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Keywords:

  • cirrhosis;
  • epidemiology;
  • HCC;
  • HCV;
  • hepatitis C;
  • prevention;
  • liver cancer

Abstract

  1. Top of page
  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References

Hepatitis C is of concern both to industrialized and developing countries. Preliminary unpublished estimates of the global burden of disease (GBD) attributable to HCV-related chronic liver disease seem to be substantial. Therefore, the reduction of global mortality and morbidity related to chronic hepatitis C should be a concern to public health authorities, and primary, secondary and tertiary prevention activities should be implemented and monitored in each country, with precise targets set to be reached. In order to decide on national health policies, there is a need to estimate the burden of disease, globally, regionally and nationally. To evaluate the GBD, three components have to be assessed: 1) The global, regional and national burden of morbidity and mortality associated with HCV infection, based on prevalence, incidence, transmission and economics; 2) The natural history of HCV infection, including ‘healthy individuals’; and 3) The areas for which more research is needed. A working group was created to assist the World Health organization (WHO) in estimating the GBD associated with HCV infection.

Hepatitis C is nowadays recognized as a disease of global importance. It is of concern both to industrialized and to developing countries. Given that the preliminary unpublished estimates of the global burden of disease (GBD) attributable to hepatitis C virus (HCV)-related chronic liver disease seem to be substantial, the reduction of global mortality and morbidity related to chronic hepatitis C, particularly in those areas of our globe where resources are scarce, should be a concern to public health authorities. Based on our existing preventive and therapeutic arsenal, primary, secondary and tertiary prevention activities should be implemented and monitored in each country (1), with precise targets set to be reached. In order to decide on national health policies, there is a need to estimate the burden of disease, globally, regionally and nationally. In the past, the World Health Organization (WHO) estimated the global prevalence of HCV infection (2–4); however, these estimates need to be updated, a work currently in progress.

To address these needs, three components have to be assessed:

  • 1
    The global, regional and national burden of morbidity and mortality associated with HCV infection.
  • 2
    The natural history of HCV infection, including ‘healthy individuals’.
  • 3
    The areas for which more research is needed.

Global burden of hepatitis C virus infection

  1. Top of page
  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References

In order to estimate the global burden of morbidity and mortality associated with HCV infection, two different issues need to be considered: (i) the present burden of disease due to past HCV infection mainly based on the current prevalence data and (ii) the future burden of disease because of HCV infections acquired today, possibly based on incidence data.

Estimating the prevalence of hepatitis C virus infection

For the estimation of the global consequences of HCV, there is a need to know about the prevalence of HCV infection in each country. These figures should be determined based on community-based studies (2); however, in most countries, such surveys are lacking and only specific groups, not representative of the general population, such as blood donors, drug users or individuals with high-risk sexual behaviours, have been studied. Stratifications according to age, gender or sub-national (e.g. cities, mountain areas) districts are mostly lacking. Therefore, the global estimates for the prevalence of HCV in the year 2008 are still associated with some uncertainty.

Overall, the available data suggest that the prevalence of HCV infection is approximately 2.2–3.0% worldwide (130–170 million people). While individual estimates from the different regions or countries have undergone some change since the first estimates made by WHO in 1997, the overall picture is still similar, with the highest prevalence of HCV infection found in the African and the Eastern Mediterranean region (Fig. 1) (2, 5).

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Figure 1.  Global prevalence of hepatitis C.

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Estimating the incidence of hepatitis C virus infection

The direct determination of the incidence of HCV infection is not possible, because direct measurement of incidence is not feasible in community-based surveys. The estimation of the incidence from available prevalence data is therefore the most realistic approach. In addition, an age-specific estimation of incidence is not possible because of the paucity of precise, age-specific data. The incidence of HCV infection is likely a function of age and of time. During and following World War II, there was an increase in the use of injections, blood products and injection drug use. However, in the past 10 years, in some industrialized countries, the incidence of new infections has decreased, presumably reflecting a decrease in percutaneous exposures (6–9). These temporal trends need to be taken into account.

Other important sources of uncertainty in the incidence estimation include the rate at which seropositive individuals may lose antibodies to HCV (seroreversion) and whether persons with HCV infection have higher underlying mortality rates. Both seroreversion and differential mortality rates will lead to underestimation of the incidence if not taken into account. Estimating survival rates for each birth cohorts that make up today's population, as well as for the subpopulation of people infected with HCV is not practical. Therefore, issues that need further considerations for the correct estimation of the future disease burden include the following:

  • 1
    Using or not using a seroreversion rate. Seroreversion may occur among non-viraemic patients during the first 10 years after infection. If seroreversion does occur, then the prevalence in the population underestimates the proportion of the population ever infected. A 7% loss of antibodies after 25 years was reported in a transfusion study (10); however, this rate may be too high in general;
  • 2
    Work out incidence trends; and
  • 3
    Work out age-specific incidence estimates.

Transmission of hepatitis C

The routes of HCV transmission in communities have a profound impact on the global epidemiology of HCV and therefore on the GBD related to infections acquired today. After World War II and up until the 1980s, the most important source of HCV transmission in developed countries was either by parenteral exposure to contaminated blood or blood products or by the illicit use of injectable drugs. The introduction of routine testing of donated blood has virtually eliminated transmission of HCV by blood transfusion (11). Illicit use of injectable drugs is today the main source of HCV infections in most developed countries (e.g. Western Europe, US) and is becoming a major source of infection in transitional economy and developing countries, accounting for 40% or more of those infected (12). The prevalence of chronic infection with HCV in injecting drug user populations is appreciably higher than that of either HBV or human immunodeficiency virus (HIV) (13).

In developing and transitional economy countries, the nosocomial transmission of new HCV infections is a major problem because of the re-use of contaminated or inadequately sterilized syringes and needles used in medical, paramedical and dental procedures (14–16), with an estimated 2.3–4.7 million of new infections occurring each year (17, 18). In Egypt, the treatment of endemic schistosomiasis in mass programmes (discontinued in the 1980s) that frequently used unsterilized needles and syringes has led to a national HCV prevalence of more than 14%, with rates of 20–30% in young male adults (19, 20). The highest reported rates of needle re-use are found in the Middle East, South-East Asia and the Western Pacific (17), and the most frequently injected medications include antibiotics, vitamins and analgesics that could be taken orally most of the time, and that are usually administered for non-specific symptoms. Special attention should focus on the fact that injection solutions and equipments are frequently purchased outside of the formal healthcare system, and that injections are dispensed by unqualified personnel in pharmacies or marketplaces.

Other modes of transmission may be less relevant from a public health perspective. In patients on chronic haemodialysis, chronic HCV infection is common, with prevalences of 10–33% (1, 21). Sexual transmission of HCV occurs infrequently because HCV is far less likely than HBV to be transmitted by mucosal exposure (1). The risk of perinatal transmission of HCV is very low (1), although there is conflicting evidence that the risk is increased by high maternal viral loads or if the mother is co-infected with HIV. The risk posed to the infant from breastfeeding is negligible and non-sexual intrafamilial transmission is very rare (16).

The economics of hepatitis C

Although individual patients suffer greatly from chronic hepatitis C and its sequelae, policymakers and budget holders must judge whether the benefits obtainable from prevention and treatment justify the costs from a societal perspective, and how to respond to constituencies that have conflicting requests or demands. To do this in a reproducible and evident manner, the burden of disease data form the basis of economic calculations. Several studies using different methodologies, all conducted in developed countries, have consistently forecasted an increase in morbidity, mortality and economic burden based on currently existing infections, even in those countries where a decrease in incidence was observed (22–26). Cost-effectiveness ratios calculated in several studies have been shown to be comparable to other well-accepted medical interventions (27–29). However, in order to take the most adequate decision at the national level, one should be aware that disease costs, drug costs or the annual discount rate may differ for each country, not to mention the different health reimbursement systems, the different population's age, gender and ethnicity balances or quality-of-life baselines. All these may change over time, rendering study results rapidly obsolete. All this will have a profound impact on public health decisions. Antiviral treatment is unlikely to induce significant populationwide reductions; it is even suggested that mortality will continue to increase, at least in the next 10–20 years (30). Although HCV antiviral treatment appears to be expensive from a purely economic perspective, it is now established that it compares well with other medical public health interventions (28, 31–34), and this should reassure decision makers.

As treating chronic hepatitis C turns out to be cost effective, the next point to consider is whether screening for hepatitis C or its prevention is more cost effective, provided that ethical considerations permit such a distinction. As the majority of HCV-infected individuals are unaware of their infection (35), screening will identify patients who will benefit from treatment. However, mass screening for hepatitis C has substantial economic consequences, linked to: (i) the high cost of the use of screening assays on a populationwide basis, (ii) the subsequent execution of many additional tests, such as confirmatory tests, ultrasound or liver biopsies, (iii) the consequences from false-positive and false-negative results and (iv) the negative impact on the quality of life in asymptomatic individuals unaware of their infection. Therefore, mass screening for hepatitis C cannot be recommended (35–37), notwithstanding the fact that treatment can eradicate the HCV and reduce the consequences of chronic infection. Public health decisions, in this context, cannot rely on economic considerations only, and must take societal aspects into account. Even though many patients will not develop severe complications, the costs of treating decompensated liver cirrhosis and liver transplantation (in the absence of antiviral treatment) are estimated to be in the range of US$24 000–39 000 lifetime disease costs (23, 28, 34). Preventing hepatitis C infection will avoid these costs (38, 39). To achieve this, careful planning at the national level, taking into consideration the epidemiology, the demographics, the cultural sensitivities and the economics related to hepatitis C, will be necessary.

Natural history of hepatitis C virus infection

  1. Top of page
  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References

A systematic review of natural history studies was conducted and published in 2001 (40). The risk of cirrhosis varied according to the type of recruitment (highest for blood transfusion recipients and medical liver centres, and lowest for blood donors and community studies). A proportion of about 25% of infected persons will develop acute hepatitis with jaundice. Seventy per cent (uncertainty: 50–85%) of infected persons will develop chronic infection (RNA positive). It was suggested that this is age dependent: for persons who acquire HCV infection younger than age 40 years, <5% will develop cirrhosis within 20 years; this value is 20% in those infected when older than 40 years) (9). Overall, 25% of patients with chronic HCV hepatitis will ultimately develop cirrhosis (41), and a significant proportion will go on to develop hepatocellular carcinoma (HCC) (9, 42). There are good data to estimate the development of cirrhosis for the two first decades. However, beyond 20 years of chronic infection, the history of disease progression is unknown. Assuming a linear progression to cirrhosis after 20 years implies that only age at infection matters (9), but it is possible that fibrosis progression in someone infected younger than age 40 could accelerate as that person ages and reaches an age group for which progression to cirrhosis after 20 years of infection is higher. Forty years after infection, 20% (uncertainty 10–30%) of persons infected younger than age 40 will develop cirrhosis; for persons infected age 40 years or older, the estimate is 40% (uncertainty 30–50%). These figures are speculative because little evidence is currently available to document the natural history after the first two decades (9).

The annual rate of decompensation among patients with cirrhosis is estimated to be about 4%, and the annual death rate among patients with decompensated cirrhosis depends on the possibility of access to treatment: 15% in industrialized countries and 30% in developing countries (9).

The annual rate of HCC developing among patients with cirrhosis is currently estimated to be 1.6% (uncertainty: 1.5–2.5%) (9). For unknown reasons, Japan and Taiwan fall outside this range, with rates of more than 7%, although there was a decline observed in Japan (43). The annual death rate among patients with HCC also depends on access to treatment. In industrialized countries, it is estimated to be around 80%, whereas in developing countries it is around 90%. In Japan, the annual mortality rate is significantly lower (∼10%) for unknown reasons (44, 45).

Factors that may affect the natural history of hepatitis C virus infection

Patients with consistently normal alanine aminotransferase levels show slower disease progression (46–49). Steatohepatitis, rather than obesity, seems to be an important cofactor affecting progression towards fibrosis. However, one intervention study suggests that reduction in weight leads to reduction in fibrosis progression (9, 50–53). The influence of HIV and HCV co-infection depends on the CD4 counts, with a relative risk for the development of cirrhosis of about two (54–56). HBV/HCV co-infection (HBsAg and anti-HCV positive) is uncommon, although it may be emerging in China (57, 58), and co-infected patients have a higher risk of developing HCC than those who are only infected with one virus (55, 59). It is unclear whether this high risk reflects a combined effect of the two viruses in the absence of interaction or whether there are some synergistic effects. The anti-HBc alone/anti-HCV serological profile is common, and there is some evidence suggesting that the presence of anti-HBc alone might increase the risk of HCC among patients with chronic HCV infection (60). The intake of more than 50 g alcohol/day accelerates progression to cirrhosis with a relative risk of about three (39, 61, 62). There is also some evidence suggesting that smoking may influence the development of HCC (63–66).

The influence of therapy on the natural history of hepatitis C virus

Globally, the proportion of viraemic patients who undergo therapy is low, industrialized countries included. Effective treatment is not administered to all patients who would benefit from it (e.g. in correctional facilities, developing countries) (67). An encouraging fact is that specific efforts are currently being made in Egypt, where about 20 000 patients are undergoing treatment with support from the government (personal communication). The proportion of viraemic patients who will clear infection under treatment is variable, although improvements have been achieved for all genotypes, especially for genotypes 2 and 3. A sustained virological response is associated with histological improvements of lesions and fibrosis (68, 69), but the effect on overall survival is still unclear (45, 69–76). Thus, at present, the impact of therapy is unlikely to affect the natural history of HCV infection at the global population level. However, this analysis should be revised if better therapy coverage is achieved (67).

Factors that probably do not affect the natural history of hepatitis C virus infection

Evidence suggests that in general, viral load or genotypes do not influence disease severity or progression (77–82).

Areas that need further research

  1. Top of page
  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References

To better estimate the GBD associated with HCV infection, more research is needed in the following areas.

Estimates of hepatitis C virus prevalence

As stated above, in many countries, the relative contribution of the infection with HCV has not been defined with population-based epidemiological studies, and therefore, the status of the general population remains unknown, and accurate estimations of infection and disease burden are impossible. Such studies should be performed to enable countries to prioritize their public health preventive measures and to use available resources in the most appropriate manner. The two critical elements for survey quality are: (i) use of a representative sample and (ii) use of accurate diagnostic tests. Because age-specific estimates of the HCV prevalence are important to estimate incidence trends and burden of disease, these surveys should attempt to assess the prevalence of HCV according to age, gender and geographical location.

The surveillance of viral hepatitis should be integrated into a national surveillance programme, which will allow (i) the detection of outbreaks and of clusters of infections, (ii) the assessment of national trends and the impact of prevention activities and (iii) the monitoring of virus resistance to antiviral drugs.

Natural history parameters, morbidity and mortality

The natural history parameters of HCV infection should be regularly reassessed in light of new evidence being published. In addition, research needs to better evaluate: (i) the risk of fibrosis progression beyond 20 years, (ii) the risk of fibrosis progression in developing countries, (iii) the basis of spontaneous clearance of HCV infection and its long-term consequences and (iv) the patients who do or do not progress to cirrhosis (e.g. normal aminotransferase levels, gender, ethnicity, obesity, toxins and environmental factors). Morbidity and mortality associated with chronic HCV liver disease must be better characterized. The histological lesion of cirrhosis must be differentiated from: (i) the disease that results from decompensated cirrhosis and (ii) chronic hepatitis and/or chronic infection. Extrahepatic manifestations of HCV infection may be less important as they are uncommon (although the association between HCV infection and non-Hodgkin lymphoma needs confirmation). The knowledge of one's infection status is a major determinant of altered quality of life because of the increased anxiety caused by the uncertain progression of the disease with its potential consequences (83), and therefore the screening for hepatitis C in ‘healthy’ subjects has to be undertaken with all due ethical, medical and psychological precautions.

Economics

Cost-effectiveness analysis assessments should be performed, both in the general population and in high-risk groups, with considerations given to treatment with peginterferon plus ribavirin. Preliminary evidence, assessed in developed countries only, is suggesting that a screening strategy in the general population, in high-risk groups and in patients with chronic infection may be more cost-effective than a no-screening strategy (84–86). In today's context of competition for resources, it is therefore of paramount importance to evaluate the economic impacts of chronic hepatitis C, and the benefits of prevention and treatment.

Conclusions

  1. Top of page
  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References

The public health authorities of countries need burden-of-disease estimates to make policy decisions. A working group was created to assist the WHO in estimating the GBD associated with HCV infection. Work is currently in progress. In the mean time, it should be stressed that it is not necessary to wait for all scientific evidence to be proven, in order to start to implement prevention activities as early as possible. Emphasis should be placed on the reduction (and even the abolishment!) of unacceptable unsafe percutaneous practices leading to nosocomial infections. For this, the community, governments and healthcare providers must agree on the strict adherence to safe and standard medical practices (87). In light of this, the development of a vaccine preventing the infection, or at least the consequences of infection, is of thorough public health importance.

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  2. Abstract
  3. Global burden of hepatitis C virus infection
  4. Natural history of hepatitis C virus infection
  5. Areas that need further research
  6. Conclusions
  7. Conflicts of interest
  8. References
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