Theoretical rationale for the use of sequential single-drug antiretroviral therapy for treatment of HIV infection.
BACKGROUND
Subpopulations of HIV with mutations associated with resistance to antiretroviral drugs often have reduced replicative capacity, so virus with resistance mutations for all existing and new antiretroviral drugs is likely to be appreciably impaired. Issues of toxicity, quality of life and economics mean that the simultaneous use of all these drugs in combination is unrealistic. We aimed to explore the use of sequential monotherapy regimens using a mathematical model of quasi-species dynamics, to see if these could take advantage of the poor replicative capacity of highly resistant virus.


METHODS
We assume for each of seven drugs that a single mutation is associated with the ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. Parameters included were drug efficacy, the cost of resistance mutations and the number of new target cells arising daily.


RESULTS
The use of seven drugs in a daily/weekly sequential monotherapy cycle led to substantial viral suppression (in the presence of all resistant viral subpopulations) for a wider range of parameter values than a continuous five-drug regimen. Although on any one day/week there is a viral subpopulation with R > 1 (e.g. that with resistance only to the current drug), this subpopulation does not have time to grow sufficiently during the short period when that drug is being taken.


CONCLUSIONS
These results provide a rationale for trials of sequential regimens, using as wide a number of drugs with different resistance-associated mutations as possible, as a potential 'resistance-proof' strategy for achieving significant viral load suppression.
Phillips
Andrew N
AN
Royal Free Centre for HIV Medicine and Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK. a.phillips@pcps.ucl.ac.uk
Youle
Michael S
MS
Lampe
Fiona
F
Johnson
Margaret
M
Sabin
Caroline A
CA
Lepri
Alessandro Cozzi
AC
Loveday
Clive
C
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018432:Drug Resistance, Multiple / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics
D019380:Anti-HIV Agents