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Hcv infection : evolution, prevention and implications in the elderly Torna agli editoriali

Anna Giulia Cattaneo, M.D.

HCV infection is one between different viral aggression possibly affecting the human liver, and mainly hepatocytes, with a parenteral diffusion pattern. Tab. 1 is a rapid summary of different types of viral hepatitis affecting humans, showing main features of their agents, preminent modalities for interpersonal transmission and usual evolution patterns. Among them HCV infection represents an acute pathology usually limited to the young, but its slowly evolving sequences are responsible for an increased risk in the elderly. The severity of evolution - chirrosis and hepatic carcinoma - are even enhanced by coexisting and usually live long pathogenic agents, like alchol and drug abuse, multiple exposures to the agent and coinfection with other hepatotropic viruses.

Table 1 : Hepatotropic viral agents affecting humans.

The pathogenicity of HGV and of TT virus, similar to circovirus and newly proposed as hepatotropic, is under debat.
Because of its high frequence, association of unresolved HCV infection with cirrhosis and hepatocellular carcinoma and the lack of efficaciuos vaccine, HCV infection may generate very expensive burdens for Europe, USA and worldwide, if preventive measures of only limited efficacy should be adopted. Despite of its importance, studies on prevalence and incidence in population appears to be lacking predictivity concerning the future of this disease and its late consequences.
Table 2 summarizes recent studies on prevalence of HCV infection.

Table 2 . Recent studies on the prevalence of HCV infection.

In all studies here reported infection has been stated by criteria generally recognized. Anti HCV positivity has been stated by a screening immunoenzymatic assay, followed by confirmatory test in positive subjects (immunoblotting, RIBA) and by PCR to check the persistent viremia in those resulting positive to the confirmatory test.

Associated risk factors and preventive measures.

1) In search of an effective vaccine

As other viral infections spread worldwide in last decades, like HIV, also the HCV shows an elusive behaviour escaping rapid preparation of a safe vaccine able to induce an efficacious and persistent immunity in recipients. Viral antigens variability and the lack of a reliable cell culture system frustrated the attempt performed until now.
At the present, attention of researchers appears to be focused on HVR1 and CD81 viral antigens. A promising attempt has been performed by inducing HCV-like particles (HCV-LPs) in insect culture cells. These antigens appears to be able to induce the production in mice of IgG1 anti HCV E1/E2. If combined with adjuvants, the anticorpal title rises up to 10 times, and the immunitary response appears to be more complete, inducing IgG2 secretion too: this last finding should be due to the specific action of adjuvant on T-helper type1 cells. No attempts have been performed in humans exposed to the infection or multiple infection risks.
Another possibility could be the preparation af a non proteic vaccine, with recombinant DNA.
Different vectors of HCV genes have been checked and proved effective in immunization of HLA-A21- transgenic mice.

2) Acute infection and spreading : preventive measures.

The lack of a suitable vaccine,in addiction to therapeutic means expensive and with limited efficacy, forces the specialist to obtain effective means of prevention for infection, reinfection, spread of infection and chronic evolution of the disease principally by using igienic and behavioural measures. A serious knowledge of risk factors and modalities of transmission of viral infection is the most important basis for it.

Main risk factors for HCV infection are generally recognized as the inoculation or contact (percutaneous or mucosal) with infected blood and derivatives, other body secretions or tissues. Even animals can be carriers of infections: dog bites can often be an anamnestic finding in infected patients. Subjects exposed to high risk of infection and possibly responsible for the spread of virus in population could be ideally divided into three areas: individuals with degraded or hazardous life styles, patients affected by special pathologies, and the workers in certain sanitary areas. In details, drug abuse, expecially intravenous and without needle and syringes control, tatooing, body piercing, scarifications ritual or not, contacts with multiple sexual partners are the principal modalities of infection for the first area. Previous carcerations are associated with high prevalence of infection due to the frequency of risk behaviour among prisoners. In population with hazardous behaviour, anti HCV positivity frequently cohexists with other blood borne or sexually transmitted diseases, and expecially with HBV and HIV infections.

Among the illnesses associated with higher risk of infection, attention should be payed to patients submitted to hemodialysis, blood transfusions or infusions with blood derivatives, recipients of organ transplantations and in certain cases even people requiring dental care. However, in these cases the incidence of infection among patients has been effectively reduced after the adoption of safe and severe control screening protocols. On the contrary, the high prevalence of antiHCV positivity observed in certain cases in subjects admitted to psychiatric clinic appears to be not related to the mental illness itself and its consequences, but confined to subjects having a life style at risk, like drug abusers.

Finally, HCV infection as a professional risk should be recognized for sanitary workers professionally exposed to the risk of contact with contaminated material: those working in hemodialysis or in chirurgical departments, or manipulating needles, scalpels sanitary discard material or having frequent contact with at risk patients (like drug abusers). In these people an efficacious strategy for early diagnosis of infection and prevention of its chronicity should be introduced as a routine. Recommended maesures at the present (in the absence of a vaccine) are the postexposure control of anti HCV positivity and the level of alanine aminotransferase (ALT), carried out in the proximity of the insult if possibly contaminated material has been accidentally inoculated, or 6 months later if the contact has been percutaneous or mucosal. In the case of documented infection, it should be cured with a standard antiviral therapy, to avoid chronic evolution.

A particular modality of infection is the vertical transmission from the mother to the newborne: a study carried out in Norway reports a prevalence of 8.3% of newborne from mother with persistent viremia (RNA-HCV positive). Another work describes a negative association between HCV vertical infection and the presence of the antigen HLA-DR13, and propose a protective role of this locus by enhanced cellular immunity. Transmission is perinatal, breast feeding does not transmit the infection. The PCR is usually negative at the birth, but could persist for 12 until a maximum of 18 months after: 25% of positive show elevated ALT serum levels. Need of therapy is under debat.

All those consideration describe HCV infection and acute disease as an illness confined or by far more frequent in young population.
Preventive measures in these cases are to be planned as following:

  1. early identification and diagnosis of infection in subjects at risk with a standard protocol (anti HCV screening test, confirmatory RIBA in positive subjects, PCR in confirmed anti HCV positive)
  2. cautious control of blood and its derivatives, viral inactivation, screening of positive donors
  3. control of tissues for transplantation
  4. screening and prevention of accidental infections in sanitary workers, treatment of acute infection to reduce persistent viremia
  5. health education of general population, population at risk, sanitary workers. Diffusion of reports and protocols concerning the modalities of infection, new preventive measures risk evaluation etc. between physician communities, politic bureaux, spontaneous association of healthy volunteer, education and prevention in middle and high school.
  6. Severe control of igienic precautions in every care facilities (dentistry studies, laboratories , hemodialysis and surgical departments), correct and protected discard of all contaminated material.
  7. Cautions with residents in protected houses for at risk people as drug users, prisoners after dimissions from correttional settings, drug addicts that escape sanitary control and in general with all people having a hazardous behaviour. In these cases the prevention is difficult and often frustrating: a quite realistic aim could be the restriction of infection spread in general population and the treatment of acute cases requiring cure.

Treatment of acute infections could be even an efficacious preventive measure to avoid spread of virus, if it abolishes the viremia. HCV infection require therapy in selected and well stated cases, on the basis of the presence of viremia and active and persistent hepatic disease documented by ALT raising in serum and by liver biopsy.

3) Chronic sequelae and HCV infection in adult and old indivuals.

HCV infection has a typical long term course; this fact could explain how an illness having its acute onset in the younger shows higher prevalence in the elderly and has its more severe complications in aging people. The Dionysos protocol, performed in 1991-1993, stated a 8% prevalence in aged people, while it was only 3.2% in general population. These results are limited to the areas of the Northern Italy and to the period in which the observations have been carried out: being HCV described as an individual pathogenic factor only in 1989, prevalence observed in 1991-1993 describes the situation existing before preventive measures could be adopted. This fact may explain the prevalence in general population higher than in other reports. Another study from Poland confirmed higher prevalence of infection signs in older people.

Even higher prevalence, however, was found in aged subjects (60-to-90 years, divided into three decades) matched for age suffering or not from cataract : a presumptive role of infection on lens degeneration has been proposed. Cirrhosis, both compensated or not, and evolution as hepatocellular carcinoma are the preminent long term complications of an infection frequently evolved in a paucisymptomatic manner. Antiviral combined therapy is recommended only in RNA-HCV positive patients suffering from compensated cirrhosis with elevated ALT and high score for active disease in liver biopsy: at least 15-20% of these subjects could be effectively cured, obtaining slower progeression of hepatic damage.

No antiviral treatment is efficacious in scompensated cirrhosis or hepatocellular carcinoma, in which palliative care and eventually transplantation (for carcinoma) could be required. Attention should be payed to the possibility of reinfection of the transplanted liver.
In the elderly, the American NHI does not define the need for antiviral treatment: in fact, the complete therapy may be too expensive in comparison with life expectancy and quality, in the presence of extra-hepatic pathologies generally affecting older people. Igienic improvement and mainly reduction of alcohol consumption in aged indivisuals are preminent measures to ameliorate welfare and to reduce risk of cirrhosis evolution and of other major complications of the infections in this class of age.
Conditions associated to severe sequelae are multiple reinfection, as those occuring in subjects with at risk behaviour or in multiple transfusion recipient in the past, and exposure to dietary, infectious or pharmacological liver insults. Among them, the co- and overinfection with HBV and HIV, or other hepatotropic blood borne viral infections, therapeutic or recreative use of drugs, malnutrition and alcohol abuse are the most frequently observed.

The epidemiology of HCV infections differs in different groups of age, and in patients suffering from cirrhosis or hepatocellular carcinoma.
HCV-RNA (+), present in 2.3% of all patients anti HCV (+) in the Italian study, was higher in female (M/F = 0.7) and in the older. The incidence of hepatocellular carcinoma was 3% per year only in HCV-RNA positive subjects with cirrhosis and history of heavy drinking. The genotype 1b (prevalence in viremic subjects: 42%) is associated to cirrhotic or carcinomatous evolution. Genotype association with hepatocellular carcinoma development is complicated by the relevance recently recognized to two point-mutations in the viral genoma of subtype 1b genotype. The mutant sequences have been found in cancerous and adjacent normal tissues: they are coding the viral core protein, a postulated starter of hepatic carcinogenesis thougether with F protein. Both proteins share mutant N-terminal sequence of 11 Aa residues only present in patients with hepatocellular carcinoma.

A retrospective, autoptic study showed the following pattern of HCV infection prevalence in a sample of Italian population suffering from hepatic cirrhosis:

  • 1969-1979 : 35-38%
  • 1984 : 65%
  • 1989 : 77% (peak)
  • 1994 : 50%

Genotype 1 is by far the most frequently present in these material (89%). In addition, in patients with evolution of viral infection as cirrhosis or carcinoma higher levels of a leukocytic marker of DNA oxidative damage, namely 8 OH-desoxyguanidine, are present, suggesting a role in evolution of hepatocellular damage
Anti HCV positive subjects, and expecially those with viremia and chronic liver disease, shows higher frequence of non-organ specific autoantibody (NOSAs).

Recently, in an Italian sample of population the following distribution of viral genotypes have been observed:

  • 1a (22% frequence) is most frequently observed in people aged 0-15 years; it is associated to drug abuse and its frequence declines after age 45
  • 1b (35.5%) is more frequent in people aged 16-30 years, in community acquired infections and in patients with late sequelae as cirrhosis and carcinoma (89% positivity in autoptic liver affected by cirrhosis and HCV infection). It is persistently present in aged 45 or more.
  • 3a (21.4%) is most frequently observed in people aged 31-45 years; it is associated to drug abuse and its frequence declines after age 45.
  • 2 (21%) is the most prevalent genotype present after age 45, present with genotype 1b in up to 90% of positive subjects. It is associated to community acquired infections.
    From data here exposed, it should be possible that some variation in the epidemiology of HCV infection in the older will be observed in the near future, when ageing of survivals from drug abuse will be responsible of a major portion of older people living in communities for the elderly.
    It is possible to postulate in the future a decreased frequence of community acquired infections, due to amelioration of igiene, health education and screening of potentially contagious subjects. In that case the prevalence of the dangerous genotype 1b and of associated severe illnesses may be reduced, and HCV infection shifted to a more simple disease.
    The hope for a suitable vaccine and efficacious, possibly not expensive therapy are even more promising goals.

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Dipartimento di Biologia Strutturale e Funzionale, Università dell'Insubria, Varese.

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