Correspondence

Zanamivir to Prevent Influenza

N Engl J Med 2001; 344:528-530February 15, 2001

Article

To the Editor:

Hayden et al. (Nov. 2 issue)1 identified an index case with an influenza-like illness in 337 families, and assigned the family contacts to prophylaxis with either zanamivir or placebo. Among the 414 family contacts who received zanamivir, influenza developed in 7 (1.7 percent), as compared with 40 of the 423 contacts who received placebo (9.5 percent). Prophylaxis reduced the transmission of influenza by about 80 percent. But there are some problems. Although subjects with index cases of influenza-like symptoms were selected, only 165 of the 337 (49 percent) actually had influenza. Hence, as the accompanying editorial notes, 10 contacts have to receive prophylactic treatment to prevent 1 case of influenza.2 The wholesale cost of zanamivir is $44.40 per 10-day course of prophylaxis.3 Thus, the risk of influenza is small after an exposure at home, and prophylaxis is expensive. Moreover, immediately after completing the prophylaxis, the patient is again at risk for influenza. Patients and families may therefore request multiple courses of prophylaxis during an influenza season.

There is another strategy — to vaccinate the exposed family members with influenza vaccine. Antibodies develop in vaccinated persons within one week after vaccination, and the concentration of antibodies peaks in four weeks.4 The vaccine provides approximately 80 percent protection during the entire influenza season.5 Those in whom influenza-like symptoms developed within the first week after exposure to an index case (the incubation period of influenza is one to three days) could be treated with antiviral drugs.

Influenza vaccination is 80 percent effective for preventing influenza, costs $6.00, and lasts throughout the influenza season. Zanamivir is 80 percent effective for preventing influenza, costs $44.40, and lasts 10 days. Influenza vaccination is the best way to prevent influenza.

Henry M. Feder, Jr., M.D.
University of Connecticut Health Center, Farmington, CT 06030

5 References

1
Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. N Engl J Med 2000;343:1282-1289
Full Text | Web of Science | Medline

2
Wright P. Influenza in the family. N Engl J Med 2000;343:1331-1332
Full Text | Web of Science | Medline

3
Two neuraminidase inhibitors for treatment of influenza. Med Lett Drugs Ther 1999;41:91-93
Web of Science | Medline

4
Cox RJ, Brokstad KA, Zuckerman MA, Wood JM, Haaheim LR, Oxford JS. An early humoral immune response in peripheral blood following parenteral inactivated influenza vaccination. Vaccine 1994;12:993-999
CrossRef | Web of Science | Medline

5
Influenza. In: Pickering LK, ed. 2000 Red book: report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 2000:351-9.

To the Editor:

Hayden et al. report a 79 percent reduction (from 19 percent to 4 percent) in the occurrence of influenza infection in the group that received prophylaxis with zanamivir as compared with the group that was assigned to placebo. In the base-line characteristics we noticed a difference in the number of household contacts that were already infected at base line. The proportion is 16 percent in the placebo group and only 6 percent in the group assigned to zanamivir. As a consequence, the chance for other healthy family members to become infected differed between the groups. The difference that the authors found in the outcomes may, at least in part, have resulted from this difference that existed at base line. Although it was probably not foreseen, we believe that the analysis should have adjusted for this substantial difference at base line.

Johannes C. van der Wouden, Ph.D.
Reinout D.W. van Bentveld, M.D.
Roos M.D. Bernsen, M.Sc.
Erasmus University Rotterdam, 3000 DR Rotterdam, the Netherlands

Author/Editor Response

The authors reply:

To the Editor: We fully agree that preseason immunization is the most cost-effective and preferred measure for the prevention of influenza. Unlike influenza vaccine, however, antiviral drugs such as zanamivir offer the possibility of immediate protection for nonimmunized persons who are exposed in settings such as households. Most household cases develop in the first week after exposure (Figure 1Figure 1Number of Cases of Influenza That Developed in Household Contacts, Treated with Zanamivir or Placebo, during the First 21 Days after Exposure.). Zanamivir does not interfere with the immune response to the vaccine,1 so the combination of short-term prophylaxis with antiviral drugs and concurrent immunization can provide protection for exposed persons. This approach is particularly useful for high-risk patients who receive immunization after the start of the influenza season.2

In Table 1 of our article, the percentage of contacts with laboratory-confirmed influenza infection refers to those in whom infection developed after they were enrolled in the prophylaxis phase of the study — not those who were already infected at base line. At the start of prophylaxis, there were only four contacts who had symptoms and in whom laboratory-documented influenza subsequently developed (three in the zanamivir group and one in the placebo group); of these, two (one in the zanamivir group and one in the placebo group) had infections that met the definition of influenza illness that we used for the primary end point and were included in the intention-to-treat analysis of efficacy.

Wright's editorial raised a number of pertinent questions.3 Zanamivir provides protection from influenza only during the dosing interval, and our primary efficacy analysis was limited to the first 11 days after the administration of the drug was begun. In the subsequent 10-day period there were only three new cases of symptomatic influenza in contacts (one in the zanamivir group and two in the placebo group), a result consistent with the conclusion that most transmission occurs quickly within households (Figure 1).

Prophylaxis with zanamivir was associated with amelioration of illness. Among the contacts in whom influenza infection developed despite prophylaxis, illness meeting the primary end-point definition developed in 40 of the 66 in the placebo group (61 percent) and only 7 of the 26 in the zanamivir group (27 percent). Furthermore, in those in whom illness developed while they were receiving daily prophylaxis, the median time to resolution of symptoms was 5.5 days for the 7 contacts in the zanamivir group and 8.0 days for the 40 contacts in the placebo group. This 2.5-day difference in the duration of illness is similar to that observed for the subjects with index cases of influenza who were receiving treatment twice daily.

The potential efficacy of zanamivir in providing additional protection beyond that provided by vaccine was examined in a small subgroup of immunized contacts. Laboratory-confirmed infection developed in 8 of the 78 contacts in the placebo group who had been vaccinated (10 percent) and in 2 of the 57 vaccinated contacts in the zanamivir group (3.5 percent); influenza illness developed in 5 of the 78 vaccinated contacts in the placebo group (6 percent) and in none of the vaccinated contacts in the zanamivir group. Although the small numbers of vaccine failures preclude a formal efficacy analysis, these findings suggest that the protective effects of immunization and prophylaxis with antiviral drugs are additive. Moreover, inhaled zanamivir is effective in protecting immunized nursing home residents during outbreaks of influenza.4

Frederick G. Hayden, M.D.
University of Virginia, Charlottesville, VA 22908

Michael J. Elliot, M.D.
Glaxo Wellcome, Research Triangle Park, NC 27709

4 References

1
Webster A, Boyce M, Edmundson S, Miller I. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Clin Pharmacokinet 1999;36:Suppl 1:S51-S58
CrossRef | Web of Science | Medline

2
Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49:1-38
Medline

3
Wright P. Influenza in the family. N Engl J Med 2000;343:1331-1332
Full Text | Web of Science | Medline

4
Gravenstein S, Drinka P, Osterweil D, et al. A multicenter prospective double-blind randomized controlled trial comparing the relative safety and efficacy of zanamivir to rimantadine for nursing home influenza outbreak control. In: Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, September 17–20, 2000. abstract.

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