WHO Human Avian Influenza News Update

[Tsui Hart]

WHO Human Avian Influenza News Update: (on 27 Feb. 2009)

Since 2003 confirmed H5N1 human case: 408 cases with 256 died (CFR ~ 63%)
Since 2008 confirmed H5N1 human case: 44 cases with 33 died (CFR ~ 75%)
Since 2009 confirmed H5N1 human case: 13 cases with 6 died (CFR ~ 46%)

Latest Affected Country: China, Egypt & Vietnam (15th Country NOW since 2003)

China:
 19-yr old female from Chaoyang District, Beijing, symptoms on 24/12& died 5/1
 27 yr old female from Jinan City, Shandong Province,symptoms on 5/1& died 17/1;
 2 yr old female from Luliang City, Shanxi Province, symptoms on 7/1& in critical condition
 16 yr old male from Huaihua City, Hunan Province, symptoms 8/1 died on 20/1
 31-yr-old female from Urumqi, Xinjiang Autonomous Region, symptoms 10/1,died 23/1.
 29-yr-old male from Guiyang city, Guizhou; symptoms on 15/1 & in critical condition;
 18-yr-old male from Beiliu City, Guangxi Province; symptoms on 19/1and died on 26/1.
 21-yr-old female from Xupu County, Hunan province; symptoms on 23/1,clinically stable.

Egypt:
 21-months old female from 6th October Governorate, Kerdasa District; symptom on 9/1
 2-yr-old female fr Manofia Governorate, Shebin Elkom District; symptoms 23/1 & in stable condition.
 2-yr-old male from Suez Governorate, Ganain District; symptoms on 2/2, hospitalized @ Suez Fever Hospital on 3/2 ,remains stable
 18-months old male from the Maghagha District of Menia Governorate; symptoms on 6/2; hospitalized in a stable condition

Vietnam:
 32 yr old male from Kim Son district, Ninh Binh Province died on 25/2
 23 yr old female from Dam Ha District, Quang Ninh Province died on 21/2
 23-yr old woman from Dam Ha district, Quang Ninh province, symptom on 28/1 hospitalized on 31/1 in a serious condition.
 32-yr old man from Kim Son district, Ninh Binh province, symptom on 5/2 hospitalized on 13/2 in a serious condition.

Ref: WHO Web Page

[Tsui Hart]

Progress in Pandemic Influenza Vaccine Preparedness

The epidemiologic situation with H5N1 viruses

Total cases recorded since February 2003: 408 cases

Deaths recorded since February 2003: 254 deaths

Case-fatality ratio (Number of deaths per number of cases): 62%

What is happening in 2009:
13 cases including 4 deaths have been reported:
China reported 7 cases including 4 deaths;
4 cases occurred in Egypt and
2 were reported in Viet Nam.

What happened in 2008:
44 cases including 33 deaths reported in six countries
(Bangladesh, Cambodia, China, Egypt, Indonesia, Viet Nam)

Countries affected since 2003:[b]15[/b] (
Azerbaijan, Bangladesh, Cambodia, China, Djibouti, Egypt, Indonesia, Iraq, Lao PDR, Myanmar, Nigeria, Pakistan, Thailand, Turkey, Viet Nam)


The level of preparedness of countries for pandemic influenza

Most of the countries in the world have made pandemic influenza preparedness plans using WHO guidance since 2005.
Many of these plans have been exercised and revised.
Countries with H5N1 have, in general, been more active in preparedness due to a perceived closeness of the risk.
For the gains to be sustainable, however, pandemic influenza preparedness needs to be placed into the wider scope of national emergency preparedness and should be used to strengthen national capacities.
The challenge now is a misperception that the risk of a pandemic is lower than before; it is not.


Next steps on pandemic influenza preparedness

WHO is in the process of revising its global influenza preparedness plan (current version published in 2005). The revised guidance promotes a whole-of-society approach to pandemic preparedness, and introduces revised phase definitions based on observable phenomena, pandemic severity issues and a more pronounced presence of ethics and communications.


The significance of the WHO-Nobilon agreement

WHO and Nobilon (the vaccines division of Schering-Plough) have signed an agreement at WHO's headquarters in which WHO has been granted a non-exclusive license to develop, register, manufacture, use and sell seasonal and pandemic live, attenuated (or weakened) influenza vaccines (LAIV) produced on chicken eggs.
WHO will thus be able to grant sub-licenses to vaccine manufacturers in developing countries who are working within the framework of the WHO Global Pandemic Influenza Action Plan to Increase Vaccine Supply (link below). These countries will be able to provide such vaccines to their public sectors royalty-free. This last provision is of upmost importance to allow access to developing countries to this technology and contributes to a more equitable sharing of benefits.

Many experts have identified Live Attenuated Influenza Vaccine (LAIV) technology as the most promising approach for supporting national or regional pandemic influenza vaccine preparedness plans.

LAIVs have at least three major advantages compared to the currently available inactivated vaccines.


The number of doses of LAIV which can be produced per egg are much higher than with inactivated vaccines. Especially in a pandemic situation, this is considered to be a major advantage since more vaccine doses can be made available in a shorter time.
LAIVs are administered in the nose though a very simple device, which will be much easier to put into practice on a large-scale by non-medically trained staff in case of a pandemic.
Since a LAIV mimics natural infection more than injectable vaccines, it is expected that LAIV induces a more rapid and broader immune response. This may be of particular interest in pandemic situations.


WHO's assessment of the new pandemic influenza vaccine supply estimates

Although the newly expanded production capacity (see 24.02.09 IFPMA press release) would not be sufficient to meet the global need for emergency production of pandemic influenza vaccines at the time of a pandemic, it appears that current and future surplus capacity could support the production of billions of doses of H5N1 influenza vaccine prior to a pandemic for stockpiling efforts and other utilization.

This, however, will still be insufficient to meet vaccine demand in case of a pandemic. Therefore, transfer of technology to developing country vaccine manufacturers should continue to be promoted. A new call for proposals from developing countries interested in establishing or improving their influenza vaccine production capacity has been issued by WHO, both for continuation of the 6 current technology transfer projects and initiation of new ones.
Applications have been reviewed by an independent technical advisory committee and WHO is negotiating further funding allocations with all 6 original grantees. The following have been designated for new (first) grants: Vacsera (Egypt), Green Cross (Korea), Cantacuzino (Romania), Torlak (Serbia), Razi (Iran).
The total global value of all the grants (both groups of countries and both rounds) is about US $12 million.

Source: WHO Initiative for Vaccine Research; WHO Global Influenza Programme; 24 February 2009


Related links

- WHO Global Pandemic Influenza Action Plan to Increase Vaccine Supply [pdf 520kb]
- IFPMA press release - 24.02.09 [pdf 38.13kb]

Contact:
Melinda HENRY
Immunization, Vaccines and Biologicals,
World Health Organization,
Geneva
E-mail: henrym@who.int
Tel.: +41 22 791 2535

[xerkitsko]

Avian influenza – situation in Thailand Update

Situation in Thailand

The Ministry of Public Health in Thailand has today confirmed a further case of human infection with H5N1 avian influenza. The case, which was fatal, was a 9-year-old girl from the northern province of Phetchabun. She developed symptoms on 23 September, was hospitalized on 27 September, and died of severe respiratory disease on 3 October.

Investigation of the case has identified exposure to diseased chickens as the most likely cause of infection. Following the death of chickens in the child’s household, she assisted in preparation of the birds for cooking, including the plucking of feathers.

WHO stresses the importance of educating populations in affected countries, especially those living in remote rural areas, about the danger of contact with diseased birds.

Since the beginning of this year, Thailand has
reported 16 laboratory confirmed cases of H5N1 infection, of which
11 have been fatal.
FOUR of these cases during the past four weeks.

Source: WHO

[Blue Nurse]

I think the above info was mistakenly taken other influenza into H5N1.

Latest info on Thailand on H5N1 situation is
NOT any Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO case noted since 2007 till NOW .

For any updated clarification from 2003 onwards till now : please refer to WHO official web page : http://www.who.int/csr/disease/avian_in ... index.html

For those who interested on any birds or poultry outbreak on H5N1 from 2003 onwards till now, there is also an official WHO web page: http://www.who.int/csr/disease/avian_in ... index.html

Source: WHO web page

[Blue Nurse]

From the date of one of the above message dated on 16 June 2009 about Thailand,
actually was from 4 October 2004 WHO report Situation in Thailand.
Besides, the sympotms onset was actually on September and died on October.

Is there any reason why such a BIG delay noted for xerkitsko to send out on 2004 and received on 16 June 2009 on this Forum!!

[Blue Nurse]

Pandemic (H1N1) 2009 briefing note 1
Viruses resistant to oseltamivir (Tamiflu) identified

WHO has been informed by health authorities in Denmark, Japan and the Special Administrative Region of Hong Kong, China of the appearance of H1N1 viruses which are resistant to the antiviral drug oseltamivir (known as Tamiflu) based on laboratory testing.

These viruses were found in three patients who did NOT have severe disease and all have recovered. Investigations have not found the resistant virus in the close contacts of these three people. The viruses, while resistant to oseltamivir, remain sensitive to zanamivir.

Close to 1000 pandemic H1N1 viruses have been evaluated by the laboratories in the Global Influenza Surveillance Network for antiviral drug resistance. All other viruses have been shown sensitive to both oseltamivir and zanamivir. WHO and its partners will continue to conduct ongoing monitoring of influenza viruses for antiviral drug resistance.

Therefore, based on current information, these instances of drug resistance appear to represent sporadic cases of resistance. At this time, there is no evidence to indicate the development of widespread antiviral resistance among pandemic H1N1 viruses. Based on this risk assessment, there are NO changes in WHO's clinical treatment guidance. Antiviral drugs remain a key component of the public health response when used as recommended.


Source: WHO Web Page

[Tsui Hart]

________________________________________

Pandemic (H1N1) 2009 briefing note 2
WHO recommendations on pandemic (H1N1) 2009 vaccines

The Strategic Advisory Group of Experts (SAGE) on Immunization held an extraordinary meeting in Geneva to discuss issues and make recommendations related to vaccine for the pandemic (H1N1) 2009.
SAGE reviewed the current pandemic situation, the current status of seasonal vaccine production and potential A(H1N1) vaccine production capacity, and considered potential options for vaccine use.
The experts identified three different objectives that countries could adopt as part of their pandemic vaccination strategy:
• protect the integrity of the health-care system and the country's critical infrastructure;
• reduce morbidity and mortality; and
• reduce transmission of the pandemic virus within communities.

Countries could use a variety of vaccine deployment strategies to reach these objectives but any strategy should reflect the country’s epidemiological situation, resources and ability to access vaccine, to implement vaccination campaigns in the targeted groups, and to use other non-vaccine mitigation measures.

Although the severity of the pandemic is currently considered to be moderate with most patients experiencing uncomplicated, self-limited illness, some groups such as pregnant women and persons with asthma and other chronic conditions such as morbid obesity appear to be at increased risk for severe disease and death from infection.

Since the spread of the pandemic virus is considered unstoppable, vaccine will be needed in all countries. SAGE emphasized the importance of striving to achieve equity among countries to access vaccines developed in response to the pandemic (H1N1) 2009
The following recommendations were provided to the WHO Director-General:
• All countries should immunize their health-care workers as a first priority to protect the essential health infrastructure. As vaccines available initially will not be sufficient, a step-wise approach to vaccinate particular groups may be considered. SAGE suggested the following groups for consideration, noting that countries need to determine their order of priority based on country-specific conditions: pregnant women; those aged above 6 months with one of several chronic medical conditions; healthy young adults of 15 to 49 years of age; healthy children; healthy adults of 50 to 64 years of age; and healthy adults of 65 years of age and above.
• Since new technologies are involved in the production of some pandemic vaccines, which have not yet been extensively evaluated for their safety in certain population groups, it is very important to implement post-marketing surveillance of the highest possible quality. In addition, rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies among the international community will be essential for allowing countries to make necessary adjustments to their vaccination policies.

• In view of the anticipated limited vaccine availability at global level and the potential need to protect against "drifted" strains of virus, SAGE recommended that promoting production and use of vaccines such as those that are formulated with oil-in-water adjuvants and live attenuated influenza vaccines was important.

• As most of the production of the seasonal vaccine for the 2009-2010 influenza season in the northern hemisphere is almost complete and is therefore unlikely to affect production of pandemic vaccine, SAGE did NOT consider that there was a need to recommend a "switch" from seasonal to pandemic vaccine production.
WHO Director-General Dr Margaret Chan endorsed the above recommendations on 11 July 2009, recognizing that they were well adapted to the current pandemic situation. She also noted that the recommendations will need to be changed if and when new evidence become available.
SAGE was established by the WHO Director-General in 1999 as the principal advisory group to WHO for vaccines and immunization. It comprises 15 members who serve in their personal capacity and represent a broad range of disciplines from around the world in the fields such as epidemiology, public health, vaccinology, paediatrics, internal medicine, infectious diseases, immunology, drug regulation, programme management, immunization delivery, and health-care administration.
Additional participants in the SAGE meeting included members of the ad hoc policy advisory working group on influenza A(H1N1) vaccine, chairs of the regional technical advisory groups and external experts. Observers included industry representatives and regulators who did not take part in the recommendation process in order to avoid conflicts of interest.

Source: WHO web page

[Blue Nurse]

Pandemic (H1N1) 2009 briefing note 3
Changes in reporting requirements for pandemic (H1N1) 2009 virus infection



As the 2009 pandemic evolves, the data needed for risk assessment, both within affected countries and at the global level, are also changing.

At this point, further spread of the pandemic, within affected countries and to new countries, is considered inevitable.

This assumption is fully backed by experience. The 2009 influenza pandemic has spread internationally with unprecedented speed. In past pandemics, influenza viruses have needed more than six months to spread as widely as the new H1N1 virus has spread in less than six weeks.

The increasing number of cases in many countries with sustained community transmission is making it extremely difficult, if not impossible, for countries to try and confirm them through laboratory testing. Moreover, the counting of individual cases is now no longer essential in such countries for monitoring either the level or nature of the risk posed by the pandemic virus or to guide implementation of the most appropriate response measures.


Monitoring still needed

This pandemic has been characterized, to date, by the mildness of symptoms in the overwhelming majority of patients, who usually recover, even without medical treatment, within a week of the onset of symptoms. However, there is still an ongoing need in all countries to closely monitor unusual events, such as clusters of cases of severe or fatal pandemic (H1N1) 2009 virus infection, clusters of respiratory illness requiring hospitalization, or unexplained or unusual clinical patterns associated with serious or fatal cases.

Other potential signals of change in the currently prevailing pattern include unexpected, unusual or notable changes in patterns of transmission. Signals to be vigilant for include spikes in rates of absenteeism from schools or workplaces, or a more severe disease pattern, as suggested by, for example, a surge in emergency department visits.

In general, indications that health services are having difficulty coping with cases mean that such systems are under stress but they may also be a signal of increasing cases or a more severe clinical picture.

A strategy that concentrates on the detection, laboratory confirmation and investigation of all cases, including those with mild illness, is extremely resource-intensive. In some countries, this strategy is absorbing most national laboratory and response capacity, leaving little capacity for the monitoring and investigation of severe cases and other exceptional events.


Regular updates on newly affected countries

For all of these reasons, WHO will no longer issue the global tables showing the numbers of confirmed cases for all countries. However, as part of continued efforts to document the global spread of the H1N1 pandemic, regular updates will be provided describing the situation in the newly affected countries. WHO will continue to request that these countries report the first confirmed cases and, as far as feasible, provide weekly aggregated case numbers and descriptive epidemiology of the early cases.

For countries already experiencing community-wide transmission, the focus of surveillance activities will shift to reporting against the established indicators for the monitoring of seasonal influenza activity. Those countries are no longer required to submit regular reports of individual laboratory-confirmed cases and deaths to WHO.

Monitoring the virological characteristics of the pandemic virus will be important throughout the pandemic and some countries have well-established laboratory-based surveillance systems in place already for seasonal influenza virus monitoring. Even in countries with limited laboratory capacity, WHO recommends that the initial virological assessment is followed by the testing of at least 10 samples per week in order to confirm that disease activity is due to the pandemic virus and to monitor changes in the virus that may be important for case management and vaccine development.

Updated WHO guidelines for global surveillance reflect in greater detail these recommended changes, in line with reporting requirements set out in the International Health Regulations.

[Tsui Hart]

Pandemic (H1N1) 2009 briefing note 4
Preliminary information important for understanding the evolving situation

24 JULY 2009 | GENEVA -- The number of human cases of pandemic (H1N1) 2009 is still increasing substantially in many countries, even in countries that have already been affected for some time.

Our understanding of the disease continues to evolve as new countries become affected, as community-level spread extends in already affected countries, and as information is shared globally. Many countries with widespread community transmission have moved to testing only samples of ill persons and have shifted surveillance efforts to monitoring and reporting of trends. This shift has been recommended by WHO, because as the pandemic progresses, monitoring trends in disease activity can be done better by following trends in illness cases rather than trying to test all ill persons, which can severely stress national resources. It remains a top priority to determine which groups of people are at highest risk of serious disease so steps to best to protect them can be taken.
In addition to surveillance information, WHO is relying on the results of special research and clinical studies and other data provided by countries directly through frequent expert teleconferences on clinical, virological and epidemiological aspects of the pandemic, to gain a global overview of the evolving situation.

Average age of cases increasing
In most countries the majority of pandemic (H1N1) 2009 cases are still occurring in younger people, with the median age reported to be 12 to 17 years (based on data from Canada, Chile, Japan, UK and the United States of America). Some reports suggest that persons requiring hospitalization and patients with fatal illness may be slightly older.

As the disease expands broadly into communities, the average age of the cases is appearing to increase slightly. This may reflect the situation in many countries where the earliest cases often occurred as school outbreaks but later cases were occurring in the community. Some of the pandemic disease patterns differ from seasonal influenza, where fatal disease occurs most often in the elderly (>65 years old). However, the full picture of the pandemic's epidemiology is not yet fully clear because in many countries, seasonal influenza viruses and pandemic (H1N1) 2009 viruses are both circulating and the pandemic remains relatively early in its development.

Although the risk factors for serious pandemic disease are NOT know definitively, risk factors such as existing cardiovascular disease, respiratory disease, diabetes and cancer currently are considered risk factors for serious pandemic (H1N1) 2009 disease. Asthma and other forms of respiratory disease have been consistently reported as underlying conditions associated with an augmented risk of severe pandemic disease in several countries.
A recent report suggests obesity may be another risk factor for severe disease. Similarly, there is accumulating evidence suggesting pregnant women are at higher risk for more severe disease. A few preliminary reports also suggest increased risk of severe disease may be elevated in some minority populations, but the potential contributions of cultural, economic and social risk factors are not clear.

Vaccine situation
The development of new candidate vaccine viruses by the WHO network is continuing to improve yields (currently 25% to 50 % of the normal yields for seasonal influenza for some manufacturers). WHO will be able to revise its estimate of pandemic vaccine supply once it has the new yield information. Other important information will also be provided by results of ongoing and soon-to be-initiated vaccine clinical trials. These trials will give a better idea of the number of doses required for a person to be immunized, as well as of the quantity on active principle (antigen) needed in each vaccine dose.
Manufacturers are expected to have vaccines for use around September. A number of companies are working on the pandemic vaccine production and have different timelines.


Source: WHO Web page

[Tsui Hart]

________________________________________

Pandemic influenza in pregnant women
Pandemic (H1N1) 2009 briefing note 5

31 JULY 2009 | GENEVA -- Research conducted in the USA and published 29 July in The Lancet [1] has drawn attention to an increased risk of severe or fatal illness in pregnant women when infected with the H1N1 pandemic virus.
Several other countries experiencing widespread transmission of the pandemic virus have similarly reported an increased risk in pregnant women, particularly during the second and third trimesters of pregnancy. An increased risk of fetal death or spontaneous abortions in infected women has also been reported.
Increased risk for pregnant women

Evidence from previous pandemics further supports the conclusion that pregnant women are at heightened risk.
While pregnant women are also at increased risk during epidemics of seasonal influenza, the risk takes on added importance in the current pandemic, which continues to affect a younger age group than that seen during seasonal epidemics.
WHO strongly recommends that, in areas where infection with the H1N1 virus is widespread, pregnant women, and the clinicians treating them, be alert to symptoms of influenza-like illness.

WHO recommendations for treatment
Treatment with the antiviral drug oseltamivir should be administered as soon as possible after symptom onset. As the benefits of oseltamivir are greatest when administered within 48 hours after symptom onset, clinicians should initiate treatment immediately and not wait for the results of laboratory tests.
While treatment within 48 hours of symptom onset brings the greatest benefits, later initiation of treatment may also be beneficial. Clinical benefits associated with oseltamivir treatment include a reduced risk of pneumonia (one of the most frequently reported causes of death in infected people) and a reduced need for hospitalization.
WHO has further recommended that, when pandemic vaccines become available, health authorities should consider making pregnant women a priority group for immunization.


Danger signs in all patients
Worldwide, the majority of patients infected with the pandemic virus continue to experience mild symptoms and recover fully within a week, even in the absence of any medical treatment. Monitoring of viruses from multiple outbreaks has detected no evidence of change in the ability of the virus to spread or to cause severe illness.

In addition to the enhanced risk documented in pregnant women, groups at increased risk of severe or fatal illness include people with underlying medical conditions, most notably chronic lung disease (including asthma), cardiovascular disease, diabetes, and immunosuppression. Some preliminary studies suggest that obesity, and especially extreme obesity, may be a risk factor for more severe disease.

Within this largely reassuring picture, a small number of otherwise healthy people, usually under the age of 50 years, experience very rapid progression to severe and often fatal illness, characterized by severe pneumonia that destroys the lung tissue, and the failure of multiple organs. No factors that can predict this pattern of severe disease have yet been identified, though studies are under way.

Clinicians, patients, and those providing home-based care need to be alert to danger signs that can signal progression to more severe disease. As progression can be very rapid, medical attention should be sought when any of the following danger signs appear in a person with confirmed or suspected H1N1 infection:
• shortness of breath, either during physical activity or while resting
• difficulty in breathing
• turning blue
• bloody or coloured sputum
• chest pain
• altered mental status
• high fever that persists beyond 3 days
• low blood pressure.
In children, danger signs include fast or difficult breathing, lack of alertness, difficulty in waking up, and little or no desire to play.
________________________________
[1] Jamiesan DG et al. H1N1 2009 influenza virus infection during pregnancy in the USA. Lancet 2009; published online July 29, 2009


Source: WHO

[Tsui Hart]

Safety of pandemic vaccines
Pandemic (H1N1) 2009 briefing note 6

6 AUGUST 2009 | GENEVA -- WHO is aware of some media reports that have expressed concern about the safety of vaccines for pandemic influenza. The public needs to be reassured that regulatory procedures in place for the licensing of pandemic vaccines, including procedures for expediting regulatory approval, are rigorous and do not compromise safety or quality controls.

Vaccines are among the most important medical interventions for reducing illness and deaths during a pandemic. However, to have the greatest impact, pandemic vaccines need to be available quickly and in large quantities.

During the 1957 and 1968 pandemics, vaccines arrived too late to be used as an effective mitigation tool during the more severe phases of the pandemics. Influenza vaccines had not yet been developed when the 1918 pandemic swept around the world, eventually killing an estimated 50 million people.
In 2007, as part of preparedness for an influenza pandemic, WHO worked together with health officials, regulatory authorities, and vaccine manufacturers to explore a broad range of issues surrounding the regulatory approval of pandemic vaccines. [1]
Ways were sought to shorten the time between the emergence of a pandemic virus and the availability of safe and effective vaccines. Different regulatory pathways were assessed, and precautions needed to ensure quality, safety, and effectiveness were set out in detail.

Fast-track procedures for approval
Regulatory authorities have shown great flexibility in developing procedures for fast-tracking the approval and licensing of pandemic vaccines.
In some cases, pandemic vaccines are not regarded by regulatory authorities as entirely “new” vaccines, as they build on the technology used to produce vaccines for seasonal influenza, established procedures for testing and regulatory control, and an extensive body of safety data.
In such cases, approval procedures are similar to those applied to “strain changes” made each year when seasonal vaccines are modified to match circulating viruses in the Northern and Southern Hemispheres.

Specific regulatory procedures have been devised to expedite the approval of pandemic vaccines. In the USA, for example, fewer data are required when the manufacturer already has a licensed influenza vaccine and intends to use the same manufacturing process for its pandemic vaccine.
In the European Union, the European Medicines Agency uses a rolling review procedure whereby manufacturers can submit sets of data for regulatory review as they become available, without having to wait until all data can be submitted together in a single formal application.
Also in Europe, some manufacturers have conducted advance studies using a so-called “mock-up” vaccine. Mock-up vaccines contain an active ingredient for an influenza virus that has not circulated recently in human populations and thus mimics the novelty of a pandemic virus. Such advance studies can greatly expedite regulatory approval.

Special safety concerns
Influenza vaccines have been used for more than 60 years and have an established record of safety in all age groups. While some serious adverse events have been reported, these have been rare.
Nonetheless, special safety issues will inevitably arise during a pandemic when vaccine is administered on a massive scale. For example, adverse events too rare to show up even in a large clinical trial may become apparent when very large numbers of people receive a pandemic vaccine.
Some adverse events will be coincidental – that is, associated in time with vaccine administration, yet not directly caused by the vaccine. Genuine adverse events directly caused by the vaccine may also occur, but cannot be predicted in advance. Given the safety record of seasonal vaccines, such events are expected to be rare.

Time constraints mean that clinical data at the time when pandemic vaccines are first administered will inevitably be limited. Further testing of safety and effectiveness will need to take place after administration of the vaccine has begun.
For these reasons, WHO advises all countries administering pandemic vaccines to conduct intensive monitoring for safety and efficacy, and many countries have plans in place for doing so. On the positive side, mass vaccination campaigns can generate significant safety data within a few weeks.
International sharing of data from such post-marketing surveillance will be vital in guiding risk-benefit assessments and determining whether changes in vaccination policies are needed. WHO has developed standardized protocols for data collection and reporting in real-time, and will communicate findings to the international community via its web site.
_________________________
[1] Regulatory preparedness for human pandemic influenza vaccines. Report of a WHO Expert Committee on Biological Standardization. Geneva: World Health Organization, 2007 [pdf 625kb]

Source: WHO Web Page

[Tsui Hart]

________________________________________

Pandemic influenza vaccine manufacturing process and timeline
Pandemic (H1N1) 2009 briefing note 7

6 AUGUST 2009 | GENEVA -- It takes approximately five to six months for the first supplies of approved vaccine to become available once a new strain of influenza virus with pandemic potential is identified and isolated. These months are needed because the process of producing a new vaccine involves many sequential steps, and each of these steps requires a certain amount of time to complete. The vaccine development process from start (obtaining a virus sample) to end (availability of vaccine for use) is summarized below.

Activities at WHO Collaborating Centers
1. Identification of a new virus: As part of a network set up for surveillance, laboratories around the world routinely collect samples of circulating influenza viruses and submit these to WHO Collaborating Centres for Reference and Research on Influenza for analysis. The first step towards the production of a pandemic vaccine starts when a Centre detects a novel influenza virus that differs significantly from circulating strains and reports this finding to WHO.

2. Preparation of the vaccine strain (called vaccine virus): The virus must first be adapted for use in manufacturing vaccine. To make the vaccine virus less dangerous and better able to grow in hen’s eggs (the production method used by most manufacturers), the virus is mixed with a standard laboratory virus strain and the two are allowed to grow together. After a while, a hybrid is formed which contains the inner components of the laboratory strain, and the outer components of the pandemic strain. It takes roughly three weeks to prepare the hybrid virus.

3. Verification of the vaccine strain: After its preparation, the hybrid virus needs to be tested to make sure that it truly produces the outer proteins of the pandemic strain, is safe and grows in eggs. Upon completion of this process, which takes roughly another three weeks, the vaccine strain is distributed to vaccine manufacturers.

4. Preparation of reagents to test the vaccine (with reference reagents): In parallel, WHO Collaborating Centres produce standardized substances (called reagents) that are given to all vaccine manufacturers to enable them to measure how much virus they are producing, and to ensure they are all packaging the correct dose of vaccine. This requires at least three months and often represents a bottleneck for manufacturers.


Activities at vaccine manufacturers
1. Optimization of virus growth conditions: The vaccine manufacturer takes the hybrid vaccine virus that it has received from the WHO laboratories, and tests different growth conditions in eggs to find the best conditions. This process requires roughly three weeks.

2. Vaccine bulk manufacture: For most influenza vaccine production, this is performed in nine to twelve-days old fertilized hen's eggs. The vaccine virus is injected into thousands of eggs, and the eggs are then incubated for two to three days during which time the virus multiplies. The egg white, which now contains many millions of vaccine viruses, is then harvested, and the virus is separated from the egg white. The partially pure virus is killed with chemicals. The outer proteins of the virus are then purified and the result is several hundred or thousand liters of purified virus protein that is referred to as antigen, the active ingredient in the vaccine. Producing each batch, or lot, of antigen takes approximately two weeks, and a new batch can be started every few days. The size of the batch depends on how many eggs a manufacturer can obtain, inoculate and incubate. Another factor is the yield per egg. When one batch has been produced, the process is repeated as often as needed to generate the required amount of vaccine.

3. Quality control: This can only begin once the reagents for testing the vaccine are supplied by WHO laboratories, as described above. Each batch is tested and the sterility of bulk antigen is verified. This process takes two weeks.

4. Vaccine filling and release: The batch of vaccine is diluted to give the desired concentration of antigen, and put into vials or syringes, and labeled. A number of these are then tested:
• for sterility
• to confirm the protein concentration and
• for safety by testing in animals.
This process takes two weeks.

5. Clinical studies: In certain countries, each new influenza vaccine has to be tested in a few people to show that it performs as expected. This requires at least four weeks. In some countries this may not be required as many clinical trials were done with similar annual vaccine preparation, and the assumption is that the new pandemic vaccine will behave similarly.

Activities at regulatory agencies - regulatory approval
Before the vaccine can be sold or administered to people, regulatory approval is required. Each country has its own regulatory agency and rules. If the vaccine is made with the same processes as the seasonal influenza vaccine, and in the same manufacturing plant, this can be very rapid (one to two days). Regulatory agencies in some countries may require clinical testing before approving the vaccine, which adds to the time before the vaccine is available.
The full process, in a best case scenario, can be completed in five to six months. Then the first final pandemic vaccine lot would be available for distribution and use.
Key: The arrows with dotted lines preceded by non-broken arrows indicate the time period required for the first time an activity is done (non-broken arrow line) that is then repeated (dotted arrow line). The solid lines signify that the activity takes place within a finite period.

[Tsui Hart]

Recommended use of antivirals
Pandemic (H1N1) 2009 briefing note 8



21 AUGUST 2009 | GENEVA -- WHO is today issuing guidelines for the use of antivirals in the management of patients infected with the H1N1 pandemic virus.

The guidelines represent the consensus reached by an international panel of experts who reviewed all available studies on the safety and effectiveness of these drugs. Emphasis was placed on the use of oseltamivir and zanamivir to prevent severe illness and deaths, reduce the need for hospitalization, and reduce the duration of hospital stays.

The pandemic virus is currently susceptible to both of these drugs (known as neuraminidase inhibitors), but resistant to a second class of antivirals (the M2 inhibitors).

Worldwide, most patients infected with the pandemic virus continue to experience typical influenza symptoms and fully recover within a week, even without any form of medical treatment. Healthy patients with uncomplicated illness need not be treated with antivirals.

On an individual patient basis, initial treatment decisions should be based on clinical assessment and knowledge about the presence of the virus in the community.

In areas where the virus is circulating widely in the community, clinicians seeing patients with influenza-like illness should assume that the pandemic virus is the cause. Treatment decisions should not wait for laboratory confirmation of H1N1 infection.

This recommendation is supported by reports, from all outbreak sites, that the H1N1 virus rapidly becomes the dominant strain.


Treat serious cases immediately

Evidence reviewed by the panel indicates that oseltamivir, when properly prescribed, can significantly reduce the risk of pneumonia (a leading cause of death for both pandemic and seasonal influenza) and the need for hospitalization.

For patients who initially present with severe illness or whose condition begins to deteriorate, WHO recommends treatment with oseltamivir as soon as possible. Studies show that early treatment, preferably within 48 hours after symptom onset, is strongly associated with better clinical outcome. For patients with severe or deteriorating illness, treatment should be provided even if started later. Where oseltamivir is unavailable or cannot be used for any reason, zanamivir may be given.

This recommendation applies to all patient groups, including pregnant women, and all age groups, including young children and infants.

For patients with underlying medical conditions that increase the risk of more severe disease, WHO recommends treatment with either oseltamivir or zanamivir. These patients should also receive treatment as soon as possible after symptom onset, without waiting for the results of laboratory tests.

As pregnant women are included among groups at increased risk, WHO recommends that pregnant women receive antiviral treatment as soon as possible after symptom onset.

At the same time, the presence of underlying medical conditions will not reliably predict all or even most cases of severe illness. Worldwide, around 40% of severe cases are now occurring in previously healthy children and adults, usually under the age of 50 years.

Some of these patients experience a sudden and very rapid deterioration in their clinical condition, usually on day 5 or 6 following the onset of symptoms.

Clinical deterioration is characterized by primary viral pneumonia, which destroys the lung tissue and does not respond to antibiotics, and the failure of multiple organs, including the heart, kidneys, and liver. These patients require management in intensive care units using therapies in addition to antivirals.

Clinicians, patients, and those providing home-based care need to be alert to warning signals that indicate progression to a more severe form of illness, and take urgent action, which should include treatment with oseltamivir.

In cases of severe or deteriorating illness, clinicians may consider using higher doses of oseltamivir, and for a longer duration, than is normally prescribed.


Antiviral use in children

Following the recent publication of two clinical reviews, [1,2] some questions have been raised about the advisability of administering antivirals to children.

The two clinical reviews used data that were considered by WHO and its expert panel when developing the current guidelines and are fully reflected in the recommendations.

WHO recommends prompt antiviral treatment for children with severe or deteriorating illness, and those at risk of more severe or complicated illness. This recommendation includes all children under the age of five years, as this age group is at increased risk of more severe illness.

Otherwise healthy children, older than 5 years, need not be given antiviral treatment unless their illness persists or worsens.


Danger signs in all patients

Clinicians, patients, and those providing home-based care need to be alert to danger signs that can signal progression to more severe disease. As progression can be very rapid, medical attention should be sought when any of the following danger signs appear in a person with confirmed or suspected H1N1 infection:


shortness of breath, either during physical activity or while resting
difficulty in breathing
turning blue
bloody or coloured sputum
chest pain
altered mental status
high fever that persists beyond 3 days
low blood pressure.

In children, danger signs include fast or difficult breathing, lack of alertness, difficulty in waking up, and little or no desire to play.

________________________________

[1] Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: systematic review and meta-analysis of randomised controlled trials. Shun-Shin M, Thompson M, Heneghan C et al. BMJ 2009;339:b3172; doi:10.1136/bmj.b3172
[2] Prescription of anti-influenza drugs for healthy adults: a systemic review and meta-analysis. Burch J, Stock C et al. Lancet Infect Dis 2009; doi:10.1016/S1473-3099(09)70199-9

Source: WHO web Page

[Tsui Hart]

Preparing for the second wave: lessons from current outbreaks
Pandemic (H1N1) 2009 briefing note 9



28 AUGUST 2009 | GENEVA -- Monitoring of outbreaks from different parts of the world provides sufficient information to make some tentative conclusions about how the influenza pandemic might evolve in the coming months.

WHO is advising countries in the northern hemisphere to prepare for a second wave of pandemic spread. Countries with tropical climates, where the pandemic virus arrived later than elsewhere, also need to prepare for an increasing number of cases.

Countries in temperate parts of the southern hemisphere should remain vigilant. As experience has shown, localized “hot spots” of increasing transmission can continue to occur even when the pandemic has peaked at the national level.


H1N1 now the dominant virus strain

Evidence from multiple outbreak sites demonstrates that the H1N1 pandemic virus has rapidly established itself and is now the dominant influenza strain in most parts of the world. The pandemic will persist in the coming months as the virus continues to move through susceptible populations.

Close monitoring of viruses by a WHO network of laboratories shows that viruses from all outbreaks remain virtually identical. Studies have detected no signs that the virus has mutated to a more virulent or lethal form.

Likewise, the clinical picture of pandemic influenza is largely consistent across all countries. The overwhelming majority of patients continue to experience mild illness. Although the virus can cause very severe and fatal illness, also in young and healthy people, the number of such cases remains small.


Large populations susceptible to infection

While these trends are encouraging, large numbers of people in all countries remain susceptible to infection. Even if the current pattern of usually mild illness continues, the impact of the pandemic during the second wave could worsen as larger numbers of people become infected.

Larger numbers of severely ill patients requiring intensive care are likely to be the most urgent burden on health services, creating pressures that could overwhelm intensive care units and possibly disrupt the provision of care for other diseases.


Monitoring for drug resistance

At present, only a handful of pandemic viruses resistant to oseltamivir have been detected worldwide, despite the administration of many millions of treatment courses of antiviral drugs. All of these cases have been extensively investigated, and no instances of onward transmission of drug-resistant virus have been documented to date. Intense monitoring continues, also through the WHO network of laboratories.


Not the same as seasonal influenza

Current evidence points to some important differences between patterns of illness reported during the pandemic and those seen during seasonal epidemics of influenza.

The age groups affected by the pandemic are generally younger. This is true for those most frequently infected, and especially so for those experiencing severe or fatal illness.

To date, most severe cases and deaths have occurred in adults under the age of 50 years, with deaths in the elderly comparatively rare. This age distribution is in stark contrast with seasonal influenza, where around 90% of severe and fatal cases occur in people 65 years of age or older.


Severe respiratory failure

Perhaps most significantly, clinicians from around the world are reporting a very severe form of disease, also in young and otherwise healthy people, which is rarely seen during seasonal influenza infections. In these patients, the virus directly infects the lung, causing severe respiratory failure. Saving these lives depends on highly specialized and demanding care in intensive care units, usually with long and costly stays.

During the winter season in the southern hemisphere, several countries have viewed the need for intensive care as the greatest burden on health services. Some cities in these countries report that nearly 15 percent of hospitalized cases have required intensive care.

Preparedness measures need to anticipate this increased demand on intensive care units, which could be overwhelmed by a sudden surge in the number of severe cases.


Vulnerable groups

An increased risk during pregnancy is now consistently well-documented across countries. This risk takes on added significance for a virus, like this one, that preferentially infects younger people.

Data continue to show that certain medical conditions increase the risk of severe and fatal illness. These include respiratory disease, notably asthma, cardiovascular disease, diabetes and immunosuppression.

When anticipating the impact of the pandemic as more people become infected, health officials need to be aware that many of these predisposing conditions have become much more widespread in recent decades, thus increasing the pool of vulnerable people.

Obesity, which is frequently present in severe and fatal cases, is now a global epidemic. WHO estimates that, worldwide, more than 230 million people suffer from asthma, and more than 220 million people have diabetes.

Moreover, conditions such as asthma and diabetes are not usually considered killer diseases, especially in children and young adults. Young deaths from such conditions, precipitated by infection with the H1N1 virus, can be another dimension of the pandemic’s impact.


Higher risk of hospitalization and death

Several early studies show a higher risk of hospitalization and death among certain subgroups, including minority groups and indigenous populations. In some studies, the risk in these groups is four to five times higher than in the general population.

Although the reasons are not fully understood, possible explanations include lower standards of living and poor overall health status, including a high prevalence of conditions such as asthma, diabetes and hypertension.


Implications for the developing world

Such findings are likely to have growing relevance as the pandemic gains ground in the developing world, where many millions of people live under deprived conditions and have multiple health problems, with little access to basic health care.

As much current data about the pandemic come from wealthy and middle-income countries, the situation in developing countries will need to be very closely watched. The same virus that causes manageable disruption in affluent countries could have a devastating impact in many parts of the developing world.


Co-infection with HIV

The 2009 influenza pandemic is the first to occur since the emergence of HIV/AIDS. Early data from two countries suggest that people co-infected with H1N1 and HIV are not at increased risk of severe or fatal illness, provided these patients are receiving antiretroviral therapy. In most of these patients, illness caused by H1N1 has been mild, with full recovery.

If these preliminary findings are confirmed, this will be reassuring news for countries where infection with HIV is prevalent and treatment coverage with antiretroviral drugs is good.

On current estimates, around 33 million people are living with HIV/AIDS worldwide. Of these, WHO estimates that around 4 million were receiving antiretroviral therapy at the end of 2008.


Source: WHO Web page

[Tsui Hart]

Measures in school settings
Pandemic (H1N1) 2009 briefing note 10



GENEVA -- WHO is today issuing advice on measures that can be undertaken in schools to reduce the impact of the H1N1 influenza pandemic. Recommendations draw on recent experiences in several countries as well as studies of the health, economic, and social consequences of school closures. These studies were undertaken by members of a WHO informal network for mathematical modelling of the pandemic.

Experience to date has demonstrated the role of schools in amplifying transmission of the pandemic virus, both within schools and into the wider community. While outbreaks in schools are clearly an important dimension of the current pandemic, no single measure can stop or limit transmission in schools, which provide multiple opportunities for spread of the virus.

WHO recommends the use of a range of measures that can be adapted to the local epidemiological situation, available resources, and the social role played by many schools. National and local authorities are in the best position to make decisions about these measures and how they should be adapted and implemented.

WHO continues to recommend that students, teachers, and other staff who feel unwell should stay home. Plans should be in place, and space made available, to isolate students and staff who become ill while at school.

Schools should promote hand hygiene and respiratory etiquette and be stocked with appropriate supplies. Proper cleaning and ventilation and measures to reduce crowding are also advised.


School closures and class suspensions

Decisions about if and when schools should be closed during the pandemic are complex and highly context-specific. WHO cannot provide specific recommendations for or against school closure that are applicable to all settings. However, some general guidance comes from recent experience in several countries in both the northern and southern hemispheres, mathematical modelling, and experience during seasonal epidemics of influenza.

School closure can operate as a proactive measure, aimed at reducing transmission in the school and spread into the wider community. School closure can also be a reactive measure, when schools close or classes are suspended because high levels of absenteeism among students and staff make it impractical to continue classes.

The main health benefit of proactive school closure comes from slowing down the spread of an outbreak within a given area and thus flattening the peak of infections. This benefit becomes especially important when the number of people requiring medical care at the peak of the pandemic threatens to saturate or overwhelm health care capacity. By slowing the speed of spread, school closure can also buy some time as countries intensify preparedness measures or build up supplies of vaccines, antiviral drugs, and other interventions.

The timing of school closure is critically important. Modelling studies suggest that school closure has its greatest benefits when schools are closed very early in an outbreak, ideally before 1% of the population falls ill. Under ideal conditions, school closure can reduce the demand for health care by an estimated 30–50% at the peak of the pandemic. However, if schools close too late in the course of a community-wide outbreak, the resulting reduction in transmission is likely to be very limited.

Policies for school closure need to include measures that limit contact among students when not in school. If students congregate in a setting other than a school, they will continue to spread the virus, and the benefits of school closure will be greatly reduced, if not negated.


Economic and social costs
When making decisions, health officials and school authorities need to be aware of economic and social costs that can be disproportionately high when viewed against these potential benefits.

The main economic cost arises from absenteeism of working parents or guardians who have to stay home to take care of their children. Studies estimate that school closures can lead to the absence of 16% of the workforce, in addition to normal levels of absenteeism and absenteeism due to illness. Such estimates will, however, vary considerably across countries depending on several factors, including the structure of the workforce.

Paradoxically, while school closure can reduce the peak demand on health care systems, it can also disrupt the provision of essential health care, as many doctors and nurses are parents of school-age children.

Decisions also need to consider social welfare issues. Children’s health and well-being can be compromised if highly beneficial school-based social programmes, such as the provision of meals, are interrupted or if young children are left at home without supervision.

Source: WHO Web Page

[Tsui Hart]

Pandemic influenza vaccines: current status
Pandemic (H1N1) 2009 briefing note 11


24 SEPTEMBER 2009 | GENEVA -- Regulatory authorities have licensed pandemic vaccines in Australia, China and the United States of America, soon to be followed by Japan and several countries in Europe. The length of the approval process depends on factors such as each country's regulatory pathway, the type of vaccine being licensed, and the stage of manufacturers' readiness to submit appropriate information to regulatory authorities.


Production capacity

In May 2009, WHO estimated that, in a best case scenario, worldwide production capacity for pandemic vaccines would be approximately 5 billion doses per year. Since then, better information on production yield and appropriate vaccine formulation has become available.

WHO currently estimates worldwide production capacity for pandemic vaccines at approximately 3 billion doses per year. While this figure is lower than previously projected, early data from clinical trials suggest that a single dose of vaccine will be sufficient to confer protective immunity in healthy adults and older children, effectively doubling the number of people who can be protected with current supplies.

These supplies will still be inadequate to cover a world population of 6.8 billion people in which virtually everyone is susceptible to infection by a new and readily contagious virus. Global manufacturing capacity for influenza vaccines is limited, inadequate and not readily augmented.

Pandemic vaccines have their greatest impact as a preventive strategy when administered before or near the peak incidence of cases in an outbreak. Both regulatory authorities and vaccine manufacturers have made extraordinary efforts to expedite the availability of vaccines.

Many affluent countries have previously contracted with manufacturers to obtain sufficient vaccine supplies to cover their entire populations. However, most low- and middle-income countries lack the financial resources to compete for an early share of limited supplies. Vaccine supplies in these countries will largely depend on donations from manufacturers and other countries.


Availability in developing countries

Last week, donations of pandemic vaccines for use in developing countries were announced by the United States of America, in concert with Australia, Brazil, France, Italy, New Zealand, Norway, Switzerland and the United Kingdom. Similar support from additional countries is anticipated and warmly welcomed.

WHO will be coordinating the distribution of these donated vaccines. Earlier this year, WHO conducted surveys with its regional and country offices to identify countries that will not have pandemic vaccines unless supplies are donated.

Teams with expertise in field operations, vaccines, and the logistics of their distribution are now working in the JW Lee Centre for Strategic Health Operations (the SHOC room). Initially, they will be distributing an estimated 300 million doses of vaccine to more than 90 countries.

Distribution of the first batches of donated vaccines is expected to begin in November. WHO continues to recommend that health workers be given high priority for early vaccination.


Vaccine safety

National regulatory authorities for medicines carefully examine the known and suspected risks and benefits of any vaccine prior to its licensing. Because the pandemic virus is new, both non-clinical and clinical trials are being conducted to gain essential information on immune response and safety. Outcomes of trials completed to date suggest that pandemic vaccines are as safe as seasonal influenza vaccines.

Side effects are expected to be similar to those observed with seasonal influenza vaccines. Common side effects include local reactions at the injection site (soreness, swelling, redness) and possibly some systemic reactions (fever, headache, muscle or joint aches). In almost all vaccine recipients, these symptoms are mild, self-limited and last 1-2 days.

However, even very large clinical trials will not be able to identify possible rare events that can occur when pandemic vaccines are administered to many millions of people.

WHO advises all countries administering pandemic vaccines to conduct intensive monitoring for safety and to report adverse events. Many countries already have systems for monitoring vaccine safety in place.

International sharing of data from such post-marketing surveillance will be vital in guiding risk-benefit assessments and determining whether changes in vaccination policies are needed. WHO has developed standardized protocols for data collection and reporting in real-time, and will communicate findings to the international community via its web site.


Source : WHO Web Page

[Tsui Hart]

Antiviral use and the risk of drug resistance
Pandemic (H1N1) 2009 briefing note 12


25 SEPTEMBER 2009 | GENEVA -- Growing international experience in the treatment of pandemic H1N1 virus infections underscores the importance of early treatment with the antiviral drugs, oseltamivir or zanamivir. Early treatment is especially important for patients who are at increased risk of developing complications, those who present with severe illness or those with worsening signs and symptoms.[1]

The experience of clinicians, including those who have treated severe cases of pandemic influenza, and national authorities suggests that prompt administration of these drugs following symptom onset reduces the risk of complications and can also improve clinical outcome in patients with severe disease.

This experience further underscores the need to protect the effectiveness of these drugs by minimizing the occurrence and impact of drug resistance.


High-risk situations for development of drug resistance

WHO encourages clinicians to be alert to two situations that carry a high risk for the emergence of viruses resistant to oseltamivir.

The risk of resistance is considered higher in patients with severely compromised or suppressed immune systems who have prolonged illness, have received oseltamivir treatment (especially for an extended duration), but still have evidence of persistent viral replication.

The risk of resistance is also considered higher in people who receive oseltamivir for so-called “post-exposure prophylaxis” following exposure to another person with influenza, and who then develop illness despite taking oseltamivir.

In both of these clinical situations, health care staff should respond with a high level of suspicion that oseltamivir resistance has developed. Laboratory investigation should be undertaken to determine whether resistant virus is present and appropriate infection control measures should be implemented or re-enforced to prevent spread of the resistant virus.

When a drug-resistant virus is detected, WHO further recommends that an epidemiological investigation be undertaken to determine whether onward transmission of the resistant virus has occurred. In addition, community surveillance for oseltamivir-resistant pandemic H1N1 virus strains should be enhanced.

In general, WHO does not recommend the use of antiviral drugs for prophylactic purposes. For people who have had exposure to an infected person and are at a higher risk of developing severe or complicated illness, an alternative option is close monitoring for symptoms, followed by prompt early antiviral treatment should symptoms develop.

WHO has also recommended against the use of a particular antiviral where the virus is known or highly likely to be resistant to it. For this reason, zanamivir is the treatment of choice for patients who become ill while on oseltamivir prophylaxis.


Oseltamivir-resistant viruses

Systematic surveillance conducted by the Global Influenza Surveillance Network, supported by WHO Collaborating Centres and other laboratories, continues to detect sporadic incidents of H1N1 pandemic viruses that show resistance to oseltamivir. To date, 28 resistant viruses have been detected and characterized worldwide.[2]

All of these viruses show the same H275Y mutation that confers resistance to the antiviral oseltamivir, but not to the antiviral zanamivir. Zanamivir remains a treatment option in symptomatic patients with severe or deteriorating illness due to oseltamivir-resistant virus.

Twelve of these drug-resistant viruses were associated with the use of oseltamivir for post-exposure prophylaxis. Six were associated with the use of oseltamivir treatment in patients with severe immunosuppression. Four were isolated from samples from patients receiving oseltamivir treatment.

A further two were isolated from patients who were not taking oseltamivir for either treatment or prophylaxis. Characterization of the remaining viruses is under way.

These numbers are comparatively small at present. Worldwide, more than 10,000 clinical specimens (samples and isolates) of the pandemic H1N1 virus have been tested and found to be sensitive to oseltamivir.


Current conclusions

These data support several conclusions. Cases of oseltamivir-resistant viruses continue to be sporadic and infrequent, with no evidence that oseltamivir-resistant pandemic H1N1 viruses are circulating within communities or worldwide.

To date, person-to-person transmission of these oseltamivir resistant viruses has not been conclusively demonstrated. In some situations, however, local transmission may have occurred, but without any further onward or ongoing transmission.

Except for immunocompromised patients, those infected with an oseltamivir-resistant pandemic H1N1 virus have experienced typical uncomplicated influenza symptoms. No evidence suggests that oseltamivir-resistant viruses are causing a different or more severe form of illness.

The occurrence of oseltamivir-resistant viruses is expected and is consistent with observations from early clinical trials. As use of antiviral drugs continues to grow, further reports of drug-resistance viruses are certain to occur. WHO and its network of collaborating laboratories are closely monitoring the situation and will issue information and advice on a regular basis as indicated.

_______________________

[1] Briefing Note on recommendations for use of antivirals
[2] Weekly updates on cases of oseltamivir resistant pandemic H1N1 virus

Source; WHO Web Page