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As of the 3rd of July 2009, a total of 89921 confirmed cases of human infection with novel swine-origin influenza A (H1N1) virus, (S-OIV), had been documented worldwide with 382 deaths since its outbreak in April 2009. It is generally known that in influenza A viruses, two surface glycoproteins, hemagglutinin and neuraminidase in the coat of the virus are responsible for the ability of the virus to infect cells and once the virus has replicated, it will break out and spread to other cells. The proteins also define the particular strain of influenza, thus the variation of these molecules over time allows the evasion of virus from the human immune responses, hence the annual formulation of new vaccines.10 Adamantane-based drugs are designed to treat influenza but the particular influenza A (H1N1) strain isolated in the 2009 outbreak is resistant against them. Since the virus re-assorts seasonally, a cure is impossible to function for a long period as the DNA strain of the virus will mutate and develop resistance against it.
Neuraminidase Inhibitors - these do not 'kill' the virus but they slow the process of viral replication down by inhibiting an enzyme called neuraminidase that the virus needs to replicate to a level where the immune system can more easily destroy it.1 Neuraminidase is a critical protein present on the surface membrane of the S-OIV that enables the replicated influenza virus to bud from host cell and helps the virus to pass through mucous between cells in the entire respiratory tract. Neuraminidase inhibitors slow down the action of virus but not affect the patient's immune response. However, they may induce certain toxic effects. To be effective, neuraminidase inhibitors that act at the phase of viral replication must be administered within 48 hours of the onset of symptoms as the replication of S-OIV in the respiratory tract reaches its peak between 24 and 72 hours after the onset of symptoms.
Figure 2. Mechanism of Action of Neuraminidase Inhibitors.
Panel A shows the action of neuraminidase in the continued replication of virions in influenza infection. The replication is blocked by neuraminidase inhibitors (Panel B), which prevent virions from being released from the surface of infected cells.
[Mechanism of Action of Neuraminidase Inhibitors, The New England Journal of Medicine 2005, 353:1363-73.]
To observe the effectiveness of these drugs, two parallel multicenter trials were conducted in North America (38 centers) and Europe (32 centers) during the 1994-1995 influenza season of which both were randomised, double-blind, and placebo-controlled in design and tested with the same regimen of drug treatment.12 The results were published in 1997 and will be discussed later. However, the clinical effectiveness of antiviral treatment for the present S-OIV infection is unknown at the time of writing as the outbreak occurred quite recently.
There are two types of neuraminidase inhibitors approved by Centers for Disease Control and Prevention (CDC), namely Oseltamivir, ethyl (3R, 4R, 5S)-4-acetoamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate, (brand name TamifluÂ®) and Zanamivir, 2,4-dideoxy-2,3-didehydro-4-guanidinosialic acid, (brand name RelenzaÂ®).2,11 Zanamivir, a potent inhibitor, mimics the natural substrate and fits into the active site of the neuraminidase. It then engages the protein in the most energetically favourable interaction - disrupts the detachment of progeny virions from infected cells. It reduces the rate of viral replication and allows the human immune system to destroy the remaining viruses.
In the 1997 study12 of The Efficacy and Safety of Neuraminidase Inhibitor (Zanamivir) Against Influenza A and B Viruses published in The New England Journal of Medicine (NEJM), it was reported that the median times to the alleviation of influenza symptoms of those with more pronounced illness and those treated within 30 hours after the onset of the symptoms were approximately 40 percent less (shorter by three days) than that in the respective placebo group.
Figure 3. Alleviation of Symptoms in Patients Infected With Influenza A or B Virus Who Were Treated With Inhaled Zanamivir, or Placebo.
Alleviation of illness was defined as the absence of feverishness and the presence of no symptoms of headache, muscle aches, sore throat, and cough, or only mild ones, for at least 24 hours. As the P values indicate, the two zanamivir groups differed significantly from the placebo group but not from each other.
[Hayden FG, Osterhaus AD, Treanor JJ, et al, Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir in the Treatment of Influenzavirus Infections, The New England Journal of Medicine 1997, 337:874-80.]
From Figure 3, it was observed that by the third day, the proportion of patients whose illness was alleviated was higher in the zanamivir groups than in the placebo group, and this difference was maintained after the cessation of treatment.
In the study, oseltamivir was also proved efficient in reducing the duration of illness, but only by 1.3 days (30%) in adults. As of current, only one patient19 from Denmark appeared to have developed resistance to oseltamivir as compared to the strength of resistance exhibited by influenza A (H1N1) strain to adamantane-based drugs.
Figure 4. Reduction of Illness by Oseltamivir (TamifluÂ®) In Adults of 18 to 65 Years Old
TamifluÂ® significantly reduces flu duration by 1.3 days (30%) as compared to placebo (P<0.001)
[TamifluÂ®, TAMIFLU for Treatment of Influenza, http://www.tamiflu.com/hcp/influenza-treatment.aspx, retrieved on Thursday, 2nd July 2009, 7.32pm]
The source obtained from NEJM is almost certainly reliable as it is an established body of medical journal publication and all articles published are endorsed by the Massachusetts Medical Society. The articles are backed with clinical trials results, charts, and various illustrated processes.
Another source, The Journal of Infectious Diseases3 (JID) also concurs to the results published in NEJM as a study published in it indicates that zanamivir reduced the duration of symptoms by 2.75 days for twice a day of dosage and by 3 days for a quadruple dosage daily.
Vaccination is administered by either injecting inactivated vaccine or using a nasal spray (Live Attenuated Influenza Vaccine, LAIV). The flu shot consists of dead influenza viruses while the nasal spray contains weakened live viruses. Upon introduction, the immune system will recognise the weakened antigens, resulting in the increased production of antibodies by the lymphocytes. The level of antibodies will further elevate. The antibodies are specific in their mode of action, thus they will only work against a specific strain of influenza virus. According to the CDC4, "It takes about two weeks after vaccination for antibodies to develop in the body and provide protection against influenza virus infection." Unfortunately, the immunity wanes in time and might offer little protection after a year.
The mode of action of the seasonal influenza vaccine is similar to that of the influenza A (H1N1) vaccine, thus it is expected that the vaccine will act similar to the former.
In the event of the recent outbreak of S-OIV, the World Health Organisation (WHO) in collaboration with the CDC, has developed a candidate reassortant vaccine virus (IDCDC-RG15) using reverse genetics technology from an A/Texas/5/2009 (H1N1)v virus, as stated in a statement14 issued on May 27th 2009.
"The dosage requirements for the new vaccine are yet to be determined and will be based on clinical trials, which could begin as early as August."
[Press Release, Sanofi Pasteur Receives Order from US Government to Produce New Influenza A (H1N1) Vaccine - May 25th, 2009, http://www.sanofipasteur.com/sanofi-pasteur2/sp-media/SP_CORP/EN/54/759/FLU%20A%20H1N1%20US%20ORDER%20ENG%20250509.pdf?sitesite=SP_CORP, Sanofi Pasteur, retrieved on Wednesday, 1st July 2009, 9.50am.]
Statistics pertaining to the effectiveness of the vaccine is currently unavailable as the clinical trials are only expected to begin in August 2009 as mentioned in the press release of Sanofi Pasteur above.
Ethical Problems Pertaining to the Problem
The new vaccines produced to inhibit the spread of S-OIV are tested using live animal during the preclinical trials phase.
"With any candidate strain, CDC virologists will perform tests to see if the new virus can induce an immune response against the wild H1N1 strain. That's done by using a solution derived from the blood of ferrets, whose susceptibility to flu is similar to that of humans, and also by deliberately trying to infect live ferrets."
[Caleb Hellerman, Candidate Virus for H1N1 Vaccine Arrives at CDC, CNN, 22nd May 2009]
Apparently, animals are intentionally infected to observe the response of their immune system after being vaccinated. This act has raised concerns of various animal-rights activists. Animals, regardless of size, species or ownership, deserve their rights to live pain-free. Rationally, an infected animal that pose harm to the biological habitat around it should be put to sleep. This action relieves other living things of risk of an infection and eases the infected animal from its suffering. However, the act of intentional infection of animals and sequentially killing it is unethical as it gives the illusion of divinity to the perpetrators of medical testing in determining the fate of the animal, despite inducing pain and illnesses within the body before a heartless mercy-killing.
"Currently, 12 million people are officially used in scientific procedures in the European Union every year, and the use of many other animals goes unrecorded."
People for the Ethical Treatment of Animals (PETA)
[International Animal Testing Programs, People for the Ethical Treatment of Animals (PETA), http://www.stopanimaltests.com/international.asp, 2nd July 2009]
The reliability of the website of which the data is quoted may seem suspicious, but the website is a sister website of PETA which specifically fights for the halt of experiments using animals, thus it can be said that a well maintained body as PETA will surely exercise the same maintenance onto its other websites. Still, the source might be outdated as the figures produced vary over time.
The emergence of counterfeit drugs in the light of a pandemic is highly unethical. In the recent outbreak of novel influenza A (H1N1), fake TamifluÂ® pills were maliciously marketed via various media. It was reported16 that the amount of junk mails offering counterfeit TamifluÂ® for sale spiked on the internet. Obviously, the fear of S-OIV infection propels the people living in hotspots of flu spread to purchase drugs without tactful investigations.
Apparently, the fake TamifluÂ® pills contain only trace elements of the active ingredient oseltamivir, added with other harmless ingredients and offers little, if not nonexistent benefits towards the patient. FDA has addressed the issue of malicious distribution of counterfeit drugs as shown on the next page.
Figure 5. Food and Drug Administration (FDA) Counterfeit Drug Cases, FY 1997-2005
[Randall Lutter, Speech before NACDS/HDMA RFID Healthcare Adoption Summit, November 14, 2005, http://www.fda.gov/oc/speeches/2005/radiofrequencyid1114.html]
Due to lack of awareness and economical education, the public may not be able to distinguish between the real drugs from the counterfeit, and care less to spend extra money to purchase a more expensive but effective drug. The blame should also be shouldered by counterfeiters as they stealthily distribute their products21 by relabeling expired drugs or "up-labeling" low-dose drugs and illegally market their products to the public.
Figure 6. Left - Real TamifluÂ®, Right - Counterfeit TamifluÂ®
[Counterfeit Tamiflu, TamifluÂ®, http://www.tamiflu.com/images/tamiflu_counterfeit.jpg, retrieved on Wednesday, 10th June 2009, 6.34am]
The S-OIV is not as lethal as the SARS outbreak as its mortality rate17, as of June 26th, is less than 0.5% as compared to that of SARS (15-19%) and this has caused the public to take this pandemic lightly. This should not be case as the widespread of influenza A (H1N1) strain might result in the re-assortment of different strains of influenza virus into a virulent or possibly, super-virulent influenza strains. Such an occurrence might occur when various strains of influenza virus infect a host. Unfortunately, due to the lack of scientific awareness, the public seem to ignore the calls to prevent themselves from contracting the influenza virus. People are freely walking in the streets without wearing protective masks while shopping mall owners care less to sanitise handles that people touch on such as the railings and trolley handles. Also, thermographic scanners at airports are turned on without surveillance which is a clear sign of ignorance towards the outbreak.
Although medical experts view the S-OIV as harmless, they fail to highlight the potential of a rebound outbreak that may be more lethal than the current one should a different multi-viral strain re-assortment occurs. As of the 3rd of July 2009, the cumulative infected and death cases reported worldwide is as illustrated in the map shown on the next page.
Figure 7. Number of Laboratory Confirmed Cases and Deaths as Reported to WHO
[World Health Organisation, 3rd July 2009, retrieved on Saturday, July 04, 2009 from http://www.who.int/csr/don/h1n1_20090703_1100.png]
Neuraminidase inhibitors such as TamifluÂ® and RelenzaÂ® are excellent solutions to alleviating the symptoms of novel influenza A (H1N1) as they are easily consumed due to the practical design of the drugs. TamifluÂ®, available in capsule form, is taken in orally while RelenzaÂ® is inhaled using a delivery device, also orally. The process of TamifluÂ® and RelenzaÂ® intake is pain-free. Ultimately, no surgeries or extensive treatments are required to treat the S-OIV.
"You will also be 50% less likely to develop secondary complications often associated with the flu, such as bronchitis, pneumonia and sinusitis."
Cyber Chemist on the Benefits of TamifluÂ®
[Tamiflu (oseltamivir), http://www.chemist.co.nz/pm/tamiFlu.cfm, retrieved on Saturday, 4th July 2009, 5.28am]
Despite the positive feedback5, the risks and disadvantages of the stated drugs do exist. The price106 of ten 75mg TamifluÂ® pills is £43.00 while 20 doses of RelenzaÂ® cost107 £32.50. Obviously, the hefty price will be a hindrance for the poor to seek treatment, hence encouraging further spread of the flu.
Also, neuraminidase inhibitors may induce certain side effects as proved by the studies quoted below.
"â€¦post-licensure reports indicated that zanamivir may cause cough, bronchospasm, and a reversible decrease in pulmonary function in some patients."
[Anne Moscona, Neuraminidase Inhibitors for Influenza, The New England Journal of Medicine, 353:1363-73, http://www.nejm.org , 2005]
Besides, disturbances to the gastrointestinal tract too are a common drug effects, especially vomiting. As central nervous toxicity was observed in infant rats, oseltamivir is not approved for therapy in children younger than 12 months. Limited clinical data is obtainable concerning safety in this population. Also, neuropsychiatric events have been reported76 in patients treated for influenza with oseltamivir, especially from Japan.
Figure 8. Adverse Events Reported During Treatment with an Incidence â‰¥ 1% in Any Treatment Group
[A.S. Monto and colleagues, Efficacy and Safety of the Neuraminidase Inhibitor Zanamivir, The Journal of Infectious Diseases 1999, 180:254-61]
The incidence of side-effects, although at a small percentage, during treatments with zanamivir certainly affects the efficacy of the drug to treat without harming the patient. Drug manufacturers should adhere to the second code of the Hippocratic Oath, which is to do no harm to patients by endorsing medicines with unfavourable side-effects.
Alternative Views and Solutions
Since the options for alternative drug intake are very limited, the public, especially children should cultivate standard methods to prevent transmission of S-OIV when an outbreak occurs, as recommended by World Health Organisation.
Figure 9. Methods To Protect Yourselves From Influenza A (H1N1) Infection
[Methods to Protect Yourselves from Influenza A (H1N1) Infection, World Health Organisation 2009, http://www.who.int/child_adolescent_health/news/archive/2009/h1n1_protect.jpg, retrieved on Sunday, 5th July 2009, 12.48am]
N95 Respirator Mask
Despite its slightly elevated price, an N95 respirator mask should be purchased and worn at public places at times of an outbreak as it provides 95% filtration20 from contamination and is proven to prevent transmission of airborne viruses. S-OIV may be transmitted from a person to another via sneezing, thus the mask is vital at places of high transmission susceptibility and of large crowds.
Further Investigation: RNA Interference in vivo
This method involves the suppression of in vitro virus replication effectively by RNA interference. The highly conserved regions of the nucleoprotein or acidic polymerase is specifically treated with small interfering RNAs (siRNAs), which results in the inhibition of in vivo replication of novel influenza A (H1N1) virus. It inhibits the expression of gene by inducing sequence-specific degradation of homologous mRNA. This method is advantageous as it is highly specific in inhibiting gene expression and was effective13 in protecting animals against lethal challenge with highly pathogenic avian influenza A viruses of the H5 and H7 subtypes.
Further Development of Drugs
While preventative measures are taken, pharmaceutical companies must proceed with improving the current formulation of the drug to suit the general population with reduced adverse events, especially the improvisation of RelenzaÂ® for infants. The production of drugs with less toxicity, less side effects, better efficacy and increased affordability must be pushed for as they cater to a wide range of world population.
In my perspective, the advancement of medical technology and betterment of medical efficacy will not yield the desired results of eradicating the spread of novel swine-origin influenza A (H1N1) virus unless the magnitude of severity of the outbreak is comprehended by the mass and the prevalence of counterfeit drugs is not tackled soon.