Use of a stochastic model to develop understanding of the impact of different patterns of antiretroviral drug use on resistance development.
OBJECTIVE
To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns.


METHODS
We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells.


RESULTS
Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence.


CONCLUSIONS
This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.
Phillips
A N
AN
Royal Free Centre for HIV Medicine, Royal Free & University College Medical School, University College London, London, UK.
Youle
M
M
Johnson
M
M
Loveday
C
C
D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003198:Computer Simulation; D024921:Drug Resistance, Multiple, Viral; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015233:Models, Statistical; D009154:Mutation; D013269:Stochastic Processes
D019380:Anti-HIV Agents