Antiretroviral dynamics determines HIV evolution and predicts therapy outcome
Daniel I S Rosenbloom, Alison L Hill, S Alireza Rabi, Robert F Siliciano, Martin A Nowak, Daniel I S Rosenbloom, Alison L Hill, S Alireza Rabi, Robert F Siliciano, Martin A Nowak
Abstract
Despite the high inhibition of viral replication achieved by current anti-HIV drugs, many patients fail treatment, often with emergence of drug-resistant virus. Clinical observations show that the relationship between adherence and likelihood of resistance differs dramatically among drug classes. We developed a mathematical model that explains these observations and predicts treatment outcomes. Our model incorporates drug properties, fitness differences between susceptible and resistant strains, mutations and adherence. We show that antiviral activity falls quickly for drugs with sharp dose-response curves and short half-lives, such as boosted protease inhibitors, limiting the time during which resistance can be selected for. We find that poor adherence to such drugs causes treatment failure via growth of susceptible virus, explaining puzzling clinical observations. Furthermore, our model predicts that certain single-pill combination therapies can prevent resistance regardless of patient adherence. Our approach represents a first step for simulating clinical trials of untested anti-HIV regimens and may help in the selection of new drug regimens for investigation.
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References
- Palella FJ, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338:853–860.
- Vanhove GF, Schapiro JM, Winters MA, Merigan TC, Blaschke TF. Patient compliance and drug failure in protease inhibitor monotherapy. J Am Med Assoc. 1996;276(24):1955–1956.
- Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral medication adherence and the development of class-specific antiretroviral resistance. AIDS. 2009;23(9):1035–1046.
- Maggiolo F, et al. Effect of adherence to HAART on virologic outcome and on the selection of resistance-conferring mutations in NNRTI- or PI-treated patients. HIV Clin Trials. 2007;8(5):282–292.
- Harrigan PR, et al. Predictors of HIV drug-resistance mutations in a large antiretroviral- naive cohort initiating triple antiretroviral therapy. J Infect Dis. 2005;191(3):339–347.
- US Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults & Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2011 .
- Arribas JR, et al. The MONET trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV RNA below 50 copies/ml. AIDS. 2010;24:223–230.
- Taiwo B, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG a5262) AIDS. 2011;25(17):2113–2122.
- Havlir DV, et al. Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. J Am Med Ass. 2000;283(2):229–234.
- Pulido F, Arribas J, Hill A, Moecklinghoff C. No evidence for evolution of genotypic resistance after three years of treatment with darunavir/ritonavir, with or without nucleoside analogues. AIDS Res Hum Retroviruses. 2012
- Condra JH. Resistance to HIV protease inhibitors. Haemophilia. 1998;4:610–615.
- Kempf DJ, et al. Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis. 2004;189:51–60.
- Noe A, Plum J, Verhofstede C. The latent HIV-1 reservoir in patients undergoing HAART: an archive of pre-HAART drug resistance. J Antimicrob Chemother. 2005;55:410–412.
- Nowak MA, May RMC. Virus Dynamics: Mathematical principles of immunology and virology. Oxford University Press; USA: 2000.
- Chou TC. Derivation and properties of Michaelis-Menten type and Hill type equations for reference ligands. J Theor Biol. 1976;59(2):253–276.
- Shen L, et al. Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med. 2008;14(7):762–766.
- Sampah MES, Shen L, Jilek BL, Siliciano RF. Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance. Proc Natl Acad Sci USA. 2011;108(18):7613–7618.
- Drlica K. The mutant selection window and antimicrobial resistance. J Antimicrob Chemother. 2003;52(1):11–17.
- Drlica K, Zhao X. Mutant selection window hypothesis updated. Clin Infect Dis. 2007;44(5):681–688.
- Wahl LM, Nowak MA. Adherence and drug resistance: predictions for therapy outcome. Proc R Soc B. 2000;267(1445):835–843.
- Wu H, et al. Modeling long-term HIV dynamics and antiretroviral response: effects of drug potency, pharmacokinetics, adherence, and drug resistance. J Acquir Immune Defic Syndr. 2005;39(3):272–283.
- Smith RJ. Adherence to antiretroviral HIV drugs: how many doses can you miss before resistance emerges? Proc R Soc B. 2006;273(1586):617–624.
- Rong L, Feng Z, Perelson AS. Emergence of HIV-1 drug resistance during antiretroviral treatment. Bull Math Biol. 2007;69(6):2027–2060.
- Bangsberg DR, Moss AR, Deeks SG. Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. J Antimicrob Chemother. 2004;53(5):696–699.
- Perez-Valero I, Arribas JR. Protease inhibitor monotherapy. Curr Opin Infect Dis. 2011;24:7–11.
- Bangsberg DR, Kroetz DL, Deeks SG. Adherence-resistance relationships to combination HIV antiretroviral therapy. Curr HIV/AIDS Rep. 2007;4(2):65–72.
- Bliss CI. The toxicity of poisons applied jointly. Ann Appl Biol. 1939;26(3):585–615.
- Jilek BL, et al. A quantitative basis for antiretroviral therapy for HIV-1 infection. Nat Med. 2012;18(3):446–451.
- Shen L, et al. A critical subset model provides a conceptual basis for the high antiviral activity of major HIV drugs. Sci Transl Med. 2011;3(91):91ra63.
- Bangsberg DR, et al. Adherence-resistance relationships for protease and non-nucleoside reverse transcriptase inhibitors explained by virological fitness. AIDS. 2006;20(2):223–231.
- Nijhuis M, et al. A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med. 2007;4(1):e36.
- Parry CM, et al. Gag determinants of fitness and drug susceptibility in protease Inhibitor- Resistant human immunodeficiency virus type 1. J Virol. 2009;83(18):9094–9101.
- Dam E, et al. Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog. 2009;5(3):e1000345.
- Gupta RK, et al. Full length HIV-1 gag determines protease inhibitor susceptibility within in vitro assays. AIDS (London, England) 2010;24(11):1651–1655.
- Gardner EM, et al. Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance. AIDS. 2008;22(1):75–82.
- Michel JB, Yeh PJ, Chait R, Moellering RC, Kishony R. Drug interactions modulate the potential for evolution of resistance. Proc Natl Acad Sci USA. 2008;105:14918–14923.
- Cheeseman SH, et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr. 1995;8(2):141–151.
- Ruxrungtham K, et al. Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-nave, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227. HIV Medicine. 2008;9(10):883–896.
- Bonhoeffer S, Nowak MA. Pre-existence and emergence of drug resistance in HIV-1 infection. Proc R Soc B. 1997;264(1382):631–637.
- Paredes R, et al. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis. 2010;201:662–671.
- Jourdain G, et al. Association between detection of HIV-1 DNA resistance mutations by a sensitive assay at initiation of antiretroviral therapy and virologic failure. Clin Infect Dis. 2010;50:1397–1404.
- Simen BB, et al. Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment-naive patients significantly impact treatment outcomes. J Infect Dis. 2009;199:693–701.
- Gupta RK, et al. Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under who guidelines: a systematic review and meta-analysis. Lancet Infect Dis. 2009;9:409–417.
- Hoffmann CJ, et al. Viremia, resuppression, and time to resistance in human immunod-eficiency virus (HIV) subtype c during first-line antiretroviral therapy in south africa. Clin Infect Dis. 2009;49:1928–1935.
- Parienti JJ, et al. Not all missed doses are the same: sustained NNRTI treatment inter-ruptions predict HIV rebound at low-to-moderate adherence levels. PLoS ONE. 2008;3(7):e2783.
- Parienti JJ, et al. Average adherence to boosted protease inhibitor therapy, rather than the pattern of missed doses, as a predictor of HIV RNA replication. Clin Infect Dis. 2010;50(8):1192–1197.
- Liu H, et al. Repeated measures analyses of dose timing of antiretroviral medication and its relationship to HIV virologic outcomes. Stat Med. 2007;26(5):991–1007.
- Kastrissios H, et al. Characterizing patterns of drug-taking behavior with a multiple drug regimen in an AIDS clinical trial. AIDS. 1998;12(17):2295.
- Sigal A, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature. 2011;477:95–98.
- Kepler TB, Perelson AS. Drug concentration heterogeneity facilitates the evolution of drug resistance. Proc Natl Acad Sci USA. 1998;95(20):11514–11519.
- Schnell G, Price RW, Swanstrom R, Spudich S. Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol. 2010;84:2395–2407.
- van Marle G, et al. Compartmentalization of the gut viral reservoir in HIV-1 infected patients. Retrovirology. 2007;4:87.
- Best B, et al. Efavirenz concentrations in CSF exceed IC50 for wild-type HIV. J Antimicrob Chemother. 2011;66(2):354.
- Hirsch M, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society–USA panel. J Am Med Ass. 2000;283:2417–2426.
- Lima VD, et al. Differential impact of adherence on long-term treatment response among naive HIV-infected individuals. AIDS. 2008;22:2371–2380.
- Boltz VF, et al. Role of low-frequency HIV-1 variants in failure of nevirapine-containing antiviral therapy in women previously exposed to single-dose nevirapine. Proc Natl Acad Sci USA. 2011;108(2):9202–9207.
- Nowak MA, et al. Antigenic diversity thresholds and the development of AIDS. Science. 1991;254:963–969.
- Shankarappa R, et al. Consistent viral evolutionary changes associated with the progression of human immunodeficiency virus type 1 infection. J Virol. 1999;73(12):10489–10502.
- Neher RA, Leitner T. Recombination rate and selection strength in HIV intra-patient evolution. PLoS Comput Biol. 2010;6(1):e1000660.
- Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutant bacteria: measurement and potential use of the mutant selection window. J Infect Dis. 2002;185(4):561–565.
- Gullberg E, et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathog. 2011;7(7):e1002158.
- Sedaghat AR, Dinoso JB, Shen L, Wilke CO, Siliciano RF. Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle. Proc Natl Acad Sci USA. 2008;105(12):4832.
- Ribeiro RM, et al. Estimation of the initial viral growth rate and basic reproductive number during acute HIV-1 infection. J Virol. 2010;84(12):6096–6102.
- Ribeiro RM, Bonhoeffer S, Nowak MA. The frequency of resistant mutant virus before antiviral therapy. AIDS. 1998;12(5):461.
- Hartl DL, Clark AG. Principles of Population Genetics. Sinauer Associates; 2007.
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