Treatment Basics: Antivirals
Public health officials advise the public to not stockpile Tamiflu at home. But when New Scientist
magazine asked 60 public health officials, epidemiologists and flu researchers in August 2009 about their personal preparations for the 2009 H1N1 flu pandemic
, it turned out that half of them were concerned enough about a potentially more severe wave of the disease to stockpile Tamiflu—one of the two recommended drugs to treat 2009 H1N1 flu symptoms.
Similarly, concern about H5N1 avian flu is presumed to be the reason for increased prescriptions of Tamiflu and other antivirals used to treat influenza in recent years.
These two cases draw attention to a serious influenza treatment dilemma: The more we use available drugs, the less effective they become. Several influenza strains have already built resistance to some of the drugs used to treat infected people. Contributing to this problem is both the overprescription of drugs as well as the improper use of drugs by people who are not very sick but take antivirals because they are frightened.
This page provides a quick introduction to antivirals, how they work, how they are currently used and what new treatments are being explored. The information is designed to help journalists raise important questions with officials and public health experts.
How do public health officials determine the most sensible use of available drugs? How does the public feel about the government releasing only a limited supply of Tamiflu from its stockpile? And what new drugs are in the pipeline to ease the problem?
What are antivirals?
Influenza causes illness, but most people recover in about one to two weeks. The disease can create more serious health problems for the young and elderly; for those who have underlying medical conditions (such as diabetes, asthma, and cardiovascular disease); for individuals who are immunocompromised (people with HIV or transplant patients), and for women who are pregnant.
Matrix 2 (M2) ion channel inhibitors
Drugs that treat influenza and other viral infections are commonly called antivirals. There are two classes of such antiviral drugs available to treat the flu: matrix 2 (M2) ion-channel protein inhibitors (such as amantadine and rimantadine) and neuraminidase inhibitors (such as oseltamivir/brand name Tamiflu, or zanamivir/brand name Relenza). These drugs are also sometimes used prophylactically to prevent an infection in people who have been exposed to the virus.
As of October 2009, oseltamivir and zanamivir were the two FDA-approved influenza antiviral drugs that were recommended by the CDC for use against the 2009 H1N1 influenza virus.1
Matrix 2 (M2) ion channel inhibitors drugs are effective against influenza A and reduce the length of illness caused by both influenza A and B if given within 24 hours after the onset of symptoms. Drugs in this class include the amantadanes amantadine and rimantadine.2
M2 ion-channel inhibitors prevent the virus from being released in cells by stopping the internal ion exchange within the endosome (a coated particle containing the virus that has been transported inside the cell). This lack of ion flow alters internal conditions and effectively keeps the virus “bottled up” in the cell.
Both drugs have been available for a long time and have been used for both prevention and treatment of influenza A. Because of the drugs’ long history of use, some influenza A viruses have developed resistance to these adamantanes in the United States and globally. For example, 98 percent of the currently circulating H3N2 strains have developed resistance.3
Some investigators suggest that less drug usage might allow susceptible viruses to reemerge.
One of the drugs in this group, amantadine, also causes central nervous system side effects. Because of their drug resistance and side effects, the medications have limitations as single therapies. These drugs also have shown little effectiveness against highly pathogenic viruses
, such as H5N1
Neuraminidase inhibitors are part of a drug class that works by preventing the influenza virus from leaving an infected cell. Neuraminidase (N) is an enzyme required to allow newly produced virus particles to leave infected cells. Neuraminidase inhibitors therefore block this process and prevent virus particles from leaving the cell and infecting other cells.4
Two drugs in this class are oseltamivir (Tamiflu—pill or liquid) and zanamivir (Relenza; a powder that is inhaled through the mouth). These drugs reduce the duration of illness by one to three days, reduce risk of transmission to others, and reduce both the severity and number of influenza complications (such as sinusitis and bronchitis).
Both types of drugs can be used in adults and children but some classes have restrictions.
A starting dose of amantidine is 100 mg daily, but most influenza viruses are resistant. During the 2005-2006 flu season, the CDC recommended that these drugs not be prescribed any longer because of resistance issues.5
In Asia, resistance levels have reached 100%.6
Oseltamivir can be taken by adults and children older than one year and is available in both pill and liquid form. Oseltamivir has side effects that include nausea and vomiting, but these are mild and usually occur in the first two days of treatment. Recommended dosage:
||To relieve influenza symptoms, children older than age 13 and adults take 75 mg of oseltamivir twice a day for 5 days, once in the morning and once in the evening. Dosage in children is adjusted by weight; smaller children take less.
||To prevent influenza, patients take 75 mg oseltamivir once a day for 10 days or as prescribed. Dosage in children in adjusted by weight. Small children take a lower dose and can take a liquid form if they cannot swallow pills.7
Oseltamivir may provoke allergic reactions, and children and adolescents may be at increased risk of self-injury and confusion shortly after taking the drug. They should be monitored for signs of unusual behavior.8
Some seasonal influenza strains isolated from Europe during the 2007-2008 season were found to be resistant to oseltamivir. Resistance mutations in H5N1 strains have also been noted after oseltamivir use.9
Zanamivir can be taken by adults and children who are age five years and older. It should be taken within the first 12 hours of the onset of illness (Memoli 2008). Recommended dosage:
||To relieve influenza symptoms, patients take 10 mg zanamivir twice a day for five days.
||To prevent influenza, patients take 10 mg zanamivir once a day for 10 days (for influenza in households) or 28 days (for influenza widespread in communities) or as prescribed.10
Potential side effects include bronchospasm, allergic reactions, and neuropsychiatric effects. The latter, especially in young patients, includes the risk of seizures, confusion or abnormal behavior early in the illness. As with oseltamivir, patients using zanamivir should be monitored for unusual behavior.11
A few story ideas
Indiscriminate use of drugs can cause viruses to become resistant, so it is important that these drugs are not overprescribed. However, many people, including doctors and public health officials
, stockpile Tamiflu or Relenza as part of their personal pandemic preparation efforts (This is not recommended as the national stockpiles of the drugs are said to be sufficient.)
Additionally, presumably influenced by H5N1 avian flu fears, more people in recent years have pushed their doctors to prescribe Tamiflu in order to stockpile the drug.12
How is the medical system in your area dealing with growing requests for these drugs? What are your local health officials doing to inform people about the most sensible use of antivirals? And how do governments explain that they are not using national stockpiles—paid for with tax-payer money—to treat people during a mild pandemic?
The Guardian ran a story
about this topic which showed that the government in the United Kingdom rejected expert advice and distributed stockpiled Tamiflu in August.
Another problem is that only 80 percent of oseltamivir is used in the body: 20 percent of the active drug is excreted and ends up in the local water supply. This occurrence has prompted concerns about resistance in areas of heavy use and in areas in which birds live.13
Such concern about active drugs in the water is relevant for nearly all medications.
If you have a local surge in patients being treated with Tamiflu, are they being informed about the environmental impact of using the drug? Have any solutions been developed to deal with this, at least in hospitals where many patients are being treated simultaneously?
Non-drug therapies and medical care
Non-drug therapies for people who contract influenza include getting plenty of rest and drinking lots of liquids. Patients may take aspirin, but children and teenagers should avoid aspirin because of the risk of Reye syndrome. Antibiotics have no effect on influenza because they are not designed to treat viral infections.
For people with more severe symptoms or complications from the flu, there is a host of additional drugs and interventions available, such as antibiotics to treat bacterial pneumonia (a common secondary infection after a more severe case of flu) or ventilators supporting lungs weakened by the illness. (For a discussion of the challenges hospitals face when trying to prepare for a surge in patients suffering from complications from pandemic flu, also see Challenges to Communities
The drug development process
In the United States, several new drugs are being developed but they must go through an expensive multi-step process (multiple clinical trials) before they can be approved by the FDA for use in humans. Drugs usually are first tested for toxicity (preclinical trials), then advance to trials involving small numbers of patients (phase 1 clinical trials) and progress to larger trials containing a few thousand patients (clinical trials phase 2 to phase 3). Once a drug has shown to be successful in trials, it may be approved for use in humans and sold commercially.
After commercial release, the government monitors drugs for adverse side effects in patients who take them. Because conducting trials is expensive, trials are conducted on only a few thousand patients. Such trials are large enough to demonstrate drug effectiveness, but sometimes not large enough to detect side effects in subgroups of patients or rarely encountered side effects. Encountering large numbers of side effects in patients can limit the drug’s utility and may cause its withdrawal from the market.
Potential new drugs
Several tactics are being used to develop additional drugs to combat influenza. One of the most direct approaches is the chemical modification of an existing drug. Modification can alter the drug properties and make the drugs work better. Examples include peramivir and other derivatives of neuraminidase inhibitors. Modified drugs have been shown to work against viruses resistant to oseltamivir and zanamivir.
Recent drug development efforts have focused on drugs targeting unique aspects of influenza virus processes. Therapies now under development include viral receptor blockers, viral release inhibitors, viral polymerase inhibitors, and RNA interference.14
Most of these drugs are not yet commercially available, but the techniques being used to develop them may provide newer, better therapies.
U.S. Food and Drug Administration, Influenza (Flu) Antiviral Drugs and Related Information, Oct. 14, 2009. ↑
M.J. Memoli, D.M. Morens, J.K. Taubenberger, Pandemic and seasonal influenza: therapeutic challenges, Drug Discovery Today 13 (May 15, 2008): 590-595. ↑
Rick A Bright, Marie-jo Medina, Xiyan Xu, et. al., “Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern,” The Lancet 366 (Oct. 1, 2005): 1175-1181. ↑
Erik De Clercq, “Antiviral agents active against influenza A viruses,” Nature Reviews Drug Discovery 5 (December 2006):1015-1025. ↑
Centers for Disease Control and Prevention, CDC Recommends against the Use of Amantadine and Rimantadine for the Treatment or Prophylaxis of Influenza in the United States during the 2005–06 Influenza Season, January 14, 2006. ↑
Varough M. Deyde, Xiyan Xu, Rick A Bright, et. al., “Surveillance of Resistance to Adamantanes among Influenza A(H3N2) and A(H1N1) Viruses Isolated Worldwide,” The Journal of Infectious Diseases 197 (15 July 2006): 249–257. ↑
Roche Laboratories Inc., Taking Tamiful. ↑
Roche Laboratories Inc., About Tamiful/About Influenza. ↑
M.J. Memoli, D.M. Morens, J.K. Taubenberger, op. cit. ↑
GlaxoSmithKline, Full Prescribing Information, 2008. ↑
Justin R. Ortiz, Laurie Kamimoto, Ronald E. Aubert, et. al., “Oseltamivir Prescribing in Pharmacy-Benefits Database, United States, 2004–2005,” Emerging Infectious Diseases 14 (August 2008):1280-1283.↑
Gopal C. Ghosh, Norihide Nakada, Naoyuki Yamashita, et. al., “Oseltamivir Carboxylate—the Active Metabolite of Oseltamivir Phosphate (Tamiflu), Detected in Sewage Discharge and River Water in Japan,” Environmental Health Perspectives 117 (Sept. 28, 2009). ↑
M.J. Memoli, D.M. Morens, J.K. Taubenberger, op. cit.↑