Antiviral prophylaxis during pandemic influenza may increase drug resistance

Abstract

Background: Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.

Methods: Using the freely available program InfluSim, the authors examine to what extent NI-treatment and prophylaxis promote the occurrence and transmission of a NI resistant strain.

Results: Under a basic reproduction number of R0 = 2.5, a NI resistant strain can only spread if its transmissibility (fitness) is at least 40% of the fitness of the drug-sensitive strain. Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high. Antiviral prophylaxis further increases the pressure on the drug-sensitive strain and favors the spread of resistant infections. The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.

Conclusion: If the fitness of a NI resistant pandemic strain is high, any use of prophylaxis may increase the number of hospitalizations and deaths in the population. The use of neuraminidase inhibitors should be restricted to the treatment of cases whereas prophylaxis should be reduced to an absolute minimum in that case.

Figure 1

Course of disease. Model assumptions on the course of disease of cases with and without prophylaxis if people are infected with the drug sensitive virus. Without prophylaxis, one third of infected individuals remains asymptomatic, one third becomes moderately sick and one third becomes severely sick and needs medical help. Prophylaxis halves the fractions of moderately and severely sick individuals and doubles the fraction of infected individuals who remain asymptomatic, but only half of the asymptomatic infections lead to protective immunity.

Figure 2

Prevalence of infection. Prevalence of people infected with the drug sensitive virus (solid lines), the drug resistant one (dashed lines) and the sum of both (dotted lines). All cases who seek medical help receive antiviral treatment; additionally, a fraction of (a) 0%, (b) 10% and (c) 20% of all adults between 20 and 60 years of age are given prophylaxis. The grey curves and the right hand scales indicate the fractions of resistant infections among all infections. Assumptions: (1) A single drug-sensitive infection is introduced on day 0 into a Swiss population of 100,000 individuals. (2) Resistance develops de novo in 4.1% of children and 0.32% of adults who receive medication. (3) Social distancing reduces the number of contacts by 10% for all individuals; isolation additionally prevents 10%, 20% and 30% of contacts of moderately sick cases, severely sick cases at home, and hospitalized cases, respectively. (4) Antiviral treatment reduces the contagiousness of patients by 80%, their duration of sickness by 25% and their need of hospitalization by 50% if they are infected with the drug sensitive virus. (5) Prophylaxis furthermore reduces susceptibility by 50%. Upon infection, it doubles the fraction of individuals who stay asymptomatic from one third to two thirds, but only one of the two thirds becomes immune. (6) R₀ = 2.5 for the drug sensitive and the drug resistant virus (fitness = 100%).

Figure 3

Influence of antiviral prophylaxis. Influence of antiviral prophylaxis and of the fitness of the resistant strain on a pandemic wave in a population of 100,000 individuals into which a single nonresistant infection is introduced on day 0 (development of resistance and other details see Fig. 2 and text). The horizontal axis shows what percentage of the population between 20 and 60 years of age receives prophylaxis; the numbers 80 ... 100 in the graphs indicate the fitness of the resistant strain. Simulations with lower fitness values lead to curves which are nearly identical to the 80% fitness curves. The results are given as (a) total number of treatment failures due to drug resistance; (b) total number of hospitalizations; (c) expected duration of work loss per ESW (essential service worker), i.e. per person who receives prophylaxis. Even without any prophylaxis in the population, the average work loss per person is slightly modified by the fitness of circulating resistant virus (because of treatment in the population). The grey horizontal bar shows the range of work loss per person which must be expected without prophylaxis (whereby the lower values in the grey area refer to low fitness and the high ones to high fitness values).

Figure 4

Comparison of de novo development of resistance and importation of resistance. Prevalence of infection with drug sensitive (solid curves) and drug resistant infection (dashed curves) during a pandemic wave in a population of 100,000 inhabitants. Scenario (a): a drug-sensitive infection is introduced on day 0; NI resistant infection develops de novo during antiviral treatment of cases throughout the simulation (treatment parameters see Figure 2; no prophylaxis; 100% fitness of the resistant virus; black curves). Scenario (b): the importation of a drug sensitive infection on day 0 is followed by an importation of a NI resistant infection on day 28. Treatment is given as in scenario (a), but no de novo development of resistance occurs within this scenario (grey curves). The resulting curves for Scenario (a) and (b) are nearly indistinguishable.