Expanding the Treatment Options for Influenza

A 1743 headline in The London Magazine cited "news from Rome of a contagious distemper called the influenza."¹ At that time, the pathogenic "influence" visited on the citizens of Italy may have been thought to be occult or astral in origin. It is now well known, however, that a family of RNA orthomyxoviruses causes the deadly respiratory infections, which spread from person to person by the airborne route. In 1918-1919, an influenza pandemic killed 21 million people worldwide and more than 500,000 in the United States.² Currently, the Centers for Disease Control and Prevention (CDC) estimates that 20,000 people die in the United States each year from influenza, and 110,000 are hospitalized.³

The Advisory Committee on Immunization Practices of the CDC³ recommends annual vaccination for all people older than 65 years, persons residing in nursing homes or long-term care facilities, and for those with chronic diseases. Vaccination also is advised for young people (aged 6 months to 18 years) at risk for Reye syndrome because of long-term aspirin therapy,⁴ and for women who will be in the second and third trimester of pregnancy during the influenza season who are at high risk for hospitalizations due to acute cardiopulmonary illness.⁵

Influenza viruses are differentiated on the basis of ribonucleoproteins into 2 highly prevalent types, A and B. The lipid bilayer coating the virus contains specific hemagglutinin (H) and neuraminidase (N) protein spikes that define the viral subtypes. For example, the 1999-2000 vaccine contains antigens to 2 circulating subtypes of influenza A (H3N2 and H1N1) and 1 subtype of influenza B.⁶ The role of the hemagglutinin is to initiate infection by docking onto the sialic acid surface of respiratory epithelial cells. The host cell then encloses the virus in an endosome, and, subsequently, viral and cell membranes fuse.⁷ Eventually, a microscopic tunnel must be created to allow the viral genome entry into the cell after viral uncoating. At a later stage of infection, neuraminidase is responsible for cleaving the bonds between the emerging virus and the cell, freeing the virus to penetrate respiratory secretions. Matrix or M proteins at the base of the viral envelope coat are important for both structure and membrane proteins. Importantly, the M2 membrane protein modulates the pH in the microenvironment by permitting the flow of ions from the endosome into the viral interior, thereby facilitating viral uncoating.⁸

First-generation antiviral agents effective against influenza A include amantadine hydrochloride and rimantidine hydrochloride. Amantadine was licensed in 1966 in the United States for prophylaxis and in 1976 for both prophylaxis and therapy for influenza A in children and adults. The related drug rimantidine was approved in 1993 for treatment of adults and is now approved for prophylaxis.⁹ These agents inhibit the function of the M2 protein ion channels of influenza A virus and prevent viral uncoating.¹⁰ However, they have no effect on influenza B viruses, all of which lack the M2 protein. Reversible central nervous system adverse effects have been reported in 11% to 33% of young adults receiving these agents,⁹ and reduced dosage of both drugs is required in patients with renal failure. In addition, an increased frequency of seizures is associated with amantadine and rimantidine among patients with a history of seizure disorders.⁹ Viral drug resistance to both agents has emerged.^{11 - 12}

More recently, neuraminidase inhibitors with clinical activity against both influenza A and B types have been introduced. These agents target conserved segments in a central cleft common to all neuraminidase protein spikes.¹³ Zanamivir and oseltamivir phosphate are such agents and prevent the release of newly minted viruses from epithelial cells. Because of their expanded spectrum of activity, these drugs can be considered second-generation antivirals. Zanamivir is marketed as an inhaled topical agent¹⁴ and oseltamivir as an oral systemic agent. In this issue of THE JOURNAL, Treanor and colleagues¹⁵ report data on the efficacy and safety of oral oseltamivir in treating healthy adults aged 18 to 65 years who have influenza. More than 600 patients from 60 medical centers in the United States participated in this clinical trial. On average, duration of illness among individuals receiving the 75-mg twice daily dosage of oseltamivir was reduced by 1.3 days per person and duration of cough was reduced by 24 hours per person.

From a clinician's perspective, the issue is whether it is worthwhile for a patient to spend approximately $50 for a 5-day course of antiviral agents (average discount price database on diskette, Amerisource, Johnson City, Tenn) for 32 hours of relief from influenza symptoms. Whereas the cost may seem high for such a modest benefit, Americans commonly pay $40 or more for standard courses of antibacterial agents such as amoxicillin-clavulanate potassium, azithromycin, or levofloxacin. On the other hand, the natural course of a bacterial infection is substantially different from that of influenza. Based on data from the study by Treanor et al, from a population perspective, oseltamivir use would translate to 254 fewer hours of illness per 1000 patients treated and 544 fewer hours lost before return to normal activity per 1000 patients treated. A formal cost-benefit analysis could shed light on the impact of the antiviral medication nationally.

Successful treatment of influenza may have public health benefits due to reduction in the need to treat complications of viral infection. In the study by Treanor et al, approximately 6 fewer patients per 125 treated with oseltamivir also required prescribed antibiotics or 48 fewer courses per 1000 patients treated than those who received placebo. Because antibiotic resistance is related to use, such data are encouraging in light of the increasing prevalence of penicillin-resistant Pneumococcus in the United States¹⁶ and recent studies in Hungary¹⁷ and in Iceland¹⁸ showing trends for reduced rates of penicillin-resistant pneumococci with reduced penicillin use.

Would the use of oseltamivir affect mortality rates in adults with influenza? The data of Treanor and colleagues do not allow an estimate of this important outcome, but the disease burden of influenza on this group is not trivial. Ninety percent of the deaths from influenza reported each year in the United States occur in the elderly.³ However, an estimated 2000³ to as high as 8000¹⁹ influenza-related deaths occur in persons younger than 65 years, an age cohort for whom influenza vaccine is not currently recommended. Regarding morbidity, hospitalization rates for persons aged 15 to 64 years are 20 to 400 per 100,000 population vs 200 to more than 1000 per 100,000 population for those older than 65 years.³ Thus, the impact of influenza on young adults in terms of morbidity and quality of life is also substantial, even if less than that on the elderly. Preventing disease by expanding influenza vaccination may be a logical next step.

Oseltamivir has shortcomings related both to its adverse effect profile and the potential for antiviral resistance. A 10% rate of vomiting noted in the study by Treanor et al was directly attributable to the drug,¹⁵ and patients need to be advised of this problem. With respect to the emergence of antiviral resistance, the single isolate with altered neuraminidase inhibitor susceptibility that was recovered from an oseltamivir recipient underscores the critical need to monitor for resistance should the drug become used widely. Clinicians should not prescribe oseltamivir when it is clinically useless, such as for noninfluenza viral infections or late in the course of influenza.

No controlled studies exist on the efficacy of available neuraminidase inhibitors for serious diseases such as influenzal pnemonia. To date, all clinical trials have been performed among patients with uncomplicated influenza. The US Food and Drug Administration recently warned that some patients who died of serious bacterial complications of influenza received only antivirals and failed to receive appropriate antibacterial therapy.²⁰ Furthermore, the safety of zanamivir or oseltamivir for pregnant women has not been established, and the general caveat applies that occasionally unforeseen adverse effects emerge when new drugs are used by hundreds of thousands of patients.

Influenza is unquestionably a serious infection that has an important clinical impact. Although elderly patients are at especially high risk for morbidity and mortality, the American Academy of Family Physicians has recently recommended lowering the age for routine influenza vaccination to 50 years.²¹ A recommendation to vaccinate all adults without contraindications might have a significant health impact on infection and transmission and could further limit morbidity, mortality, years of life lost, and lost productivity while improving quality of life.

For young or older adults who still acquire influenza, neuraminidase inhibitors may be beneficial because of the potential individual medical benefits and public health benefits. However, for cases of sporadic influenza appearing before an epidemic of influenza is recognized, laboratory confirmation of the virus with rapid diagnostic testing should precede the use of neuraminidase inhibitors. Newer tests have a sensitivity of 76% to 93% for identifying influenza A in nasopharyngeal aspirates or swabs.²² Once a community is experiencing a well-defined epidemic, clinical characteristics probably could guide therapy. Although no clinical trials have directly compared zanamivir with oseltamivir, data from separate clinical trials suggest that these agents would be equivalent. Oseltamivir might be easier to take than zamamivir, which requires learning to use an inhaler. The advantage of zamamivir might be the lack of systemic drug absorption. These theoretical differences could be evaluated in future studies. For the time being, however, the second-generation antivirals for influenza, the neuraminidase inhibitors, represent an important, if somewhat expensive, advance in treating influenza.