Antiviral prophylaxis during pandemic influenza may increase drug resistance
© Eichner et al; licensee BioMed Central Ltd. 2009
Received: 28 May 2008
Accepted: 20 January 2009
Published: 20 January 2009
Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.
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.
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.
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.
Neglecting the possible emergence of NI resistance, modeling studies have suggested that an influenza pandemic may be contained if treatment and prophylaxis are introduced immediately [1–3]. Switzerland has stockpiled sufficient NI to treat 25% of the population and considers using some of the stockpile for prophylaxis in health care workers and essential services (fire brigade, police, etc). As influenza viruses mutate constantly, widespread use of antivirals in the case of a pandemic could cause selection pressure which could lead to the emergence and spread of NI resistant strains. De novo emergence of a resistant strain does not necessarily cause negative outcomes; it is the transmission fitness of the resistant strain which plays a major role [4–7]. Simulation studies on HIV  and HSV-2  have also shown the important role of transmissibility in driving the dynamics of drug resistance. Influenza resistant strains that show nearly the same transmission fitness as wild type strains have been detected . Also, data from the European system VIRGIL show, that a NI resistant seasonal influenza A (H1N1) strain circulates in several countries . NI resistance leads to treatment failures and thus, to an increased number of hospitalizations and deaths attributable to influenza. As antiviral prophylaxis and treatment are relevant for future interventions against influenza, understanding the implications of NI resistance and the dynamics of its spread is essential. We examine how NI treatment and prophylaxis contribute to the emergence and circulation of NI resistant strains and to changes in the epidemiology of infection.
We extend the freely available deterministic simulation program InfluSim by including the emergence and the spread of NI resistance . InfluSim version 2.2 distinguishes drug sensitive and resistant infections, and allows for prophylaxis .
Simulations start with a single drug sensitive infection in a Swiss population of 100,000 inhabitants. We assume that 4.1% of children up to 12 years of age and 0.32% of teenagers and adults infected with the drug sensitive virus develop a NI resistant infection if they take antiviral drugs [16, 17]. The probability that they pass on the resistant virus to others is small, as on average their contagiousness has already decreased considerably before the resistant virus appears. This is because (i) patients seek medical treatment on average 24 hours after onset of symptoms, (ii) their contagiousness is assumed to decline exponentially over time with 90% of the total infectiousness being spent within the first half of the infectious period, and (iii) if de novo NI resistance occurs in a patient, it occurs at a random time point between treatment and the end of contagiousness. The resistant virus can have a reduced transmissibility (fitness) compared to the drug-sensitive strain, while having the same pathogenicity, causing the same natural history of disease and inducing the same degree of immunity, but cases infected with the NI resistant virus no longer respond to antiviral drugs. Simulations are performed for a variety of parameter values: The fitness of the NI resistant strain is varied from 80 to 100%. The percentage of adults between 20 and 60 years of age who receive prophylaxis is varied from 0 to 20%. Prophylaxis is assumed to reduce the susceptibility of the recipient by 50% (varied in an uncertainty analysis from 0 to 100%). Fifty percent of prophylactically treated individuals who experience asymptomatic infection become immune after clearing the infection (varied in an uncertainty analysis from 0 to 100%). We run simulations with and without prophylaxis, with and without resistance, and observe the total number of hospitalizations due to severe influenza and the total work loss for people who receive prophylaxis. No ethics committee was required to grant permission for this investigation.
Figures 2a–c show how the prevalence of infection with the drug sensitive and the resistant virus change during the pandemic wave if all severe cases are treated with NI and if additionally 0%, 10% or 20% of the people between 20 and 60 years of age receive prophylaxis (assuming that the fitness of the NI resistant strain is as high as that of the drug-sensitive one, i.e. 100%). The simulations start with one drug-sensitive infection in a susceptible population of 100,000 individuals. NI resistance develops de novo and gradually builds up during the epidemic wave. If no prophylaxis is given, the drug-sensitive strain dominates most of the epidemic wave (full curve) and the resistant strain (dashed curve) only becomes prevalent in the end (Fig. 2a).
Prophylaxis increases the pressure on the drug sensitive strain and favors the transmission of the resistant strain. The prevalence of the NI resistant strain increases considerably if 10% of all people between 20 and 60 years of age are given prophylaxis (Fig. 2b). If the prophylaxis coverage is increased to 20%, the resistant strain very quickly dominates the epidemic wave and the majority of cases are infected with the resistant strain (Fig. 2c). With increasing prophylaxis coverage, the peak number of infected individuals increases from 17,000 to 25,000 and the total number of infected individuals increases from 62,000 to 72,000 (Figs. 2a–c).
In the following, we investigate the influence of parameter uncertainty by systematically varying the values of two unknown parameters:
(a) The susceptibility to infection x sus of people who take prophylaxis is varied from 0 to 100% (baseline value 50%). The results only deviate from the values shown in Figs. 3a–b by up to 1240 treatment failures and by up to 21 hospitalizations per 100,000 inhabitants (with a slight tendency towards higher deviations for combinations of high prophylaxis coverage and high fitness values). The parameter x sus strongly influences the expected work loss of people who take prophylaxis. If only few people take prophylaxis (cf. Fig. 3c), the expected work loss varies between nearly 0 days (x sus = 0) and 1.2 days (x sus = 1) for low fitness values, and from 0.9 to 1.6 days for high fitness values. If 10% of the population between 20 and 60 years of age take prophylaxis, the expected work loss varies from 0.1 day (x sus = 0) and 1.1 days (x sus = 1) for low fitness values, and it is about 2.2 days (irrespective of x sus ) for high fitness values.
(b) The fraction x imm of asymptomatic cases who develop protective immunity if they have received prophylaxis, is varied from 0 to 100% (baseline value 50%). The results only deviate from the values shown in Figs. 3a–c by up to 240 treatment failures, by up to 7 hospitalizations and by up to 0.1 days of work loss per person.
Quick calculation formula of the critical fitness of the resistant strain
Here, s is the susceptible fraction of the population, r SD is the reduction of transmission due to social distancing, r iso is the reduction due to case isolation, r tr is the reduction of transmission due to antiviral treatment of cases, r pro is the fraction of the population protected by prophylaxis and f is the fitness of the resistant strain (for more details, see the additional file SupplementaryData.doc). An infection can only be transmitted if the effective reproduction number is larger than 1. For the NI resistant strain, is larger than 1 if the fitness f is larger than (R 0 s (1- r SD )(1 - r iso ))-1. In a fully susceptible population (s = 1) where no interventions are performed (r SD = r iso = 0), the fitness f must be larger than = 40%. Immunity in the population and contact reductions increase the critical value of f. NI resistance only becomes a problem if the resistant strain spreads more efficiently than the drug sensitive one, i.e. if . This is the case if f > (1 - r tr )(1 - r pro ). Note that the critical value of f is independent of contact reduction measures; it only depends on the effects of treatment and prophylaxis. If the overall treatment effect is r tr = 0.188 (see additional file SupplementaryData.doc), the critical fitness of the resistant strain is about 81% if no prophylaxis is given. If the fitness exceeds this value, the resistant strain will invariably take over. The critical value for the fitness drops to 73% and 65%, respectively, if 10% or 20% of the population receive prophylaxis.
Although NI resistant viruses may emerge de novo in treated patients in such a late state of their course of disease that most patients may not pass on the infection, our simulation study shows that the resistant strain will become highly prevalent in the population if its relative fitness is high and if NI treatment or prophylaxis are common. Prior to the 2007/8 influenza season, NI resistant strains were only infrequently found in patients after treatment with oseltamivir and in patients not exposed to oseltamivir. Early surveillance data from the 2007/8 influenza season on the northern hemisphere suggest that an oseltamivir resistant influenza virus type A (H1N1) circulates in several European countries and in North America [6, 7, 11]. Resistance infections have been reported from over two third of the countries which have implemented an influenza surveillance system and test for antiviral resistance. Furthermore, the proportion of resistant infections has become alarmingly high (between 4% and 70%) in the afflicted countries. Even in a fully susceptible population, a resistant virus can only spread if its fitness exceeded 40%. The populations in which the resistant seasonal influenza virus is spreading are far from being susceptible which further increases the minimum fitness of the resistant strain.
Considering the growing prevalence of resistant infections in spite of extremely low treatment rates, the fitness of the current resistant strain must indeed be very high. It is conceivable that a pandemic influenza strain may also become resistant without a considerable loss of transmissibility although this may be regarded as a worst case scenario. In a pandemic scenario, NI treatment is one of the major means of intervention and will be used extensively. Containing a potential pandemic within the country of its origin by widespread antiviral prophylaxis has been suggested [1, 3]. Prophylaxis has also been considered for local interventions after the international spread of the pandemic virus.
Surveillance of the appearance of NI resistant infections and, most importantly, of the fitness of resistant strains will be crucial to manage a pandemic wave. Uncontrolled use of NI may do more harm than good. If a NI resistant pandemic strain is reported to spread, the use of NI should mainly be restricted to the treatment of cases whereas prophylaxis must be reduced to an absolute minimum. If the fitness of the NI resistant pandemic strain is high, any use of prophylaxis may increase the number of hospitalizations and deaths in the population. Thus, public health systems should diversify intervention strategies by using prophylaxis in a very restrictive manner, by stockpiling different types of antiviral drugs and by supplementing pharmaceutical interventions with social distancing measures [22, 23].
This work has been supported by a project of the SFOPH (contract no. 06.001333/304.0001-108), and by the EU projects SARScontrol (FP6 STREP; contract no. 003824) (HPD) and INFTRANS (FP6 STREP; contract no. 513715) (MS). We thank M. Mäusezahl and H. C. Matter for their support and for reviewing a previous version of the manuscript.
- Ferguson NM, Cummings DA, Cauchemez S, Fraser C, Riley S, Meeyai A, Iamsirithaworn S, Burke DS: Strategies for containing an emerging influenza pandemic in Southeast Asia. Nature. 2005, 437 (7056): 209-214. 10.1038/nature04017.View ArticlePubMedGoogle Scholar
- Longini IM, Halloran ME, Nizam A, Yang Y: Containing pandemic influenza with antiviral agents. Am J Epidemiol. 2004, 159 (7): 623-633. 10.1093/aje/kwh092.View ArticlePubMedGoogle Scholar
- Longini IM, Nizam A, Xu S, Ungchusak K, Hanshaoworakul W, Cummings DA, Halloran ME: Containing pandemic influenza at the source. Science. 2005, 309 (5737): 1083-1087. 10.1126/science.1115717.View ArticlePubMedGoogle Scholar
- Alexander ME, Bowman CS, Feng Z, Gardam M, Moghadas SM, Rost G, Wu J, Yan P: Emergence of drug resistance: implications for antiviral control of pandemic influenza. Proc R Soc Lond B Biol Sci. 2007, 274 (1619): 1675-1684. 10.1098/rspb.2007.0422.View ArticleGoogle Scholar
- Lipsitch M, Cohen T, Murray M, Levin BR: Antiviral Resistance and the Control of Pandemic Influenza. PLoS Med. 2007, 4 (1): e15-10.1371/journal.pmed.0040015.View ArticlePubMedPubMed CentralGoogle Scholar
- Regoes RR, Bonhoeffer S: Emergence of drug-resistant influenza virus: population dynamical considerations. Science. 2006, 312 (5772): 389-391. 10.1126/science.1122947.View ArticlePubMedGoogle Scholar
- Stilianakis NI, Perelson AS, Hayden FG: Emergence of drug resistance during an influenza epidemic: insights from a mathematical model. J Infect Dis. 1998, 177 (4): 863-873.View ArticlePubMedGoogle Scholar
- Blower SM, Gershengorn HB, Grant RM: A tale of two futures: HIV and antiretroviral therapy in San Francisco. Science. 2000, 287 (5453): 650-654. 10.1126/science.287.5453.650.View ArticlePubMedGoogle Scholar
- Blower SM, Porco TC, Darby G: Predicting and preventing the emergence of antiviral drug resistance in HSV-2. Nat Med. 1998, 4 (6): 673-678. 10.1038/nm0698-673.View ArticlePubMedGoogle Scholar
- Yen HL, Ilyushina NA, Salomon R, Hoffmann E, Webster RG, Govorkova EA: Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo. J Virol. 2007, 81 (22): 12418-12426. 10.1128/JVI.01067-07.View ArticlePubMedPubMed CentralGoogle Scholar
- Lackenby A, Hungnes O, Dudman SG, Meijer A, Paget WJ, Hay AJ, Zambon MC: Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro surveill. 2008, 13 (5):Google Scholar
- Eichner M, Schwehm M, Duerr HP, Brockmann SO: The influenza pandemic preparedness planning tool InfluSim. BMC Infect Dis. 2007, 7: 17-10.1186/1471-2334-7-17.View ArticlePubMedPubMed CentralGoogle Scholar
- InfluSim. [http://www.influsim.info]
- Chowell G, Nishiura H, Bettencourt LM: Comparative estimation of the reproduction number for pandemic influenza from daily case notification data. J R Soc Interface. 2007, 4 (12): 155-166. 10.1098/rsif.2006.0161.View ArticlePubMedGoogle Scholar
- Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F: Impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations. Arch Intern Med. 2003, 163 (14): 1667-1672. 10.1001/archinte.163.14.1667.View ArticlePubMedGoogle Scholar
- Aoki FY, Boivin G, Roberts N: Influenza virus susceptibility and resistance to oseltamivir. Antivir Ther. 2007, 12 (4 Pt B): 603-616.PubMedGoogle Scholar
- Tamiflu. Arzneimittel-Kompendium der Schweiz. [http://www.kompendium.ch]
- Handel A, Regoes RR, Antia R: The role of compensatory mutations in the emergence of drug resistance. PLoS Comput Biol. 2006, 2 (10): e137-10.1371/journal.pcbi.0020137.View ArticlePubMedPubMed CentralGoogle Scholar
- Updated review of influenza antiviral medicinal products for potential use during pandemic by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA). [http://www.emea.europa.eu/htms/human/pandemicinfluenza/antivirals.htm]
- Moghadas SM, Bowman CS, Rost G, Wu J: Population-wide emergence of antiviral resistance during pandemic influenza. PLoS ONE. 2008, 3 (3): e1839-10.1371/journal.pone.0001839.View ArticlePubMedPubMed CentralGoogle Scholar
- Moghadas SM: Management of drug resistance in the population: influenza as a case study. Proc R Soc B. 2008Google Scholar
- Duerr HP, Brockmann SO, Piechotowski I, Schwehm M, Eichner M: Influenza pandemic intervention planning using InfluSim: pharmaceutical and non-pharmaceutical interventions. BMC Infect Dis. 2007, 7 (1): 76-10.1186/1471-2334-7-76.View ArticlePubMedPubMed CentralGoogle Scholar
- McCaw JM, Wood JG, McCaw CT, McVernon J: Impact of emerging antiviral drug resistance on influenza containment and spread: influence of subclinical infection and strategic use of a stockpile containing one or two drugs. PLoS ONE. 2008, 3 (6): e2362-10.1371/journal.pone.0002362.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/9/4/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.