Situation updates - Avian influenza

1 July 2009
Avian influenza - situation in Egypt - update 20

2 June 2009
Avian influenza - situation in Egypt - update 19

1 June 2009
Avian influenza - situation in Egypt - update 18

28 May 2009
Avian influenza - situation in Egypt - update 17

22 May 2009
Avian influenza - situation in Egypt - update 16

15 May 2009
Avian influenza - situation in Egypt - update 15

6 May 2009
Avian influenza – situation in Viet Nam - update 6

6 May 2009
Avian influenza - situation in Egypt - update 14

23 April 2009

Oseltamivir is indicated for the treatment and prevention of infections due to influenza A and B virus in people at least one year of age. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days, beginning within 2 days of the appearance of symptoms and with decreased doses for children and patients with renal impairment. Oseltamivir may be given as a preventive measure either during a community outbreak or following close contact with an infected individual. Standard prophylactic dosage is 75 mg once daily for patients aged 13 and older, which has been shown to be safe and effective for up to six weeks. The importance of early treatment is that the NA protein inhibition is more effective within the first 48 hours. If the virus has replicated and infected many cells the effectiveness of this medication will be severely diminished, especially over time.^[4][5]

The standard recommended dose incompletely suppresses viral replication in at least some patients with H5N1 avian influenza, increasing the risk of viral resistance and rendering therapy less effective.^[6] Accordingly, it has been suggested that higher doses and longer durations of therapy should be used for treatment of patients with the H5N1 virus.^[6][7]

Clinical trials for an increased dosage were set to begin by May 2007. All avian influenza cases in Indonesia, Thailand, and Vietnam will be inducted into the trial. The trial will also include 100 cases of severe seasonal influenza from each of those countries, plus the United States. Half of cases will receive the current standard dosage, and half will receive a double dosage, but for the standard length of time.^[8][9]

Chokephaibulkit et al. recommend the use of oseltamivir for children with avian influenza, based on experience with one patient

 Adverse effects

Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1% of clinical trial participants) include: nausea, vomiting, diarrhea, abdominal pain, and headache. Rare ADRs include: hepatitis and elevated liver enzymes, rash, allergic reactions including anaphylaxis, and Stevens-Johnson syndrome.^[4][5]

Various other ADRs have been reported in postmarketing surveillance including: toxic epidermal necrolysis, cardiac arrhythmia, seizure, confusion, aggravation of diabetes, and haemorrhagic colitis.^[4]

There are concerns that oseltamivir may cause dangerous psychological, neuropsychiatric side effects including self harm in some users. These dangerous side effects occur more commonly in children than in adults.^[13] This stems from cases in Japan, where the drug is most heavily prescribed, consuming 60% of the world's production^[14]. Concern has focused on teenagers, but problems have also been reported in children and adults. ^[15]

In March 2007, Japan's Health Ministry warned that oseltamivir should not be given to those aged 10 to 19.^[16] The Ministry had previously decided, in May 2004, to change the literature accompanying oseltamivir to include neurological and psychological disorders as possible adverse effects, including: impaired consciousness, abnormal behavior, and hallucinations.^[14]

According to Japan's Health Ministry, between 2004 and March 2007, fifteen people aged 10 to 19 have been injured or killed by jumps or fallen from buildings after taking oseltamivir, and one 17-year-old died after he jumped in front of a truck.^[17][18][19] A renewed investigation of the Japanese data was completed in April 2007. It found that 128 patients had been reported to behave abnormally after taking oseltamivir since 2001. Forty-three of them were under 10 years old, 57 patients were aged 10 to 19, and 28 patients were aged 20 or over. Eight people, including five teens and three adults, had died from these actions.^[20][21][22]

In October 2006, Shumpei Yokota, a professor of pediatrics at Yokahama City University, released the results of research involving around 2,800 children which found no difference in the behavior between those who took oseltamivir and those who did not. A media source notes that Chugai Pharmaceutical Co. (which produces Tamiflu in Japan) gave Yokota's department 10 million yen (about US$105,000) over five years.^[23][24]

To determine whether to lift the 2007 ban, a research team from the Japanese Health, Labour and Welfare Ministry studied 10,000 children under the age of 18 who had been diagnosed with influenza since 2006. The study was finalised in April 2009. Taking into account all degrees of abnormal behaviour, including minor behavioural problems such as incoherent speech, the study found that children who took Tamiflu were 54 per cent more likely to exhibit abnormal behaviour than those who did not take the drug. When the team limited its analysis to children who had displayed serious abnormal behaviour that led to injury or death, it found those who had taken Tamiflu were 25 per cent more likely to behave unusually.^[25]

In November 2006, the United States Food and Drug Administration (FDA) amended the warning label to include the possible side effects of delirium, hallucinations, or other related behavior.^[26] This went further than the FDA's previous pronouncement, from a year before, that there was insufficient evidence to claim a causal link between oseltamivir use and the deaths of 12 Japanese children (only two were from neurological problems, although more have died since then).^[27] The change to a more cautionary stance was attributed to 103 new reports that the FDA received of delirium, hallucinations and other unusual psychiatric behavior, mostly involving Japanese patients, received between August 29, 2005 and July 6, 2006. This was an increase from the 126 similar cases logged between the drug's approval in 1999 and August 2005.^[28]

Roche points out that Tamiflu has been used to treat 50 million people since 1999, and states that influenza may itself cause psychological problems.^[29][30]

In March 2007, the European Medicines Agency said that the benefits of oseltamivir outweighed the costs, but that it would closely monitor reports from Japan.^[31]

In April 2007, South Korea issued a safety warning against prescribing Tamiflu to teenagers except in special cases.^[32]

 Mode of action

Oseltamivir is a neuraminidase inhibitor, serving as a competitive inhibitor towards sialic acid, found on the surface proteins of normal host cells. By blocking the activity of the neuraminidase, Oseltamivir prevents new viral particles from being released by infected cells.^[4]

Resistance

As with other antivirals, resistance to the agent was expected with widespread use of oseltamivir, though the emergence of resistant viruses was expected to be less frequent than with amantadine or rimantadine. The resistance rate reported during clinical trials up to July 2004 was 0.33% in adults, 4.0% in children, and 1.26% overall. Mutations conferring resistance are single amino acid residue substitutions in the neuraminidase enzyme.^[7]

Mutant H3N2 influenza A virus isolates resistant to oseltamivir were found in 18% of a group of 50 Japanese children treated with oseltamivir.^[33] This rate was similar to another study where resistant isolates of H1N1 influenza virus were found in 16.3% of another cohort of Japanese children.^[7] Several explanations were proposed by the authors of the studies for the higher-than-expected resistance rate detected. First, children typically have a longer infection period, giving a longer time for resistance to develop. Second, Kiso et al. claim to have used more rigorous detection techniques than previous studies.^[33]

High-level resistance has been detected in one girl suffering from H5N1 avian influenza in Vietnam. She was being treated with oseltamivir at time of detection.^[34][35]

de Jong et al. (2005) describe resistance development in two more Vietnamese patients suffering from H5N1, and compare their cases with six others. They suggest that the emergence of a resistant strain may be associated with a patient's clinical deterioration. They also note that the recommended dosage of oseltamivir does not always completely suppress viral replication, a situation that could favor the emergence of resistant strains. Moscona (2005) gives a good overview of the resistance issue, and says that personal stockpiles of Tamiflu could lead to under-dosage and thus the emergence of resistant strains of H5N1.^[36]

Resistance is of concern in the scenario of an influenza pandemic (Wong and Yuen 2005), and may be more likely to develop in avian influenza than seasonal influenza due to the potentially longer duration of infection by novel viruses. Kiso et al. suggest that "a higher prevalence of resistant viruses should be expected" during a pandemic.^[33]

The genetic sequence for the neuraminidase enzyme is highly conserved across virus strains. This means that there are relatively few variations, and there is also evidence that variations that do occur tend to be less "fit." Thus, mutations that convey resistance to oseltamivir may also tend to cripple the virus by giving it an otherwise less-functional enzyme. The lack of variation in neuraminidase gives two advantages to oseltamivir and zanamivir, the drugs that target that enzyme. First, these drugs work on a broader spectrum of influenza strains. Second, the development of a robust, resistant virus strain appears to be less likely.^[7] It is worth noting that the oseltamivir-resistant strains detected by Kiso et al. all appeared within individual children after treatment with oseltamivir – the children did not catch the resistant strains in human-to-human or bird-to-human transmission.^[33]

In 2007, Japanese investigators detected neuraminidase-resistant Influenza B virus strains in individuals who had not been treated with these drugs. The prevalence was 1.7%.^[37] In 2008, the World Health Organization announced that preliminary results from experiments with Canadian Influenza A virus subtype H1N1 showed that 8 out of 81 samples were resistant to oseltamivir.^[38] Tamiflu-resistant strains have also appeared in the EU, which remain sensitive to zanamivir.^[39][40]

According to the CDC, Tamiflu may not be able to treat Flu type A, the most common influenza virus in 2008. Doctors are being warned to watch out for it so they can attempt to use other treatments if Tamiflu doesn't work.^[41]

Pandemic fears

Oseltamivir was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. In response to the epidemic, various governments – including those of the United Kingdom, Canada, Israel, United States and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic. Although large, the quantities stockpiled would not have been sufficient to protect the entire population of these countries.^{[citation needed]}

In late October 2005, Roche announced that it was suspending shipments to pharmacies in the United States and Canada until the North American seasonal flu outbreak began, to address concerns about private stockpiling and to preserve supplies for seasonal influenza. It said that, when distribution resumes in Canada, the remaining available drug will be saved for use in high-risk settings like long-term care facilities and hospitals.^[42][43][44] Sales were suspended in Hong Kong as well, and on November 8, 2005, also in China. Roche said it would instead send all supplies to China's health ministry.^[45]

On November 9, 2005, Vietnam became the first country to be granted permission by Roche to produce a generic version of oseltamivir.^[46] The week before, Thai authorities said they would begin producing generic oseltamivir, claiming that Roche had not patented Tamiflu in Thailand.^[47] The first Thai generic oseltamivir was produced in February 2006 and was to have been available to the public in July 2006.^[48]

In December 2005, Roche also signed a sublicense for complete oseltamivir production with China's Shanghai Pharmaceuticals, and by March 2006 a sublicense had also been granted to India's Hetero.^[49][50] In June 2006, the Chinese government gave Shanghai Pharmaceuticals permission to proceed, based upon tests of the domestic production. The company said it planned to market the drug by the end of the month.^[51][52]

In late May 2006, the World Health Organization asked Roche to be ready to ship an emergency stockpile of oseltamivir to Indonesia if needed. The alert was in response to suspected human-to-human transmission within a family and was planned to last for two weeks.^[53][54]

In December 2008, the Indian drug company, Cipla won its case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the World Health Organization certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the World Health Organization list of prequalified medicinal products.^[55]

On April 24, 2009, with three cases of swine flu identified in Texas, Governor Rick Perry requested 37,430 doses of Tamiflu from the Centers for Disease Control and Prevention.^[56][57]

[edit] U.S. Government policy and oseltamivir

In November 2005, U.S. President George W. Bush requested that Congress fund US$7.1 billion in emergency spending for flu pandemic preparedness (the Senate had already passed an US$8.1 billion bill).^[58] Bush's plan included US$1.4 billion for government purchases of antiviral drugs.^[59]

A future influenza pandemic may unfold in a similar manner, say the NIAID authors, whose paper in the Oct. 1 issue of The Journal of Infectious Diseases is now available online. Therefore, the authors conclude, comprehensive pandemic preparations should include not only efforts to produce new or improved influenza vaccines and antiviral drugs but also provisions to stockpile antibiotics and bacterial vaccines as well.

The work presents complementary lines of evidence from the fields of pathology and history of medicine to support this conclusion. "The weight of evidence we examined from both historical and modern analyses of the 1918 influenza pandemic favors a scenario in which viral damage followed by bacterial pneumonia led to the vast majority of deaths,” says co-author NIAID Director Anthony S. Fauci, M.D. "In essence, the virus landed the first blow while bacteria delivered the knockout punch.”

NIAID co-author and pathologist Jeffery Taubenberger, M.D., Ph.D., examined lung tissue samples from 58 soldiers who died of influenza at various U. S. military bases in 1918 and 1919. The samples, preserved in paraffin blocks, were re-cut and stained to allow microscopic evaluation. Examination revealed a spectrum of tissue damage "ranging from changes characteristic of the primary viral pneumonia and evidence of tissue repair to evidence of severe, acute, secondary bacterial pneumonia,” says Dr. Taubenberger. In most cases, he adds, the predominant disease at the time of death appeared to have been bacterial pneumonia. There also was evidence that the virus destroyed the cells lining the bronchial tubes, including cells with protective hair-like projections, or cilia. This loss made other kinds of cells throughout the entire respiratory tract — including cells deep in the lungs — vulnerable to attack by bacteria that migrated down the newly created pathway from the nose and throat.

In a quest to obtain all scientific publications reporting on the pathology and bacteriology of the 1918-1919 influenza pandemic, Dr. Taubenberger and NIAID co-author David Morens, M.D., searched bibliography sources for papers in any language. They also reviewed scientific and medical journals published in English, French and German, and located all papers reporting on autopsies conducted on influenza victims. From a pool of more than 2,000 publications that appeared between 1919 and 1929, the researchers identified 118 key autopsy series reports. In total, the autopsy series they reviewed represented 8,398 individual autopsies conducted in 15 countries.

The published reports "clearly and consistently implicated secondary bacterial pneumonia caused by common upper respiratory flora in most influenza fatalities,” says Dr. Morens. Pathologists of the time, he adds, were nearly unanimous in the conviction that deaths were not caused directly by the then-unidentified influenza virus, but rather resulted from severe secondary pneumonia caused by various bacteria. Absent the secondary bacterial infections, many patients might have survived, experts at the time believed. Indeed, the availability of antibiotics during the other influenza pandemics of the 20th century, specifically those of 1957 and 1968, was probably a key factor in the lower number of worldwide deaths during those outbreaks, notes Dr. Morens.

The cause and timing of the next influenza pandemic cannot be predicted with certainty, the authors acknowledge, nor can the virulence of the pandemic influenza virus strain. However, it is possible that — as in 1918 — a similar pattern of viral damage followed by bacterial invasion could unfold, say the authors. Preparations for diagnosing, treating and preventing bacterial pneumonia should be among highest priorities in influenza pandemic planning, they write. "We are encouraged by the fact that pandemic planners are already considering and implementing some of these actions,” says Dr. Fauci.