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Last updated: 15-Jan-2007

Hepatitis Viruses

The term “hepatitis virus” has traditionally been reserved for viruses that are hepatotropic, i.e., having a special affinity for or exerting a specific effect on the liver. Hepatitis B and C qualify, as they are strongly associated with liver infection, as well as liver cancer. The history of grouping such viruses together according to disease rather than virological properties means that at least four different virus families are represented by hepatitis viruses. Thus hepatitis B virus (HBV) belongs to the Hepadnaviridae family, and hepatitis C virus (HCV) to the Flaviviridae.[1] Neither of these viruses are singular agents; they each exhibit multiple genotypes, which may in turn represent variation in natural history and response to treatment (though the current evidence for variable disease expression with HCV subtypes is mixed).[2],[3],[4],[5] A further complication is the fact that several viruses can be implicated in a particular case of liver disease, including hepatitis B and C interacting together, as well as Epstein Barr virus and HIV.[6],[7],[8],[9],[10]

 

Transmission of the Agent

As summarized in the epidemiological overview table above, there is a high risk of chronic HBV and / or HCV infection leading to liver cancer. Naturally, this is especially a concern in areas with an elevated infection rate in the first place. For example, more than 8% of the population in Africa and Asia are chronic carriers of HBV. This contrasts with the less than 2% prevalence in Western Europe, North America and Australia.[11] The prevalence of hepatitis C is also under 2% in developed countries, though in this case the mean worldwide rate is not much higher (i.e., the average global prevalence of HCV is 3%—about half that of chronic HBV).[12] This means that HCV is a widespread problem, not isolated geographically. It is, for instance, the most common bloodborne infection in the US.[13]

Hepatitis B is transmitted primarily by contact with contaminated blood or blood products—though saliva, semen, vaginal fluids, tears, breast milk and urine also can contain the virus.[14] Infection occurs in several ways:

  • direct injection of infected blood or serums through transfusions, treatment with blood products, or accidental needlesticks
  • haemodialysis
  • transmission through skin openings such as burns or scratches
  • direct introduction of saliva or blood into inner body surfaces (i.e., mucosa)
  • breathing microscopic blood droplets or aerosols
  • indirect transfer of blood or other secretions from obviously soiled surfaces or objects.

In endemic areas such as Asia, perinatal (or so-called vertical) transmission from mother to child during or soon after delivery is the most common means of spreading HBV. A related topic is the risk of infection through normal breastfeeding; the evidence to date strongly suggests “that any risk of transmission associated with breast milk is negligible compared to the high risk of exposure to maternal blood and body fluids at birth.”[15] Any risks that do exist can be virtually eliminated through routine vaccination of infants.

In regions like North America where endemicity is low, the predominant means of hepatitis B transmission is horizontal, especially sexual activity and intravenous drug use.[16] The risk of HBV infection is notably high in homosexual men with multiple partners. For health care workers, being stuck with contaminated needles and syringes or being splattered with blood are also important ways of becoming infected with HBV.

Prior to the implementation of new policies surrounding therapeutic blood supplies in the early 1990s, receiving a transfusion during an operation was a risk factor for contracting hepatitis B and C; organ transplantation also fell into this category before new precautions were instituted. Today, the risk of new infection by these means in developed countries is approaching zero for several viruses,[17],[18] though further progress needs to be made with HBV detection specifically,[19] as well as screening tissue grafts.[20] Unfortunately, with its long latency period, chronic hepatitis originally derived through transfusions and transplants will continue to manifest itself for some decades.

Hepatitis C is transmitted by blood to blood contact only. This means that blood infected with hepatitis C must come into direct contact with the bloodstream of another person. Even the smallest amounts of blood can transmit hepatitis C.

Transmission occurs through:

  • sharing of equipment used to inject drugs
  • unsterile tattooing, body piercing and skin penetration procedures
  • household practices (such as sharing razor blades and toothbrushes)
  • occupational procedures (e.g., needlestick and sharps injuries)
  • haemodialysis
  • certain sexual activities
  • mother to baby

In the setting of developed countries, intravenous drug use stands out as the predominant behavioural risk factor, accounting for over 40% of HCV cases (or 3 times the proportion due to sexual activities).[21],[22] Almost 80% of injecting-drug users in the US are known to be infected with HCV.[23]

By contrast, the risk of either sexual or perinatal transmission of HCV is estimated to be only about 5%.[24],[25] A 2005 study revealed that one third to one half of children infected with HCV acquired the virus in utero.[26] Again, breastfeeding is a matter of some interest; as with hepatitis B, the current conclusion is that it is safe for mothers with hepatitis C to breastfeed.[27]

 

Co-factors and Correlates

Other than hepatitis infection, the main modifiable risk factors for liver cancer in developed countries are excessive alcohol consumption and cirrhosis. In fact, these factors, as well as diabetes (and perhaps obesity), interact synergistically with viral infection to increase the rate of cancer development.[28] The same multiplicative effect applies with exposure to aflatoxin in poorly stored grains, though this mainly affects populations in sub-Saharan Africa and Asia.[29]

Co-infections are an especially difficult problem. Combined hepatitis virus infections account for 5 to 10% of all HCV cases; such patients, infected with HCV and HBV (and sometimes hepatitis D), are often associated with more severe forms of liver disease and less responsiveness to interferon (see below). HCV is a common co-infection with HIV; a unique challenge is the fact that HIV drug treatments can themselves be hepatotoxic.[30]

 

Natural History and Carcinogenesis

Understanding the disease course in hepatitis B and C is a complex task, partly impeded by incomplete epidemiological data.

The course of hepatitis B from a clinical perspective can be categorized into four stages of varying duration: [31]

    I. Active viral replication / immune system tolerance.

    II. Initial immune response, inflammation and hepatic tissue injury.

    III. Clearance of virus-infected cells.

    IV. Full immunity.

If a person does not proceed beyond stage II, they become by definition chronic carriers of HBV. Cirrhosis and hepatocellular carcinoma (HCC) are common sequelae of a (usually) prolonged experience of chronic HBV; these diseases occur in 25-30% of carriers.[32]

This general progression needs to be modified according to the age when the infection occurs. In the perinatal type of transmission experienced in endemic areas, a large percentage of the infected infants become carriers; in contrast, a smaller proportion of those infected as children or adults develop chronic forms of the disease. Of HBV carriers, 1 to 2% develop cirrhosis each year (some studies put the rate as high as 10 to 12%). The presence of cirrhosis is a major risk factor for hepatocellular carcinoma. Cancer develops in 1.5 to 4% of cirrhotic hepatitis B patients each year, usually decades after they had first become infected.[33] As indicated in the table above, this progression to HCC eventually accounts for 40 to 60% of liver cancers worldwide.

The natural history and epidemiology of hepatitis C infection is still being elucidated, which is not surprising given that the virus was only identified 15 years ago.[34] Some facts have become clearer; for instance, research has shown that fully 75% of persons with HCV will develop chronic infection.[35] Beyond that, it seems that HCV progresses less intensely than HBV. A systematic review of the literature in 2001 suggested that for persons infected with HCV in young adulthood, less than 10% will develop cirrhosis within 20 years.[36] A Markov modelling exercise from 2002 pegged the rate more precisely at 7% after 20 years, and only 20% after 40 years of infection.[37] However, the risks more than double for people infected after age 40.[38] The annual incidence of hepatocellular carcinoma among cirrhotic HCV patients is similar to that with HBC, 1.5 to 2.5%.[39] Putting it differently, the total risk for developing liver cancer among viral cirrhosis patients is approximately 7%.[40]

As indicated earlier, this end-point for HCV infection accounts for 20 to 30% of the global burden of liver cancer. Although creating less cancer than HBV, the sobering fact remains that liver carcinoma derived from any source is deadly; the annual death rate is about 80% in industrialized countries.[41]

 

Preventive Interventions

The urgency for preventive measures around the hepatitis viruses arises not just from current rate of liver cancer and its high mortality, but from the impact of other serious diseases such as cirrhosis and the risks related to the vast “reservoirs” of viral carriers around the world. Exacerbating this scenario is that fact that HBV, HCV and HIV have similar transmission routes, leading to high co-infection rates; the conditions caused by these viruses interact synergistically, with the potential for “a major health care catastrophe in the coming years.”[42] This “perfect storm” of conditions and circumstances ought to motivate a concerted effort to control if not eradicate these viral threats.

We will now examine each of the categories of prevention in reference to HBV and HCV, and, where possible, review their effectiveness in reducing the burden of cancer.

Early Primary Prevention

Because the relative importance of various modes of transmission differs from country to country, the most relevant control strategies for each setting need to be carefully selected.[43] Another consideration in setting priorities is that while HCV has a lower global prevalence than HBV, HCV causes the most hepatocellular carcinoma in economically developed regions.[44] A final factor to note is that the ranking of interventions is a moving target. For example, now that the blood supply has been made almost completely risk-free, this is no longer a preventive area where substantial new gains can be made (though the robust maintenance of safety programs remains an issue).

As for HBV in a context like Canada, the first focus for preventing exposure to the virus should be public health education and other interventions around high-risk sexual practices and intravenous drug use. These measures to prevent transmission are also important for HCV (and HIV—see below); this is especially true for the area of drug injection. Assuming that Canada parallels the US, we can conclude that “prevention of illegal drug injecting will eliminate the greatest risk factor for HCV infection.”[45]

Obstacles. The control of hepatitis infection can be seen as a paradigm for the challenges encountered with regard to many of the agents in this report. The obstacles to developing preventive strategies include: asymptomatic carriers; limitations in testing procedures; long latency before cancer development; the fact that addictions are difficult to overcome; surveillance difficulties; socioeconomic forces influencing prosecution; the complication of psychological problems and full mental illness; lack of trust of authorities; concerns about privacy and discrimination (regarding test results and participation in public programs); insufficient political capital for more controversial “harm reduction” or legal measures; and (as always) limited resources.

Effectiveness of Programs. It is outside the scope of this chapter to systematically describe and evaluate the multitude of drug and sexually-transmitted infection (STI) programs in use around the world. Aside from the sheer volume of information to consider, there is the fact that it is rare for the interventions, if they have been evaluated at all, to be tied to the specific end-point of reduced hepatitis prevalence and / or lower cancer rates. With regard to STI programs, in particular, we would need to depend on evaluations related to other viruses to serve as a proxy for hepatitis control. Whatever the obstacles, based on the assumption of favourable impacts on disease when risky behaviours are eliminated or mitigated, a few notable drug use prevention programs will be described, as well as studies related to individual- or group-based approaches. With respect to STI prevention, we refer the reader to the description of approaches under the human papillomavirus section above.

Syringe and Needle Exchange Programs. The centrepiece of many harm reduction initiatives for injection drug users (IDUs) is the prescription or distribution of sterile injection equipment to prevent re-use by a single person and (more pertinent to our topic) sharing between users. The Centers for Disease Control and Prevention (CDC) in the US officially recommended community-based syringe and needle-exchange programs in 1998, though the calls for such an approach and the first pilot projects go back to the 1980s.[46],[47] As of 2002, 180 needle-exchange programs were operating in the US.[48] The CDC report noted that several studies up to 1998 had produced two crucial conclusions: such measures can be effective in reducing the incidence of bloodborne virus transmission; and they do not lead to the negative side effect of increased drug use. An example of a study from that era was conducted in Tacoma; non-use of the exchange program was associated with a sixfold greater risk of hepatitis B and a sevenfold greater risk of hepatitis C.[49] Subsequent research has confirmed that equipment exchange programs can reduce syringe sharing among IDUs[50] and decrease HCV prevalence in this at-risk population.[51] However, other results suggest that an exchange program alone may not be enough to produce positive results; the same lead researcher from the Tacoma study found contrary results in a Seattle-based syringe exchange program.[52] Likewise, after almost a decade of operation, the needle exchange initiative in Vancouver (the largest in North America) had failed to have much impact on needle-sharing behaviour or HCV rates.[53] Other studies confirm that, while prevention efforts among IDUs have managed to control HBV and HIV rates, the transmission of HCV has continued at very high levels.[54] One fact put forward to explain this is the high efficiency of bloodborne transmission with HCV.[55] As well, the special vulnerability of and expanding cohort of newer (usually younger) IDUs has suggested the need to target them with prevention messages and measures.[56]

The most comprehensive analysis of equipment exchange programs was carried out by Australian researchers in 2002, though some of the methodology has been questioned.[57] They evaluated their own country’s 16-year old exchange effort very positively; an estimated 21,000 HCV infections and 90 deaths had been averted. The cost of the various programs, at $122 million, was more than made up by $2.4 billion in avoided government costs related to treatment of HCV and HIV.[58] Nonetheless, the study acknowledged that overall HCV rates in Australia had continued to rise over the 1990s, reinforcing the fact that an integrated approach using several interventions is probably going to be more effective than a needle exchange program alone (see below).

At the same time, the exchange programs themselves may need enhancement. Different authorities have advocated offering a variety of options for syringe access by relevant populations, including prescriptions and syringe deregulation.[59],[60] In addition, given the efficiency of HCV transmission by blood, it may be important to focus on modifying more than needle-sharing behaviours in IDUs.[61],[62],[63] As one review concluded, “control of HCV may necessitate the use of practices that guarantee elimination of exposure to equipment contaminated with even small amounts of blood.”[64]

Integrated Approaches with Injecting Drug Users. Although there has been circumstantial evidence that comprehensive harm reduction approaches may have a positive impact on HCV rates, notably in the UK, more recent data has called this conclusion into question.[65],[66] Nonetheless, there is a sound face-value rationale for multi-intervention strategies, such as The City of Vancouver’s well-known Four Pillars program, as well as its pilot project involving a safer injection site.

Other Interventions. Having identified the priority “front-line” approaches to controlling exposure, it is also important to maintain vigilance around well-established areas. This includes continuing high standards around screening for HCV in donated blood supplies. The latency period means that improvements in screening introduced in the 1990s should result in a decreased incidence of HCV-positive liver cancer in 2010 to 2015.[67]

Primary Prevention

Vaccination. Both adults and children can be protected by an HBV vaccine developed over 20 years ago. It is considered to be one of the great public health achievements.[68] A special instance is vertical (from mother to newborn) transmission; this can be avoided by vaccinating infants born to HBV-positive women. The case for universal vaccination of children is more controversial, though such a policy is in place in many countries.[69] For example, in Taiwan, where HBV-related childhood liver cancer was once endemic, the effect of universal HBV vaccination has almost eradicated this form of paediatric cancer.[70]

HCV vaccine development remains at an early stage, and progress is characterized as being “agonisingly slow”[71],[72]

Co-factors. Any of the many programs to reduce excessive drinking would theoretically reduce the rate of liver cancer, even in people with existing hepatitis infections.[73] However, the health effects of reduced drinking in infected patients have not yet been quantified; the same gap exists in research around obesity, though one study of weight reduction did show a reversal of hepatic fibrosis.[74]

Testing & Treatment. Information on the effect of virus eradication from asymptomatic carriers on the subsequent risk of liver cancer is not available. This makes the benefit of routine testing for hepatitis virus infection rather questionable, at least from the perspective of cancer control. The usual indication for antiviral treatment (at least that which will be covered by government or third party payers) is the presence of symptoms, i.e., detection of a certain stage of fibrosis development, as diagnosed by a liver biopsy. Developing non-invasive methods to predict disease severity is an active area of research.[75]

There is good evidence that removing HCV from chronic hepatitis patients significantly reduces the risk of liver cancer.[76],[77],[78] A sustained HCV response after antiviral therapy for hepatitis can lead to more than a 90% reduction in the risk of primary liver cancer, though some studies demonstrate a more modest 50% reduction.[79],[80] The same type of effect is seen in patients with full cirrhosis, though the reduction in risk is less dramatic. The main issue at hand is: exactly how much of a sustained viral response can be achieved?

The traditional drug of choice to clear hepatitis viruses has been interferon, a protein that modulates biological responses. As demonstrated in a Cochrane review, interferon is effective in clearing acute HCV infections in about a third of patients.[81] The results with chronic infection with hepatitis viruses are more modest.

In addition to interferon, lamivudine is approved for HBV. Neither have been particularly effective in clearing a chronic infection, and few studies support the use of such chemotherapy for actually preventing HBV-associated liver cancer.[82],[83],[84]

Combination therapy with ribavirin improves the HCV response rate to interferon (as much as doubling it), as does altering the interferon molecule in a process called pegylation.[85] The latter technology is more expensive than conventional interferon combined with ribavirin, but the improved response rates (i.e., 40 to 85% for HCV, depending on the genotype) probably make it cost-effective.[86] The improvement rates using interferon are much lower for relapsing and cirrhotic patients (i.e., those with severe liver disease, most in need of treatment—many of whom are infected with HCV of genotype 1).[87]

Several novel therapies for hepatitis virus infections have entered phase I trials in the last two years.[88] The relatively poor response to current HBV therapies is motivating adoption of combination treatments that make use of nucleoside analogues and immunomodulators alongside interferon. This approach is also proving useful for the significant proportion of the HCV-infected population that does not respond to interferon therapy.[89]

In addition to the universal use in children and adolescents, HBV vaccination is recommended for those with chronic liver disease. The increased risk with co-infection also suggests the routine use of hepatitis A vaccine with such patients.[90]

Secondary Prevention

Screening. Patients who do not respond to antiviral treatment may progress to full cirrhosis. They may be screened for the emergence of early cancer lesions, though the efficacy and the cost-effectiveness of such protocols have not been proven.[91] Lesions that are detected can prompt treatments that may cure the cancer, from surgical resection and other ablative procedures to full liver transplantation.[92] The use of interferon as a conservative measure to treat liver cancer has shown enough promise to warrant further research.[93]

Treatment. A specialized form of prevention with liver cancer involves protecting against recurrence or a new primary cancer after a patient has received surgery, ablation or other therapies for their initial liver cancer. Successful interventions in this regard have included the use of retinoids (compounds related to vitamin A) and interferon.[94],[95],[96]

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[73] See the information from the Alcohol and Cancer Working Group of the Toronto Cancer Prevention Coalition at http://www.apolnet.org/resources/apu0003.pdf. Accessed June 2005.

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