Prevention and control of viral hepatitis in France: lessons learnt and the way forward (2004)

The Viral Hepatitis Prevention Board held its autumn meeting November 18-19, 2004, in Veyrier-du-Lac, France. The objectives of the meeting were to provide an overview of viral hepatitis in France, and reviewing, evaluating and providing updates on:

• The epidemiology of viral hepatitis;
• Surveillance systems for infectious diseases and adverse events following vaccination;
• France’s viral hepatitis research activities;
• Viral hepatitis prevention and control measures;
• Lessons learned from the French experience: achievements, challenges, and the way forward.

The healthcare system in France

• France is facing difficulties similar to other countries in sustaining high levels of health expenditures, with no guarantees of increased funding. This is due to an increasing ageing population (approximately ten million people in France are sixty-five years or older), relatively low birth rates, increasing levels of unemployment, and increased health costs for new therapies.
• Despite indicators showing a relatively healthy population in France, other core indicators show a high rate of premature mortality due to high-risk behaviour, such as high consumption of alcohol and tobacco, and to accidental deaths. Higher mortality and morbidity rates are also found in areas of the country with high levels of unemployment, where high-risk behaviour is frequent.
• Decision-making within France’s healthcare administration is centralised at national level. However, the recently enacted Public Health Policy law of August 2004 provides for implementation of strategies at a decentralised level. While mandatory immunisation policies are decided and implemented at national level, strategies to administer recommended vaccines may be taken at regional level, which accounts for disparities in vaccination coverage levels by geographical area.
• In order to address the huge imbalance between France’s healthcare expenditures for prevention, (only 2.3% spent on prevention programmes in 2003) and for treatment, further studies will need to be carried out to help demonstrate the cost-effectiveness of prevention in the healthcare system.

National strategy for prevention and control of viral hepatitis

France's viral hepatitis prevention and control programmes are based on strategies to reduce the risk of HBV and HCV transmission through updating and reinforcing hepatitis C prevention and control measures, and implementing new measures for hepatitis B prevention.

France's national prevention and control plan for hepatitis B and C have led to enhanced screening campaigns, an effective network of reference centres, and excellent research programmes. Major achievements of these programmes have led to:

• Primary prevention measures aimed at populations at highest risk of viral hepatitis infections;
• Mandatory notification of nosocomial HCV infection;
• Effective screening campaigns and increased HCV testing;
• Improvement of access to care and treatment, particularly in hospital services;
• Improved and easy patient access to therapy with costs fully reimbursed; and
• New capacities for diagnosing large numbers of patients.

Challenges facing France's healthcare system are the continuing hepatitis C epidemics among injecting drug users, the relatively low participation of general practitioners in networks that are outside of the specialised reference centres, and the need for more research capacity and strategic planning for long-term projects, cohort studies and large-scale trials. Evaluation of the viral hepatitis programme, in terms of short-term indicators, is also needed.

Hepatitis A in France

Epidemiology
Hepatitis A is not a reportable disease in France, where endemicity is low. The prevalence of anti-HAV antibodies in French military recruits decreased from 1978 to 1997. As this group is representative of the male population in France, these data show an increasing number of susceptible adults in the general population. Outbreaks still occur due to person-to-person transmission and food contamination among groups living in close contact, and among men who have sex with men.

Immunisation
France's hepatitis A immunisation recommendations are targeted to groups considered at increased risk of HAV infection.

Surveillance
As France has no surveillance of acute HAV infection, the possibilities are limited for monitoring epidemiological trends, assessing risk factors, identifying outbreak sources, and assessing risk-group vaccination coverage of outbreaks. France has a sentinel surveillance system that has been in place since 1991, but the system is limited by under-reporting by participating general practitioners, and is not designed to detect outbreaks.

A pilot study was conducted between 1999 and 2000 to detect hepatitis A outbreaks, to document incidence and HAV exposures. Participation of clinical laboratories was voluntary; at the same time, there was an insufficient number of participating laboratories, and a lack of capacity to identify clusters at district level. One positive aspect of this study was the willingness of the biologists to participate.

A proposal has been submitted to France's Upper Council for Public Health (CSHPF - Conseil Supérieur d’Hygiène Publique de France) for mandatory notification of hepatitis A by biologists to district medical officers. A decision on this proposal, accepting the principle of mandatory notification of hepatitis A, has been taken on November 26, 2004.

Hepatitis B in France

Epidemiology
Incidence of hepatitis B infection in France is low. Nevertheless, there is a need to optimise the current strategy of prevention and vaccination to reduce further the number of acute cases of HBV infection. Measures to improve prenatal screening need
to be reinforced to prevent perinatal HBV transmission to newborns.

There has been a shift in acute cases of hepatitis B from younger people in the 20 to 29-year age group (1991-1994) to those in the 30 to 39-year age group (March 2003-March 2004), a trend which may reflect the positive impact of France's hepatitis B vaccination strategy targeted to pre-teenagers and adolescents in 1994.

There is a need for further epidemiological studies on HBV prevalence within the general population and risk groups. A nationwide survey is being carried out on prevalence of chronic hepatitis B and C infections (results are pending). A new surveillance system was set up in 2003 and is now producing new data to monitor hepatitis B prevalence and incidence trends in France.

Surveillance
Notification of hepatitis B has been mandatory in France since March 2003, when France's new health surveillance system was put into place. Since then, all acute cases of hepatitis B must be reported by biologists and clinicians to their district health office, which reports to the national Institute of Health Surveillance (InVS - Institut de Veille Sanitaire). However, the system needs to be improved in terms of its completeness in notification of cases.

Preliminary results show that during the first year of mandatory notification (March 2003 to March 2004) two-thirds of all acute HBV cases could have been prevented had hepatitis B vaccination of risk groups been systematically carried out. These
data highlight the need for reinforced prevention strategies to protect newborns of HBV-infected mothers.

National reference centres for hepatitis A, B, and C are contributing to the new surveillance system by providing a regulatory basis for molecular epidemiological research and for surveillance in blood donors.

Immunisation
France has recommended hepatitis B vaccination since 1982 for all workers exposed to HBV and other persons at risk of HBV infection. Since 1991 hepatitis B vaccination has been compulsory for healthcare workers. Universal hepatitis B vaccination in France has been recommended by the CSHPF since 1994. The latest recommendations were made in March 2002. The 2004 schedule recommends systematic immunisation of all children under 13 years of age, preferably during infancy,and of all risk groups. The immunisation policy is reviewed every year and takes into account newly available vaccines in France and the benefit / risk assessment of vaccination. Although vaccination policies have been agreed, infant and child vaccinations are not adequately implemented. Two hexavalent vaccines, while available, are only used on a limited basis in France as they are not reimbursed through the healthcare system.

Prevention and control measures
1. Residual risk of HBV infection following blood transfusions:
Blood screening in France for HBV began in 1971 using HBsAg enzyme immunoabsorbent assays (ELISA), and is one of the most successful aspects of France's national health programme. Nucleic acid testing (NAT) had been considered for HBV testing in 2001 but it was decided not implement this technology in France due to its estimated limited impact on minimising residual risk in blood and blood products.
2. Healthcare workers:
Hepatitis B coverage levels remain less than optimal among certain groups of healthcare workers. According to 1997 data, only 79% of surgeons practicing in France had been vaccinated against HBV. There are also ongoing discussions of whether to allow healthcare workers who are in remission of HBV DNA and on long-term monotherapy, to perform invasive procedures.
3. Prisoners:
One of the major goals within France's committal population is to ensure that HBV-seronegative inmates upon admission to prison remain seronegative throughout their prison term.
Harm-reduction measures to help reduce high-risk behaviour in French prisons still need to be reinforced. Syringe-exchange programmes are not allowed in France despite proposals that would require distribution of syringes that are pre-filled with injectable buprenorphine or methadone. While injecting drug use is allowed within French prisons, syringe exchange is prohibited within a legislative context.
Further innovative measures need to be introduced within the prison environment to allow for more homogenous access to opiate maintenance treatments, pilot programmes, and enhancement of prisoner information services. Prevention strategies will need to be devised to encourage behavioural change among inmates that will lead to higher uptake levels of hepatitis B vaccination. Further clinical research is needed as well as new treatment strategies to improve management of patients with addictions.

Hepatitis C in France

Epidemiology
In 1994, the prevalence of anti-HCV positivity in France was estimated at 1.05%, a figure which represents approximately half a million HCV-infected persons. Between 400,000 and 500,000 persons are estimated to have chronic (HCV-RNApositive) infections. Preliminary survey data (2004) indicate a prevalence of 0.86%. HCV incidence remains a problem among IDUs, with current values estimated at 10-40% person-years.

HCV genotypes 3 and 1a are dominant in injecting drug users (IDUs) in France; for blood recipients and nosocomial sources, genotypes 1b and 2 are dominant. HCV genotype 4 has emerged in France infecting IDUs and immigrants from Egypt and sub-
Saharan Africa.

Older HCV-infected patients represent a great burden for reference centres that are operating under heavy work loads. These patients present special healthcare challenges in terms of treatment failure, the risks of developing cancer and end-stage liver disease, and the need for transplantation. Strategies for improved treatment compliance and treatment for nonresponders will need to be devised.

Surveillance
The aims of a hepatitis C surveillance programme are to provide data that allow evaluation of the national viral hepatitis prevention programme and to adapt public health actions accordingly. Such surveillance programmes also serve as alerting
mechanisms for intervention, and provide hypotheses for research. In general, surveillance systems should be regarded as intelligence tools that allow rapid interaction with coordinating networks and partners.

Surveillance systems in France are administered and coordinated by the Institut National de Veille Sanitaire (InVS) and France's national federation of reference centres and hepatitis networks (Fédération Nationale des Pôles de Référence et Réseaux Hépatites - FNPRRH). These surveillance systems are based on the following:

• Laboratory-based surveillance of HCV serology (screening);
• Newly referred HCV-infected patients in hepatology reference centres;
• Mandatory notification of nosocomial-related hepatitis C (or B);
• Surveillance of residual risk in blood donors.

Prevention and control measures
Sixty percent of new hepatitis C patients were diagnosed in 2002; the latest programme objective is to diagnose 100% of HCVinfected patients by 2005. Although many risk groups are being reached, there needs to be improvement in diagnosing patients at low risk of HCV infection. Screening and treatment should be carried out as early as possible for co-infected patients to prevent severe morbidity from HBV and HCV infections.

Prevention and control of nosocomial infections
Notification of HCV nosocomial infection has been mandatory in France since July 2001. Although frequency is low, cases still occur (13 notifications in France since 2001). More efforts are needed to prevent blood-borne virus infections based on the findings of expert steering groups, and stricter compliance with standard hygiene precautions.

• The mechanism of patient-to-patient transmission is very often unknown, occurring in various settings such as haemodialysis, digestive endoscopy, contacts with diabetic children, anaesthesiology, transplantation, and surgery. Some well-known mechanisms are sharing injection material and products, and breaches in barrier precautions and material disinfection.
• To reduce patient-to-healthcare worker (HCW) transmission, preventive measures need to be introduced in France to protect HCWs from blood-borne infection during medical care. For at-risk surgical procedures, safer suturing techniques and alternatives to prevent parenteral exposure should be considered, as well as reinforcing campaigns against recapping needles to lower risk of percutaneous injury.
• HCW-to-patient transmission mostly occurs through blood exposure during orthopaedic and cardiothoracic surgery and other procedures involving gynaecology and anaesthesiology. Recent recommendations in France require that HCWs know their HCV status. HCWs aware of being HCV-infected must undergo a group evaluation during which time the HCW is advised to consider using less exposure-prone procedures; also discussed are the risks in continuing employment in a medical setting. An official French ecommendation is that HCVinfected HCWs carry out less invasive procedures to minimise risk.

Residual risk of HCV infection following blood transfusions
Nucleic acid testing (NAT) for HCV screening has been used in France since 2001 in order to minimise the risk in blood and blood products. The benefits of NAT include the introduction of new methods in blood screening, a high level of blood
component safety, and improvement in diagnosing infection in blood donors. Since implementation of NAT, the risk of a blood recipient in France becoming infected with a hepatitis virus is extremely low (1 in 10,000,000 blood donations for HCV).

Prisoners
Harm-reduction measures need to be strengthened. For example, material disinfection with bleach, used in French prisons since 1997, is not adequately promoted in terms of its preventive action. Syringe-exchange programmes, although recommended by the French Health-Justice mission in 2000, are still not allowed, despite proposals to distribute syringes pre-filled with injectable buprenorphin or methadone.

Improving the working relationships between staff and inmates and promoting existing harm-reduction tools will contribute to decreasing risk behaviour within the committal population.

Prediction of HCV-related morbidity and mortality burden in France
Using mathematical modeling, based on a back-calculation approach of past HCV infections, is a useful tool in allowing prediction of disease burden in a given population and economic evaluation of hepatitis C treatment programmes. The model shows that improvements in hepatitis C therapy have been too recent and too few patients diagnosed and deemed treatable to induce a decrease or even a stabilisation of HCV-related mortality.

Hepatitis B and C registries

A population-based registry is a structure that continuously records all new cases of a disease in a well-defined population. Recorded data from registries are also useful as a basis for research studies. Population-based registries in France contribute to enhanced epidemiological knowledge of HBV and HCV, allowing:

• Evaluation of the impact of screening campaigns and guidelines;
• Evaluation of health networks and their effectiveness;
• Examination of the natural history of hepatitis, on a long-term basis, in the general population.

Hepatitis E in France

Hepatitis E outbreaks occur in high-endemic areas (e.g., Africa, Asia). Sporadic cases have also occurred in low-endemic areas (e.g., in Europe, North America). Data from the French national reference centre for enterically transmitted hepatitis show decreasing anti-HEV seroprevalence and circulation of HEV in France among persons without any recent travel history to endemic areas.

There is a potential animal reservoir of HEV (e.g., swine HEV sequences are closely related to those of human HEV strains) but the transmission route between humans and the animal reservoir is not yet clear.

Viral hepatitis research in France

France is one of the leading countries conducting fundamental research, with a long tradition of excellence in clinical research. Diverse sources of funding come from institutions, hepatitistargeted projects, external grants, scholarships, and industry.

At the institutional level, institutions such as CNRS (Centre National de la Recherche Scientifique), and INSERM ((Institut Nationale de la Santé et de la Recherche Médicale) provide the basic infrastructure for research as well as funding for salaries and research budgets.

The ANRS / ANRH (Agence Nationale de Recherches sur le SIDA et les Hépatites Virales), France's national agency for research on AIDS and viral hepatitis, operates under the auspices of the French government. Currently there is more research targeted to hepatitis C than to hepatitis B due, in part, to the low incidence of hepatitis B in France. More hepatitis B projects need to be carried out, particularly multi-disciplinary projects, clinical trials independent of industry, and public health studies targeted to epidemiological research on HBV infection and data on chronic carriers and, more generally, research into the social sciences and quality of life.

Henri Mondor University Hospital is one of France's leading institutions conducting viral hepatitis research.

At European level, hepatitis-targeted projects are funded through the Fifth and Sixth Framework Programmes of the European Commission. Although these programmes represent a good potential source of funding, more viral hepatitis research projects need to be added and could clearly benefit from additional lobbying at European level to help increase funding within the Sixth Framework Programme (2002-2006).

Other funding sources are available through regional or local administrations, international grants, private foundations and industrial sponsors such as diagnostic and pharmaceutical companies partnering with post-doctoral research fellows.

Hepatitis B vaccine safety issues

In France, there is no specific pharmacovigilance for vaccines, which are considered medical products. The current French pharmacovigilance system is a passive surveillance system, based on a decentralised collection and validation of safety data through regional centres and a centralised evaluation and decision-making process at the French Health Products Safety Agency (AFSSAPS - Agence Française de Sécurité Sanitaire des Produits de Santé). Reporting of suspected adverse drug reactions is mandatory for prescribers and pharmacists. The methodology is based on medically-confirmed case reports.

There have been no changes in France's hepatitis B vaccination schedule since 1998. Hepatitis B vaccination remains recommended in infants and adolescents, and adults who are at increased risk of HBV infection. Nevertheless, hepatitis B coverage has not recovered to its previous levels since France's 1998 hepatitis B vaccination crisis.

Scientific data support the safety and efficacy of hepatitis B vaccine, and expert committees and the VHPB continue to support WHO’s recommendations on hepatitis B immunisation. However, there is still a need for firm political commitment from French authorities to affirm the safety of hepatitis B vaccination to help re-establish confidence in the vaccine.

 

Further information is available in the corresponding Viral Hepatitis Issue or  meeting web page.