.

Keywords

Cirrhosis; Genotypes; Hepatitis C virus; Hepatocellular carcinoma

Chapter Outline

Introduction

Epidemiology of Hepatitis C Virus Genotypes and Genotypic Variations Around the World

Hepatitis C Virus Genotype Patterns in North Africa and the Middle East

Hepatitis C Virus Genotype Patterns in Sub-Saharan Africa

Hepatitis C Virus Genotype Patterns in Southeast Asia

Hepatitis C Virus Genotype Distribution in Eastern Europe

Hepatitis C Virus Genotype Patterns in the South America

Conclusions

Abbreviations

References

Introduction

Hepatitis C virus (HCV) is a positive-strand RNA virus distantly related to the Flaviviridae family. The HCV genome consists of about 9400 nucleotides, with one large open reading frame encoding for a polypeptide about 3000 amino acids long, consisting of structural and nonstructural domains. The sequence contains a 5′ untranslated region (5′ UTR) of 341 bases, a long open reading frame coding for a polyprotein of 3011 amino acids, and a 3′ untranslated region of about 27 bases. The three N-terminal HCV proteins (C, E1, and E2/NS2) are probably structural, and the four C-terminal proteins (NS2, NS3, NS4, and NS5) are believed to function in viral replication [1,2] (Fig. 1.1.1).

The HCV lifecycle begins with the attachment of a virion to its specific receptors on hepatocytes [2]. The high-density lipoprotein receptor scavenger receptor class B type I, tetraspanin CD81, tight-junction protein claudin-1, and occludin are the known cellular receptors initiating the attachment step of HCV infection. After binding with its receptor complex, the viron is internalized, and the nucleocapsid is released into the cytoplasm. Uncoating then occurs with exposure of the genomic RNA, which is used both for polyprotein translation and replication in the cytoplasm. HCV replication takes place within the replication complex containing the viral nonstructural proteins and cellular proteins [1] (Fig. 1.1.2).

Figure 1.1.1  Structure of hepatitis C virus.

Figure 1.1.2  Life cycle of hepatitis C virus.

HCV replication is catalyzed by the NS5B protein and other viral nonstructural proteins. The NTPase/helicase domain of the NS3 protein is related to viral replication, including RNA-stimulated NTPase activity, RNA binding, and unwinding of RNA regions of extensive secondary structure. NS4B initiates the formation of a replication complex that supports HCV replication. The NS5A protein also plays an important regulatory role in virus replication. A number of cellular factors are involved in HCV replication, such as cyclophilin A, required for HCV replication through its interaction with NS5A and the NS5B, and microRNA-122, which helps HCV replication through its binding with the 5′ UTR of the HCV genome. Therefore, host factors may also become the potential targets for anti-HCV therapies. At present, at least two host-targeted agents have reached clinical development, including specific inhibitors of cyclophilin A and antagonists of microRNA-122 [1–4].

The genomes of HCV display significant sequence heterogeneity and have been classified into genotypes and subtypes. To date, six genotypes (1–6) have been recognized [2]. Genotypes differ from each other by 30%–35% of nucleotide sequences. More variability is concentrated in regions such as the E1 and E2 glycoproteins, whereas sequences of the core gene and some of the nonstructural protein genes, such as NS3, are more conserved. The 5′ UTR contains a relatively well-conserved region that has a 92% homology among different HCV genotypes [3]. Some genotypes are further divided into subtypes (a, b, c, etc.), which typically differ from each other by 20%–25% in nucleotide sequences. Within a given individual, multiple quasi-species can exist [4,5].

Epidemiology of Hepatitis C Virus Genotypes and Genotypic Variations Around the World

HCV is divided into six distinct genotypes throughout the world with multiple subtypes in each genotype class. A genotype is a classification of HCV virus based on the genetic material in the RNA strands (Fig. 1.1.3).

Genotypes 1, 2, and 3 (HCV G1, G2, and G3) have a worldwide distribution [5,6]. Types HCV G1a and G1b predominate in Europe, North and South America, and Japan, accounting for about 60% of global infections. HCV G2 is common in Japan and China and is found in the United States and in northern, western, and southern Europe [6,7]. HCV G3 is prevalent in Southeast Asia, India, and Australia and is variably distributed in Europe and the United States [5,6]. HCV G4 is principally found in the Middle East, Egypt, and central Africa [8,9]. HCV G5 is almost restricted to South Africa [10], and HCV G6 is found in specific regions in Asia [11,12] (Fig. 1.1.4).

Figure 1.1.3  Genotypes of hepatitis C virus.

Figure 1.1.4  Geographical distribution of hepatitis C virus genotypes.

The origin and evolution of HCV genotypes in humans is still not clear. It is believed that the virus has evolved over several thousand years [1]. The huge genetic diversity of genotypes HCV G1, G2, and G4 in western and central Africa [12–17] and of HCV genotypes G3 and G6 in the Indian subcontinent and South East Asia [11,12] suggests that HCV has been endemic in these populations for a long time. The appearance of new risk groups and routes of transmission such as blood transfusion, the medical use of unsterilized needles, and (especially in industrialized countries) injection drug use and the sharing of injection equipment allowed the rapid spread and global distribution of genotypes HCV G1, G2, and G3 to Western and other nontropical countries over the past 30–70  years [15]. However, a close association between specific genotypes and specific geographic regions is observed, such as the prevalence of HCV G4a in Egypt [13–15] and HCV G5a in South Africa [10]. In Western countries, specific genotypes circulate in various risk groups, including HCV G1a and G3a in injecting drug users (IDUs) and HCV G1b, G2a, G2b, G2c, and G4a throughout the Mediterranean area [13,15].

Over the past decade, the epidemiology and distribution of HCV genotypes have shown marked variations in some geographic areas and have been relatively stable in others. Much of the HCV genotype variability detected between geographic regions can be explained by the different HCV epidemic histories in these regions, the frequency and extent to which different risk factors have contributed to the transmission of HCV, and population dynamics, which directly or indirectly introduced specific genotypes and their hosts into new environments and promoted the circulation of genotypes different from HCV G1, G2, and G3 [18].

Hepatitis C Virus Genotype Patterns in North Africa and the Middle East

The genotype distribution in the Middle East is characterized by two main patterns: the prevalence of HCV G4 in Arab countries in the eastern regions of the Middle East, including Egypt [8,13–15], Saudi Arabia [9], Syria, and the United Arab Emirates [13,14], and the predominance of genotype HCV G1a or G1b in western areas of North Africa such as Tunisia and Morocco [19] and in non-Arab countries such as Turkey and Iran [20]. Egypt has the highest prevalence of HCV worldwide (13%) [18] and almost 90% of those infected with HCV in this country have HCV G4 [13,14]. The current sequence diversity and phylogenetic tree structure of HCV G4a in Egypt are compatible with the introduction of HCV into that population through parenteral treatment for schistosomiasis with indispensable and poorly sterilized needles in the 1950s and 1960s [13]. Although subtype HCV G4a is the dominant Egyptian HCV strain, recent studies revealed that other subtypes are also present, indicating that HCV G4 in Egypt is extremely variable not only in terms of sequence but also in terms of functional and immunologic determinants [22,23]. In Saudi Arabia, HCV G4 constitutes 62% of HCV infection, followed by HCV G1 (24%), HCV G3 (9%), and HCV G5 (0.3%). Unlike the predominance of subtype 4a in Egypt, however, subtypes HCV G4c and G4d are the most prevalent in Saudi Arabia, suggesting that the origin and transmission of HCV G4 in that country might be different from those in Egypt [9].

Hepatitis C Virus Genotype Patterns in Sub-Saharan Africa

HCV is highly prevalent in Africa, with more than 30 million individuals infected [12,13,21]. The distribution of HCV genotypes in sub-Saharan countries is less well documented than in other geographic areas. Infections in West Africa are caused predominantly by HCV G2 [13], whereas those in central Africa, such as the Democratic Republic of Congo and Gabon, are caused by genotypes HCV G1 and G4 [17,21]. In both regions, genotypes HCV G1, G2, and G4 are highly heterogeneous, with 20–30 subtypes detected in some regions. This finding indicates a unique pattern of long-term HCV infection that has not been observed elsewhere. It has been thus hypothesized that these HCV genotypes originated and diversified for long periods in West or Central Africa before spreading to other regions [13,16,17,21]. The high population density in Africa, population shift, migration, and poor socioeconomic conditions—and importantly the high adaptation of HCV to its human host—ensured the long persistence of HCV infection and its successful ongoing transmission.

HCV G5 is the predominant genotype in South Africa (40%), followed by HCV G1 (33%), HCV G2 and G3 (21.5%), and HCV G4 (2.3%) [10,21]. A phase of exponential spread in South Africa was characterized by high growth rates indicative of rapid epidemic spread. A slowdown was observed around 1950, but this does not appear to be consistent with transmission through blood products, which continued until 1990. The South African dynamics might perhaps reflect an iatrogenic intervention in the early 20th century, such as the use of unsterilized medical equipment [10].

Hepatitis C Virus Genotype Patterns in Southeast Asia

Southeast Asia is characterized by a high prevalence of HCV, with more than 32  million individuals infected. Genotypes HCV G3, G1, G6, and G2 are prevalent in this area [1,2]. The high prevalence of HCV and the genotypic diversity in Southeast Asia have important epidemiologic implications given the increasing numbers of Asian immigrants in Europe and the United States and the dynamic population mobility in Asia.

Genotypes HCV G1, G2, G3, and G6 are found in China, with different geographic and demographic distributions. HCV G1b is the most widely distributed, and HCV G3 and G6 are more prevalent in southwest China [24–26]. In Taiwan, HCV subtypes