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Hepatitis C is a global health issue that affects almost every region across the world. It is well recognized as the leading cause of end stage liver disease and primary liver cancer. Hence, endemicity, chronicity of HCV infection leading to major complications has made HCV a major health care burden globally.
Discovery of hepatitis C
In 1975, a Non-A, non-B viral hepatitis (NANBH) associated with blood transfusions was identified (1, 2). Subsequently the efforts were directed to identify the distinct virus. Finally, in 1989 Choo and coworkers were able to discover a single-stranded RNA virus of 9.5kb, 40-50 nm in diameter that belongs to family Flaviviridae and recognized as Hepatitis C virus (HCV) (1-4). Humans are the only known host, however, in chimpanzees experimental transmission of hepatitis C has been established(5).
Scope/paradigm of hepatitis C
Hepatitis C could manifests as acute or chronic infection. In general acute hepatitis C presents as milder disease and only up to 20-30% individuals develop symptoms (5). However, up to 80% cases exposed are predisposed to develop chronic infection. Subsequently, up to 20% individuals develop cirrhosis within 20-30 years. Following the development of cirrhosis there is a significant risk to develop hepatocellular carcinoma (HCC) (5-7). Globally, up to 27% cases of cirrhosis and 25% HCC have been estimated to be due to HCV (12). Moreover, HCV is accountable for approximately 20%, 70%, and 30% cases of acute hepatitis, chronic hepatitis and liver transplants respectively (8). Nonetheless, 7,96000 and 6,16000 deaths were attributed to cirrhosis and primary hepatocellular carcinoma in 2002(9) and perhaps up to 20% of these deaths were linked to HCV infection(10). These figures are alarming even for industrialized countries where the accesses to health care facilities are relatively easy. On the other hand, the number of untreated patients, morbidity and mortality due to underlying HCV cirrhosis are continuously growing. This is in general due to inadequate detection, unavailability of antiviral therapy and considerably high cost incurred to anti-viral therapy especially in developing countries (9). Hence, endemicity, chronicity of HCV infection leading to major complications has made HCV a major health care burden globally.
Economic burden of hepatitis C
The predisposition to develop cirrhosis and subsequent complications including HCC and improvement in sustained viral response with currently available Pegylated Interferon and Ribavirin therapy justifies early detection and treatment of HCV infection. Moreover, liver transplantation improves the survival for patients with decompensated cirrhosis and HCC (9). However, the cost of antiviral therapy, managing end-stage liver disease and liver transplantation per se is very high and overblown due to referrals from developing countries to transplant centers in other regions (11). Only in n 1995, 27,000 hospitalizations were due to HCV related liver disease in United States. Again the estimated cost incurred to treat HCV was $ 693 million in 1998 with $1-$1.3 billion total expenditure per year that was quite high (12, 13). However, the differences exist in health care delivery systems, economical status and availability of facilities to treat HCV with or without complications, hence, it is difficult to approximate weather these costs are equivalent or higher to the cost for other countries (13). Furthermore, most of such estimates incur direct costs but ignores indirect costs that include cost for work loss due to illness or early mortalities related to HCV liver disease(12). Hence, the actual costs could be much higher if these indirect costs are taken in to account especially in case of developing countries.
Global burden of hepatitis C
Currently HCV is the most common cause of transfusion related hepatitis. Although it is endemic to most part of the world, variability in HCV prevalence has been notified widely with the geographical locations as well as within the populations(14).
The data available from most parts of the world in fact lacks population based studies. Rather most of the studies reports the estimated prevalence from a selected group of population that mainly consist of blood donors, hence underestimate the actual prevalence (13). The World Health organization (WHO) has compiled the available data regarding epidemiology of HCV in 1997 that was updated subsequently. Out of 266, 166 studies were identified that covers 116 countries/areas using preselected criteria of representativeness. According to WHO estimates HCV affects in general 3% or 170 million individuals throughout the world and more than 350,000 individuals die annually due to HCV liver disease(15). Taking in to account geographical locations, countries were divided in to six regions of the world: Americas, Africa, Eastern Mediterranean, Europe, South-east Asia and western pacific regions (8, 10, 13, 15, 16).The highest prevalence reported was 5.3% from Africa followed by 4.6% from Eastern Mediterranean region. The lowest HCV prevalence of 1.03% was found in Europe. Among countries, highest prevalence (15-20%) has been reported from Egypt and the lowest 0.01-1% was from UK and Scandinavia (3, 13, 17). Moreover, up to 75% individuals who were seropositive for HCV were found to have chronic infection with HCV. However, considering absence of data from 57 countries one can expect that the actual number of individuals infected might be higher than what is estimated(13). In following section we describe the epidemiology of HCV among different WHO defined regions.
WHO Region of the Americas:
In United States of America (USA) HCV is the most common cause of liver transplantation (18). Fivefold increase in annual number of liver transplantation for HCV related cirrhosis has been reported during 1990-2000 (13). Centers for Disease Control (CDC) conduct National Health and Nutrition Examination Survey (NHANES) periodically in USA. According to a recent NHANES(1999-2002) 1.6% or 4.1 million people found seropositive for HCV, predominantly affecting men, non-Hispanic blacks and Mexican Americans (19). However, further evaluation by testing HCV RNA reveled 1.3% or 3.2 million cases of chronic hepatitis C (CHC)(20). In both NHANES III (188-1994) peak HCV incidence was found in birth cohort of 1945-1964; hence showing increasing prevalence with increasing age (19, 21). Earlier than 1992, transfusion of contaminated blood and blood products was the primary mode responsible for HCV transmission. Whereas, currently IVDU and percutaneous exposure due to high-risk sexual behaviors are the major factors responsible for HCV spread(3). However, one should not ignore the possible underestimation of overall HCV prevalence due to underrepresentation of incarcerated and homeless individuals in NHANES data (22). In a study conducted in 2002 all new entrants into the Maryland Division of Correction and the Baltimore City Detention Center were evaluated between 28 January and 28 March 2002. Out of 3914 inmates and detainee, 29.7% were found to be affected by HCV(22). Moreover, 44% of 418 homeless veterans were found HCV seropositive in another study that was significantly associated with history of substance abuse (odds ratio 6.86, P < 0.001) and services during the Vietnam era (OR 4.66, P 0.01)(23).
Complications related to hepatitis C related cirrhosis results in 8000 to 10,000 deaths every year in USA (3). Perhaps as compared to 1993 threefold increase in HCC development rate attributed to hepatitis C which is quite alarming (24, 25). Hence, it is appropriate to say that despite declining trend in incident HCV cases (26-28), HCV-associated morbidity and mortality is predicted to increase significantly in next 20-30 years (3, 13, 27, 29, 30).
In Latin America, in general HCV seroprevalence is 1.23% with some variability from region to region and ranged 0.2-3.4%. Blood transfusion and high risk sexual behaviors were found to be the main risk factors associated with HCV (31, 32).
In Canada, the estimated prevalence of HCV infection is 0.8% and majority of the cases lies between 15 to 39 years of age. According to the national "Enhanced Hepatitis Strain Surveillance System", the incidence of HCV per 100,000 individuals has been declined from 3.3 to 2.1 cases from 1998 to 2004(33). This decline is credited to the safe blood transfusion practices. Currently injection drug use (IDU) is the major factor associated with HCV spread, however the sexual transmission found uncommon(34).
WHO African Region
According to the WHO estimates 5.3% or 31.9 million individuals are affected by hepatitis C in Africa(6). However, variability in different regions of Africa have been found like 6%, 2.4% and 1.6% HCV prevalence have been reported from Central Africa, west Africa and east Africa respectively. Furthermore, clusters of higher prevalent areas have been notified like Burundi with 11.3% and Cameroon with 13.8% HCV prevalence(35). The individuals > 40 years of age are affected mostly. Like other developing countries unsafe therapeutic injections and blood transfusions are the most common attributable factor responsible for HCV spread. Whereas, beside the cases with HCV and HIV co-infection, vertical transmission is uncommon and so is correct for IDUs (36-39).
WHO Eastern Mediterranean region
There are 21 member countries in this region including Egypt, Iran, Saudi Arabia, Afghanistan and Pakistan(16). Over all up to 4.6% (21.3 million) population is affected by HCV in this region with highest figures of 15-20% HCV prevalence from Egypt (6, 40-42). However, variability has been notified in HCV prevalence across the Egypt per se i.e. 8% in Cairo & Alexandria, 8-16% in middle and upper Egypt and 15% in lower Egypt or rural areas of Nile Delta (41). The predominant reason behind such a high HCV prevalence is the Intravenous therapy for Schistosomiasis administered between 1961 and 1986 results in epidemic of HCV infection (42, 43). In a recent population based study incidence rates and risk factors were evaluated in rural Egypt. The overall HCV incidence was 2.4/1000 person years and injections were the most common associated risk factor (reference).HCV genotype 4 is the most common one affecting 90% of the cases. Moreover, up to 60-78.5% HCC cases are attributed to HCV in Egypt (44, 45).
WHO South-East Asia Region
A total 11 countries were including India, Bangladesh, Indonesia, Korea, Sri Lanka, etc are included in this region. The major limitation of the prevalence data from South-East Asia is the lack of large population based studies. According to WHO estimates up to 2.1% (32.3 million) individuals are affected by HCV in this region(10). Among the member countries of the region HCV sero-prevalence was found to be 2.9%, 2.4%, 1.3%, 1.2%, 2.5%, 1.8%, 1.1%, 1.6% and 1.4% in Thailand, Bangladesh, Bhutan, India, Indonesia, Maldives, Nepal, Korea and Sri Lanka respectively(10, 46, 47).
Relatively higher HCV seroprevalence of 2.1% HCV have been reported from Indonesia with prior blood transfusion, surgeries, IVDU and acupuncture as predominant associated risk factors(48). In Thailand, the evidence is based upon data from voluntary blood donors that showed HCV seroprevalence of 1.37%-2.9% in different studies (49, 50). Nonetheless, much higher HCV prevalence i.e. 86-92.5% (51, 52), and 9.5%(53) has been reported in IDUs and commercial sex workers respectively; hence, representing these factors next to unsafe injection practices and blood transfusion (51).
The reported estimates for HCV prevalence are based upon studies involving blood donors where higher HCV prevalence are reported among commercial blood donors (55.3% to 87.3%) as compared to voluntary blood donors (1.5-4.3%)(54). Up to 3.3-31.5% cases of cirrhosis and 15.1-42% cases of HCC are attributed to HCV in India (20). Transfusions of contaminated blood and blood products and IDUs have been recognized as the major risk leading to HCV transmission in India (54, 55).
Pakistan is placed in Eastern Mediterranean region by WHO. However, geographically it is recognized as the part of south-Asia; hence we discuss it in current section. Like the other countries of South-East Asia, the overall prevalence of hepatitis C is increasing. Most of the studies conducted in past were carried out in particular settings or among blood donors. In general most of the prevalence estimates for HCV range between 2.4%-6.5% among adults(56, 57) and 0.44-1.6% among children(58). Recently a countrywide survey was conducted by the Pakistan Medical Research Council in 2007-2008 to get the actual prevalence of hepatitis B and C. The survey estimated that 4.9% (8.8 million) of population in Pakistan is affected by hepatitis C(59). Transfusion of contaminated blood and blood products, therapeutic injections by contaminated and re-used syringes, and re-use of razors are major factors responsible for the spread of hepatitis in Pakistan. Additionally barber shops where infected razors can transmit the infection are another route. However, IVDU and sexual transmission are minor contributors in HCV transmission in this country (56, 60). HCV genotype 3 is the most prevalent one here. The phylogentic analysis indicates that HCV genotype 3 appeared in Pakistan in 1920s further rapid spread in 1950s (56, 61).
WHO Western Pacific region
There are 27 member countries in WHO-Western pacific region including Australia, Cambodia, China, Japan, Malaysia, Mongolia, Nauru, New Zealand, Philippines, Korea, Singapore and Viet Nam (16). According to WHO estimates HCV prevalence is 3.9%(62.2 million) in this region(10). In Australia according to the estimates of 2001, 210,000 individuals are affected by HCV with 16,000 incident cases diagnosed every year (62). About 80% to 90% of HCV infections are attributed to IVDU due to persistently increasing practices of IDU despite introduction of needle and syringe programs (63). Hence, HCV is considered as the most commonly notified communicable disease in Australia. During 1992-1995 a national survey conducted in China reported 3.2% HCV seroprevalence in general population and IDU was recognized as the most important risk factor (64). Moreover, 61.4% of IDUs were found to be affected by hepatitis C (65). In Japan HCV is the leading cause of HCC and 2% of Japanese are affected by HCV (66).Blood transfusions, IVDU, and unsafe needle use and age> 70 years are the identified attributable factors in Japan (67).
The other member country i.e. Samoa HCV prevalence of 0.2% to 0.6% have been reported that is probably due to the low rate of IDUs (68). While in Korea 1% of general population is seropositive for HCV (69).
WHO European Region
WHO included the 57 countries in European region(16). However, based upon the available data WHO estimated HCV prevalence for 32 member countries of this region. Considering WHO estimates for these member countries, 7.3 million i.e. 1.1% individuals are seropostive for HCV. The Southern and Eastern European countries were found to have higher rates i.e. >1.25% while lower rates of â‰¤ 0.1% were found in Northern Europe. Nonetheless, > 86000 deaths were attributed to HCV related cirrhosis and HCC in WHO European region in 2002(70).
In England hepatitis C affects C 0.6% of adult population. It has been estimated that by 2010, 6000 and 1500 affected individuals will develop cirrhosis and end-stage liver disease or HCC respectively and further increase in these rates are expected in next decades (71-73). These results are supported by a cross sectional study in which sera of adult patients submitted to 19 laboratories of England were tested to determine average HCV prevalence between 1986 and 2000. The results showed HCV seroprevalence of 1.07 %( 39/3647), 0.55 %( 31/5634), 0.73 %(43/5924) and 1.20(61/5068) for the year 1986, 1991, 1996 and 2000 respectively. Higher HCV prevalence was found among males and birth cohort of 1950-1970. Moreover, higher HCV prevalence was found in London (1.27%), Eastern (1.41%) and South West (1.25%) regions of UK (74). IDUs have been found to be at the highest risk to acquire HCV in UK (75).
Coming to the Western Europe 5 million are seropositive for hepatitis C(8). The estimated HCV prevalence in France is 1.1-1.2% (400 000-500 000) and 80% of them i.e. 400 000-500 000 have chronic HCV infection. IDUs, inmates and HIV infected patients are the most vulnerable to acquire HCV(76).
Incidence of HCV
As acute hepatitis C remains asymptomatic in most of the cases and due to lack of well-established surveillance systems, it is very difficult to ascertain the actual incidence of hepatitis C. However, the incidence data is available from few developed countries. In United States age-specific incidences were calculated by model that includes reported cases of acute HCV infection. A decline in estimated annual HCV incidence from 180,000 in 1980s to 28,000 in 1995 was observed. However, since 1989, incidence of new HCV cases have been declined >80% (28, 77).Likewise, decreasing trends in HCV incidence have been reported from European countries like France and Italy (78, 79). Conversely, steady increase in HCV prevalence was reported from 1961-2001 in Australia (62). The declining incidence could be attributed to the implementation of safe blood transfusions and universal precautions. However, unsafe therapeutic injections especially in developing countries and needle sharing for IDUs are still responsible new cases (8). However, one should not forget the fact that the actual annual incidence might be higher due to underreporting and asymptomatic infection in most of the cases.
Genotypes Distribution across the world
Based upon the heterogenecity of HCV genome, 11 HCV genotypes (genotypes 1 to 11) and many subtypes (a, b, c, and so forth) have been recognized. The most prevalent genotype is 1a and 1b that constitute up to 60% of HCV cases across the world. However, there is some variability in their distribution; genotype 1a is largely prevalent in Northern Europe, North and America, while genotype 1b is mostly found in Southern-Eastern Europe and Japan. Genotype 2 is the predominant genotype in Europe. Genotype 3 is endemic in South-East Asia, and genotype 4 is characteristic for the Middle East, Egypt, and central Africa. Genotype 5 is almost entirely prevalent South Africa, and genotypes 6 to 11 are mostly dispersed in Asia. The identification of genotype is important with respect to the response to the treatment as genotype 2 & 3 are known to have best response with anti-viral therapy, genotype 1 has poorer response while genotype 4 usually have intermediate response (19, 61, 80, 81).
Risk factors/ epidemiology of HCV transmission
Being a blood born pathogen, the primary mode of transmission for HCV is via parentral exposure to contaminated blood or blood products (12). Sharing of contaminated needles, equipments and sharp objects like razors are common sources leading to iatrogenic spread of hepatitis C especially in developing countries (3, 12, 56, 82, 83). One of the major examples of this is Egypt where the highest HCV prevalence has been reported due to the reuse of needles for Schistosomiasis vaccination program (42). The implementation of regular screening of blood and blood products started in 1991that had lead to a significant decrease in the incidence of transfusion associated HCV in developed countries. However, in developing countries due to lack of regular screening of blood and blood products transfusion related transmission of HCV is still the primary mode (46, 83).
Therapeutic injection given by used syringes is one of the common risk factor for hepatitis C in developing countries. It's mainly due to people's belief in the quick action of injections and lack of awareness about their risks that lead to over use of therapeutic injections. Furthermore, injections given by unqualified practitioners and reuse of syringes augment the risk (84, 85).
Though it's less frequent among monogamous couples, mucosal exposures to blood or serum-derived fluids through sexual contacts does lead to transmission of HCV (7, 9, 20). In certain studies 4-5% HCV seroprevalence has been found among household and sexual partners, but these results are suspected to be confounded by possible concomitant exposure to other risk factors (86, 87). However, mucosal spread of HCV among HIV-infected men, who have sex with men (MSM) is a one of the common cause in high risk population and the risk correlates with the numbers of sexual partners and high-risk sexual practices (70). Vertical transmission of hepatitis C is estimated to be < 5%. Though, this risk increases > two folds if the mother is co-infected with HCV and HIV(14).
Intravenous drug use (IDU) has emerged as another major risk factor for acquisition of HCV especially in high risk population like inmates and drug users(3). In developed countries >50% of HCV cases are acquired through illegal drug use mainly IDUs followed by intranasal cocaine especially among injecting drug users (12, 87). In a study 50-94% of IDUs have been found to be effected by hepatitis C. The risk of acquiring HCV is correlated to the duration of drug use (7, 88). Traditional folk remedies and other needle practices like acupuncture, tattooing, body piercing via contaminated needles are also found responsible for transmission of HCV(3).
Inmates are challenging population and are considered to be at greater risk of blood born infections including hepatitis C due to high-risk related behaviors during and prior to imprisonment (89, 90). The global HCV prevalence among prisoners ranges from 2% to 65%(89, 91-94). Even in United States 39% of all Americans with HCV infection have a history of incarceration (91, 92). Furthermore, approximately 38% (95), 34%(96) and 30% (97)HCV prevalence has been reported from Italy, Australia and Iran respectively. Recently we conducted a study in Central Prison Karachi Pakistan. Out of 750 adult inmates 18.4% inmates in total and 84.2% IDUs were found to HCV seropositive. Therapeutic injections given by glass syringes, IDU, sharing of razors and illiteracy were the significant associated factors for HCV(98).
Transplantation of infected tissue or organ grafts, haemodialysis, needle stick injuries that exposed the healthcare workers in an occupational setting are also recognized as the attributable factors for acquisition of hepatitis C (86, 87, 99).
Strategies to prevent and control hepatitis C
Due to its ability to mutate rapidly HCV behaves as a genetically heterogeneous virus. It escapes to detection by immune system and in general the knowledge in the protective immune response following infection is limited. Hence, the development of vaccine get complicated and so far no effective vaccine is available for hepatitis C(6, 10). Immunoglobulins are not effective for post-exposure prophylaxis. Considering these facts we are left with primary prevention to reduce exposure to HCV and secondary prevention activities that reduce the risk to develop chronic disease and its complications(87).
Stringent strategies are required to reduce the risk of exposures to the factors that could lead to transmission of HCV. Implementation of regular practices to screen blood and blood products, use of sterile syringes, needles, medical and dental equipment are essentially required especially in developing countries. Introduction of molecular testing via PCR method to screen blood and blood products would further decrease the risk of HCV transmission. However, such strategies would probably be unaffordable in most of the developing countries. Unintentional needle sticks injuries among health care professional personnel should be avoided (2). Identification, proper counseling and providing health education to individuals who are at higher risk to acquire HCV like injecting drug users, those who practice unprotected sex with multiple partners will help to eliminate the risk for transmission of HCV especially in developed countries. Community based needle exchange program, drug and sexually transmitted disease's treatment services would help to reduce high-risk behaviors and associated risk of transmission(87). Hence, the primary prevention strategies could have a great impact to decrease incident cases and ultimately the disease burden.
Those who have already acquired HCV infection, proper diagnosis and provision of appropriate treatment including anti-viral therapy would reduce the risk for chronic disease and their subsequent complications. Effective treatment with Pegylated Interferon and Ribavirin is the standard of care globally. Addition of new drugs i.e. protease inhibitors e.g. Telapravir are expected to increase the treatment response further especially among difficult to treat population(100). However, the treatment is costly and beyond the resources available in many countries especially the underdeveloped countries. Moreover, the response rate after treatment is not optimal especially in case of HCV genotype 1 and in the presence of advanced disease. Proper counseling of HCV-infected persons to reduce or abstain from alcohol intake may prevent the synergestic hepatic injury and disease progression (87).
Incident cases of HCV due to transfusion of blood and blood products continue to occur in resource poor settings(14). Establishment and strict implementation of proper screening strategies for blood and blood products is a real challenge. Likewise, community based campaigns to educate individuals as well as the health care providers about use of sterile syringes, establishing and implementing a law requires cost, human resources and large efforts. Similarly, Implementation of community based programs to decrease high risk behaviors including needle exchange programs, health educations for IDUs are important. Implementation of screening, treatment for HCV and health education for inmates would be a great challenge for countries where these facilities are not available. There is also a desperate need to develop effective vaccine for hepatitis C and alternate or adjuvant treatment for non-responders and relapsers to standard antiviral therapy. Furthermore, there is need to refocus the research priorities across the world to identify the attributable factors and the interventions to reduce the burden of disease.
Hepatitis C is a genetically a heterogenic virus and the burden of disease is variable across the world. Transmission through contaminated blood and blood products, reuse of syringes are the major routs of transmission in resource poor countries. While, IDUs and high risk sexual activities are the predominant modes of transmission in developed countries and may be on the rise in several areas. The overall prevalence is declining in some developed countries but increasing in underdeveloped countries in general. In the absence of effective vaccine the role of primary prevention is essential. The current treatment of HCV is effective but is costly and requires further improvement. Efforts are needed to increase the awareness of common men about prevention and different strategies to prevent further spread of hepatitis C.