Norwegian Surveillance System for Antiviral Resistance (RAVN)
RAVN was established following the ‘National Strategy for prevention of infection in the health service and antibiotic resistance (2008-2012)’ issued by the Ministry of Health and Care Services.
RAVN consists of the RAVN register at the Norwegian Institute of Public Health and the RAVN Advisory Council that work together to plan and monitor viral resistance in collaboration with participating regional laboratories. The Advisory Council was formally appointed in 2010 and has biannual meetings.
Since July 2014, RAVN was included in the Resistance Registry Regulations, and the Norwegian Institute of Public Health was asked to establish a national surveillance system for viral resistance that includes other viruses than influenza.
RAVN includes the surveillance of viral resistance for influenza virus, human immunodeficiency virus (HIV), hepatitis B virus (HBV), cytomegalovirus (CMV) and herpes simplex virus (HSV). Hepatitis C virus (HCV) will be included once the new resistance testing methodology is established at the reference laboratory at the Norwegian Institute of Public Health.
Antiviral resistance is increasing
In recent years, several new antiviral medicines have become available. In particular, there have been many advances in antiviral therapy for HIV infection and hepatitis. However, we have seen similar problems with viruses as with bacteria – strains occur that are resistant to these medicines. If resistant viruses spread, virus infections become difficult to treat.
We have seen changes in resistance to anti-influenza medicines; viruses that were resistant to Tamiflu (oseltamivir) in 2007 were able to spread just as well as non-resistant viruses. Antiviral resistance may also cause problems with HIV and hepatitis.
Genotypic resistance testing of HIV-1 protease and reverse transcriptase has been performed at Haukeland since 1998, at Rikshospital since 2001 and at Oslo University Hospital, Ullevål since 2002. Since the national reference laboratory for HIV was established at Ullevål, testing has been centralised there.
Since January 2006 the Norwegian Institute of Public Health has collected reverse transcriptase and protease gene sequences from individuals with newly diagnosed HIV 1 infection.
In 2014, sequences were collected from 139 of 249 newly diagnosed patients with HIV-1 infection and the mutation prevalence related to HIV 1 resistance was 6.5 per cent.
In recent years, the coverage for primary resistance testing was between 50 and 60 per cent. RAVN aims to raise this.
Resistance that occurs during treatment is more common than transferred resistance. Today there is no systematic monitoring of treatment-induced HIV 1 resistance in Norway. However, the resistance data are included in the proposed HIV health registry.
HIV resistance is carried out by the Department of Microbiology at Oslo University Hospital, Ullevål.
The Department of Virology at the Norwegian Institute of Public Health is the WHO National Influenza Centre (NIC) and is appointed by the Ministry of Health and Care Services as the national reference laboratory for influenza. The laboratory monitors the occurrence of influenza virus in Norway.
A volunteer network of sentinel doctors submit nasal and throat swabs from patients with influenza-like illness. In addition, all the microbiological laboratories in the country send in confirmed strains to the influenza laboratory. These samples are analysed by virus cultivation and other methods.
Resistance surveillance uses both genotypic (partial / full sequencing, pyrosequencing and PCR) and phenotypic resistance testing of virus isolates. The data are recorded in a format that is compatible with international database formats. The influenza laboratory has published annual reports of influenza resistance surveillance and numerous research results in international journals. In the influenza season, resistance results have been published weekly.
Since 1999, a worldwide network for surveillance of resistance to neuraminidase inhibitors (NISN) has operated. 2287 isolates were analysed up until 2002, and no increase in the incidence of resistance during this period was observed.
As part of the framework of European cooperation, resistance testing is performed for viruses that the national laboratories in the European Influenza Surveillance collaboration (EISN) send to the WHO reference laboratory in England. Work is continuing on standardization, advice, training and establishing of analyses in countries that want to do their own testing. Norway participates in this surveillance and has sent influenza virus isolates to the WHO Collaborating Centre for Reference and Research on Influenza in England for resistance testing, while also performing analysis here.
Resistance surveillance is necessary to select the best treatment and updated knowledge about resistance is crucial for the best possible pandemic preparedness.
The 2009-2010 pandemic was caused by the A (H1N1) virus originating from swine, and demonstrated the need for continuous resistance surveillance. Studies in the early stages of the pandemic showed that the virus responded to oseltamivir and zanamivir but was resistant to M2 blockers. Later it was observed that a small number of viruses had acquired resistance to neuraminidase inhibitors in other countries too.
Hepatitis B virus (HBV) and Hepatitis C virus (HCV) resistance
Resistance studies for hepatitis B virus were introduced in 2004 at the Norwegian Institute of Public Health, which is the National Reference Laboratory for HBV and HCV. The reference laboratory receives samples for resistance testing from patients with failure of antiviral treatment. In addition, there is a general surveillance of resistance in a selection of samples from patients with chronic infection where genotyping is carried out.
In 2011, the first specific antiviral medicine against HCV, a protease inhibitor, was approved in Norway. Since then, other protease inhibitors, polymerase inhibitors and NS5A inhibitors have become available.
Several different resistance mutations have been described for HCV against the new medicines but the clinical significance of this is uncertain. Methods for resistance testing are being developed by the reference laboratory in collaboration with RAVN in order to increase knowledge.
Cytomegalovirus (CMV) and Herpes simplex virus (HSV)
Ganciclovir is the current treatment of choice for CMV infections among immunosuppressed patients. Its use is increasing as a range of conditions are treated with immunosuppressive or immunomodulatory medicines. If resistance to ganciclovir is confirmed, foscarnet or cidofovir can be used.
Genotypic resistance testing of CMV in Norway is performed at Oslo University Hospital, Rikshospitalet.
HSV-1, HSV-2 and VZV can be treated with acyclovir. Resistance is a minor problem. Samples for genotypic resistance testing are sent to the Public Health Agency in Sweden.
For resistance testing contact the Department of Microbiology at Oslo University Hospital, Rikshospitalet.
RAVN Advisory Council
The Advisory Council aims to promote high quality surveillance activities within RAVN. The Council collaborates with the RAVN register about arrangements for annual surveillance of viral resistance and evaluation of data before they are published in annual reports.
The Council evaluates applications for access to RAVN data and issues a statement on research applications related to RAVN. The Council considers applications for research grants and prioritizes these in collaboration with the RAVN register. The Council and RAVN register will protect the interests of the participating laboratories. The RAVN registers annual report and accounts are submitted to the council each year.
Advisory Council Meetings
The Council meets at least twice per year. The leader of the RAVN register is responsible for arranging the meetings and writes the minutes. The agenda is set by the leaders of the Council and the RAVN register. All those present are entitled to vote on matters that require a decision from the Council and the chairman of the Council has the casting vote.
Composition of the RAVN Advisory Council
The Council should contain a medical microbiologist (virologist) from each regional laboratory (4) and from the Norwegian Institute of Public Health (1) to ensure both geographical and institutional representation. In addition, there should be one molecular biologist and one infectious disease specialist. A representative from one of the non-regional microbiology laboratories must be included. The Council should not exceed 8 members and should be chaired by a medical microbiologist.
The Council includes the following professionals:
- Medical microbiologist from Oslo University Hospital
- Medical microbiologist from Haukeland University Hospital
- Medical microbiologist from St. Olav's Hospital Trondheim University Hospital
- Medical microbiologist from the University Hospital of North Norway
- Medical microbiologist from the Norwegian Institute of Public Health
- Medical microbiologist from one of the non-regional microbiology laboratories
- Molecular biologist
- Infectious disease specialist
The members and chairman of the Council are elected for four-year terms and are eligible for re-election, with a total of up to eight consecutive years of office for each member. Members who have previously served on the Council for an earlier period earlier can be re-elected.
The members are appointed by the director of the Division of Infectious Disease Control at the Norwegian Institute of Public Health. When new members are appointed continuity should be maintained, so that less than half of the members should be replaced at a time.
Advisory Council Members 2019:
- Andreas Christensen, St. Olav's Hospital, Trondheim University Hospital
- Anne-Marte Bakken Kran, Norwegian Institute of Public Health
- Vidar Ormåsen, Oslo University Hospital, Ullevål
- Birgitta Åsjø, Haukeland University Hospital
- Garth Tylden, University Hospital, Northern Norway
- Heidi Syre, Stavanger University Hospital
- Kathrine Stene-Johansen, Norwegian Institute of Public Health
- Rikard Rykkvin, Norwegian Institute of Public Health