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Comparative Study
. 2000 Jul 5;97(14):7681-6.
doi: 10.1073/pnas.97.14.7681.

Production of resistant HIV mutants during antiretroviral therapy

R M Ribeiro  1 , S Bonhoeffer
Affiliations
Comparative Study

Production of resistant HIV mutants during antiretroviral therapy

R M Ribeiro et al. Proc Natl Acad Sci U S A. .

Abstract

HIV drug therapy often fails because of the appearance of multidrug-resistant virus. There are two possible scenarios for the outgrowth of multidrug-resistant virus in response to therapy. Resistant virus may preexist at low frequencies in drug-naive patients and is rapidly selected in the presence of drugs. Alternatively, resistant virus is absent at the start of therapy but is generated by residual viral replication during therapy. Currently available experimental methods are generally too insensitive to distinguish between these two scenarios. Here we use deterministic and stochastic models to investigate the origin of multidrug resistance. We quantify the probabilities that resistant mutants preexist, and that resistant mutants are generated during therapy. The models suggest that under a wide range of conditions, treatment failure is most likely caused by the preexistence of resistant mutants.

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Figures

Figure 1
Figure 1
Graphical comparison of the full (solid line) and simplified (dashed line) models under drug therapy (see text). In A, we compare the increase in the number of susceptible cells and in B, the decrease in the infected cell population. Notice that in both cases, the simplified model overestimates the full model. Parameters are as follows: λ = 106, b = 5 × 10−8, bd = rb = 2.25 × 10−8, a = 0.5, δ = 0.05. Thus, Rb = 2 and Rd = 0.9.
Figure 2
Figure 2
Behavior of Θ (the ratio between the likelihood of emergence of resistant mutants emergence during therapy and the likelihood of preexistence of resistant mutants) with Rd and Rb, for γ = 10. For most of the parameter region, the ratio is smaller than one. The ratio Θ becomes close to one only when Rd, the basic reproductive ratio during therapy, is also close to one.
Figure 3
Figure 3
Behavior of Θn with (A) increasing selective disadvantage and (B) larger number of point mutations separating the wild type and the resistant mutant. Notice in A that the ratio Θn is bigger than one only for large values of the selective disadvantage. Parameters are as in Fig. 1 except for the ones indicated; in A, n = 3 and in B, s = 0.1.
See this image and copyright information in PMC

Comment in

  • HIV therapy: managing resistance.
    Wodarz D, Nowak MA. Wodarz D, et al. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8193-5. doi: 10.1073/pnas.97.15.8193. Proc Natl Acad Sci U S A. 2000. PMID: 10899988 Free PMC article. No abstract available.

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