Emergence of drug resistance: implications for antiviral control of pandemic influenza

Abstract

Given the danger of an unprecedented spread of the highly pathogenic avian influenza strain H5N1 in humans, and great challenges to the development of an effective influenza vaccine, antiviral drugs will probably play a pivotal role in combating a novel pandemic strain. A critical limitation to the use of these drugs is the evolution of highly transmissible drug-resistant viral mutants. Here, we develop a mathematical model to evaluate the potential impact of an antiviral treatment strategy on the emergence of drug resistance and containment of a pandemic. The results show that elimination of the wild-type strain depends crucially on both the early onset of treatment in indexed cases and population-level treatment. Given the probable delay of 0.5-1 day in seeking healthcare and therefore initiating therapy, the findings indicate that a single strategy of antiviral treatment will be unsuccessful at controlling the spread of disease if the reproduction number of the wild-type strain (R0s) exceeds 1.4. We demonstrate the possible occurrence of a self-sustaining epidemic of resistant strain, in terms of its transmission fitness relative to the wild-type, and the reproduction number R0s. Considering reproduction numbers estimated for the past three pandemics, the findings suggest that an uncontrollable pandemic is likely to occur if resistant viruses with relative transmission fitness above 0.4 emerge. While an antiviral strategy is crucial for containing a pandemic, its effectiveness depends critically on timely and strategic use of drugs.

Figure 1

Dynamics of influenza A virus infection, corresponding to the results obtained from model fitting to data of viral titre in experimentally infected immunocompetent adults with H1N1 influenza A (Baccam et al. 2006).

Figure 2

Model structure for development of drug resistance during a course of therapy.

Figure 3

(a) Profile of treatment rate ($r_{a_0}$) that decreases towards the end of the window of opportunity for starting an effective course of antiviral therapy. (b) Rate of emergence of drug resistance (${\rho }_{a_0}$) during treatment within the window of opportunity.

Figure 4

The feasible region for the control of wild-type disease (shaded area), as a function of delay in initiating antiviral treatment and its level, corresponding to the profile of $r_{a_0}(u)$ and ${\rho }_{a_0}(u)$ in figure 3a,b, respectively, with the relative transmission fitness δ_r=0.2 of resistant virus and (a) $R_0^{\text{s}}=1.4$; (b) $R_0^{\text{s}}=1.6$; (c) $R_0^{\text{s}}=1.8$; (d) $R_0^{\text{s}}=2$.

Figure 5

The feasible region for containing the epidemic of the wild-type strain, as a function of delay in the onset of treatment and the level of treatment. Each contour corresponds to a particular value of $R_0^{\text{s}}$ (labelled between 1.1 and 1.8), above which $R_{\text{c}}^{\text{s}}$ is less than one and the wild-type strain can be eliminated.

Figure 6

Time-courses of wild-type infections without treatment for (a) $R_0^{\text{s}}=1.6$; and (b) $R_0^{\text{s}}=2$. Time-courses of wild-type and resistant infections with one day delay in onset of treatment and 60% coverage of treatment for (c) $R_0^{\text{s}}=1.6$; and (d) $R_0^{\text{s}}=2$. Initial values are S₀=100 000 and I_U(0)=1.

Figure 7

Time courses of untreated resistant infections for $R_0^{\text{s}}=1.6$ (blue) and $R_0^{\text{s}}=2$ (black) with δ_r=0.6. Initial values are S₀=100 000 and I_U(0)=1.

Figure 8

The region for the occurrence of a self-sustaining epidemic of the resistant strain (shaded region) as a function of the relative transmission fitness of the resistant virus (δ_r) and the reproduction number of the wild-type virus ($R_0^{\text{s}}$).