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Standing genetic variation and the evolution of drug resistance in HIV.

Pennings PS - PLoS Comput. Biol. (2012)

Bottom Line: We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation.We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-arameters which determine the probability that resistance evolves from standing genetic variation.Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America. pennings@fas.harvard.edu

ABSTRACT
Drug resistance remains a major problem for the treatment of HIV. Resistance can occur due to mutations that were present before treatment starts or due to mutations that occur during treatment. The relative importance of these two sources is unknown. Resistance can also be transmitted between patients, but this process is not considered in the current study. We study three different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment with a single dose of nevirapine and interruption of treatment. For each of these three cases good data are available from literature, which allows us to estimate the probability that resistance evolves from standing genetic variation. Depending on the treatment we find probabilities of the evolution of drug resistance due to standing genetic variation between 0 and 39%. For patients who start triple-drug combination therapy, we find that drug resistance evolves from standing genetic variation in approximately 6% of the patients. We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation. We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-arameters which determine the probability that resistance evolves from standing genetic variation. Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.

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Drug level and population size during and after a treatment interruption.Drug level (dashed line) and viral population size (solid line) during and after a treatment interruption. Red bars indicate when drugs are taken.
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pcbi-1002527-g005: Drug level and population size during and after a treatment interruption.Drug level (dashed line) and viral population size (solid line) during and after a treatment interruption. Red bars indicate when drugs are taken.

Mentions: During a treatment interruption, drugs are first removed from the body, which can take from a couple of hours to a several days or even weeks ([45], [46], [47]. With some delay, depending on the half-life of the drugs, the viral population begins to grow, which is observed as an increase of viral load (see figure 5). Published data show that after treatment is stopped, viral load quickly increases in almost all patients (e.g., [2]. Davey et al [31] show that average viral load plateaus four weeks after treatment is interrupted. Garcia et al [48] and Trkola et al ([49]) both report that a plateau is reached between four and eight weeks after treatment interruptions. An interruption is ended when treatment is started again and viral load goes down, hopefully to undetectable levels. Figure 1 shows a cartoon of the pharmacodynamics and population dynamics of a treatment interruption.


Standing genetic variation and the evolution of drug resistance in HIV.

Pennings PS - PLoS Comput. Biol. (2012)

Drug level and population size during and after a treatment interruption.Drug level (dashed line) and viral population size (solid line) during and after a treatment interruption. Red bars indicate when drugs are taken.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369920&req=5

pcbi-1002527-g005: Drug level and population size during and after a treatment interruption.Drug level (dashed line) and viral population size (solid line) during and after a treatment interruption. Red bars indicate when drugs are taken.
Mentions: During a treatment interruption, drugs are first removed from the body, which can take from a couple of hours to a several days or even weeks ([45], [46], [47]. With some delay, depending on the half-life of the drugs, the viral population begins to grow, which is observed as an increase of viral load (see figure 5). Published data show that after treatment is stopped, viral load quickly increases in almost all patients (e.g., [2]. Davey et al [31] show that average viral load plateaus four weeks after treatment is interrupted. Garcia et al [48] and Trkola et al ([49]) both report that a plateau is reached between four and eight weeks after treatment interruptions. An interruption is ended when treatment is started again and viral load goes down, hopefully to undetectable levels. Figure 1 shows a cartoon of the pharmacodynamics and population dynamics of a treatment interruption.

Bottom Line: We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation.We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-arameters which determine the probability that resistance evolves from standing genetic variation.Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.

View Article: PubMed Central - PubMed

Affiliation: Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, United States of America. pennings@fas.harvard.edu

ABSTRACT
Drug resistance remains a major problem for the treatment of HIV. Resistance can occur due to mutations that were present before treatment starts or due to mutations that occur during treatment. The relative importance of these two sources is unknown. Resistance can also be transmitted between patients, but this process is not considered in the current study. We study three different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment with a single dose of nevirapine and interruption of treatment. For each of these three cases good data are available from literature, which allows us to estimate the probability that resistance evolves from standing genetic variation. Depending on the treatment we find probabilities of the evolution of drug resistance due to standing genetic variation between 0 and 39%. For patients who start triple-drug combination therapy, we find that drug resistance evolves from standing genetic variation in approximately 6% of the patients. We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation. We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-arameters which determine the probability that resistance evolves from standing genetic variation. Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.

Show MeSH
Related in: MedlinePlus