Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations

Theoretical Biology and Medical Modelling Transient antiretroviral therapy selecting for common HIV-1 mutations substantially accelerates the appearance of rare mutations Tinevimbo Shiri 0 1 Alex Welte 0 1 0 South African Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University , South Africa 1 School of Computational and Applied Mathematics, University of the Witwatersrand , Private Bag 3, Johannesburg , South Africa Background: Highly selective antiretroviral (ARV) regimens such as single dose nevirapine (NVP) used for prevention of mother to child transmission (PMTCT) in resource-limited settings produce transient increases in otherwise marginal subpopulations of cells infected by mutant genomes. The longer term implications for accumulation of further resistance mutations are not fully understood. Methods: We develop a new strain-differentiated hybrid deterministic-stochastic population dynamic type model of healthy and infected cells. We explore how the transient increase in a population of cells transcribed with a common mutation (modelled deterministically), which occurs in response to a short course of monotherapy, has an impact on the risk of appearance of rarer, higher-order, therapy-defeating mutations (modelled stochastically). Results: Scenarios with a transient of a magnitude and duration such as is known to occur under NVP monotherapy exhibit significantly accelerated viral evolution compared to no-treatment scenarios. We identify a possibly important new biological timescale; namely, the duration of persistence, after a seminal mutation, of a sub-population of cells bearing the new mutant gene, and we show how increased persistence leads to an increased probability that a rare mutant will be present at the moment at which a new treatment regimen is initiated. Conclusion: Even transient increases in subpopulations of common mutants are associated with accelerated appearance of further rarer mutations. Experimental data on the persistence of small subpopulations of rare mutants, in unfavourable environments, should be sought, as this affects the risk of subverting later regimens. - Background The rapidity of human immunodeficiency virus (HIV) replication, combined with its high reverse transcriptase error rate [1], leads to rapid viral evolution, in particular the emergence of drug resistance. Treatment that is unable to sufficiently inhibit viral replication allows the appearance and/or selection of drug-resistant strains. Further accumulation of resistant variants may limit therapeutic efficacy and jeorpadize subsequent treatment options. A single dose nevirapine (NVP) regimen for prevention of mother to child transmission (PMTCT) is a well known example of a suboptimal regimen that inevitably, if temporarily, exerts selective pressure in favour of resistant strains. This is still a major concern in developing countries where a prophylactic regimen of single dose NVP is widely used for PMTCT [2]. Given the high frequency of mutation, some minority resistant mutants are always preexisting, albeit in trace quantities, at the moment therapy is initiated. Because of the long half-life of single dose NVP, with blood levels detectable up to 23 weeks after exposure [3,4], the duration of sub-therapeutic NVP concentrations may present a significant hazard of developing resistance for the mother. There is a risk of treatment failure after single dose NVP exposure, if the treatment includes a NNRTI [5]. The question arises whether, and to what extent, a transient treatment-induced boost to an otherwise marginal subpopulation results in increased risk of accumulation of further resistance mutations that could potentially increase the risk of subsequent NNRTIbased treatment failure. In the search for better PMTCT regimens, improved efficacy has been demonstrated for a number of short course regimens for PMTCT in resource-limited settings. For example, 1) use of single dose NVP with additional short course of zidovudine/lamivudine during 37 days postpartum [6], 2) addition of single dose NVP to zidovudine short course during the antenatal period [7] and, recently, 3) use of intrapartum single dose of combined tenofovir/ emtricitabine taken after antenatal short course of zidovudine plus intrapartum single dose NVP [8]. These regimens improve on single dose NVP either in efficacy for PMTCT or reduction of NVP resistance in the mother, or both. However they appear suboptimal in that they select for NNRTI-resistant strains and therefore increase the mothers' risk of virologic failure for subsequent NNRTIbased therapy. For example, in the MASHI study [7] a total of 218 women started post partum NVP-based therapy after they had received zidovudine from 34 weeks of gestation through delivery. Of these, 112 had received single dose NVP, whilst the rest had received a placebo during labour. After 6 months of post partum treatment with a NVP-based regimen, women without prior NVP exposure were less likely to have virologic failure compared to women who had received intrapartum NVP. Strikingly, of women who started NVP-based therapy within 6 months, 41.7% from the single dose NVP group, but none from the control group, had virologic failure. In-vivo mathematical models have been useful in exploring the evolution of drug resistance, suggesting that significant evolution can occur during treatment or before initiation of treatment [9-15]. Based on the models, the authors argued that chances of resistance evolving during treatment are small compared to chances of resistance evolving before suppressive therapy. However these studies did not explore, in any dynamically consistent framework, the emergence/accumulation of multiple mutations in a possibly non constant environment. In this study, we extend these standard models to explicitly investigate the consequences of population dynamical effects amongst common resistant mutants. We show how the deterministic dynamics of the common mutants affects the time taken to produce the rarer mutants. We start from an ordinary differential equation (ODE)type model of in-vivo viral replication in the deterministic regime, applicable to cell populations that are large enough for statistical fluctuations to be relatively small (wild-type and common mutant strains). We explicitly add expressions for Poisson rates for the occurrence of rare mutations. Using standard survival analysis, we compute, as a function of time, the probability of avoiding a mutation event. Furthermore, we introduce an additional timescale to the 'survival function' to capture the time over which cells infected by an unfit genome persist before being ecologically overwhelmed. This 'survival function' is a continuous state variable that is incorporated into the system of ODEs without much complexity. We apply our modelling framework to clinically inspired scenarios. Firstly, we explore the quasi steady state that correspon (...truncated)