Abstract
Structured Treatment Interruptions (STI) during HIV drug therapy were thought to potentially reduce side effects and toxicity, boost immune involvement, and possibly lower the viral set-point. Clinical trials of STI regimens, however, have had mixed results. We use an established mathematical model of HAART to estimate possible therapeutic outcomes for STI and for other, similar patterns in HIV combination therapy. We perform an exhaustive search of patterns of up to 60 days, for triple-drug combinations involving accurate pharmacokinetics for 12 specific antiviral drugs. The results of this analysis are consistent with recent clinical trials which have demonstrated that STI-type patterns, involving therapy interruption of weeks or months, are rarely optimal. Our analysis predicts, however, that the benefit of treatment can often be improved by including very short drug-free periods, during which the patient effectively “coasts” for a day or two on adequate drug concentrations due to the long half-life of some pharmaceuticals. Our analysis predicts many cases in which this may be achieved without increasing the risk of drug-resistance. This suggests that “drug coasting” patterns, significantly shorter than STI patterns, may merit further clinical investigation in efforts to find drug-sparing regimens for HIV.
Article PDF
Similar content being viewed by others
References
AIDSinfo Home Page, U.S. Department of Health and Human Services (DHHS) project. http://aidsinfo.nih.gov/. Retrieved 1 December 2005.
Ammassari, A., Murri, R., Pezzotti, P., Trotta, M.P., Ravasio, L., De Longis, P., Lo Caputo, S., Narciso, P., Pauluzzi, S., Carosi, G., Nappa, S., Piano, P., Izzo, C.M., Lichtner, M., Rezza, G., Monforte, A., Ippolito, G., d’Arminio Moroni, M., Wu, A.W., Antinori, A.A.S.G., 2001. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J. Acquir Immune Defic. Syndr. 5(28), 445–449.
Anderson, P.L., Kakuda, T.N., Kawle, S., Fletcher, C.V., 2003. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 17(15), 2159–2168.
Bajaria, S.H., Webb, G., Kirschner, D.E., 2004. Predicting differential responses to structured treatment interruptions during HAART. Bull Math. Biol. 66(5), 1093–1118.
Blankson, J.N., Siliciano, R.F., 2001. Structured therapeutic interruptions: a review. Hopkins HIV Rep. 13(1), 8–9, 13.
Boffito, M., Back, D.J., Blaschke, T.F., Rowland, M., Bertz, R.J., Gerber, J.G., Miller, V., 2003. Protein binding in antiretroviral therapies. AIDS Res. Hum. Retroviruses 19(9), 825–835.
Bonhoeffer, S., Rembiszewski, M., Ortiz, G.M., Nixon, D.F., 2000. Risks and benefits of structured antiretroviral drug therapy interruptions in HIV-1 infection. AIDS 14(15), 2313–2322.
Campbell, T.B., Young, R.K., Eron, J.J., D’Aquila, R.T., Tarpley, W.G., Kuritzkes, D.R., 1993. Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine. J. Infect. Dis. 168(2), 318–326.
Carr, A., Cooper, D.A., 2000. Adverse effects of antiretroviral therapy. Lancet 356(9239), 1423–1430.
Chesney, M.A., 2000. Factors affecting adherence to antiretroviral therapy. Clin. Infect. Dis. 30(Suppl. 2), S171–S176.
Chun, T.W., Fauci, A.S., 1999. Latent reservoirs of HIV: obstacles to the eradication of virus. Proc. Natl. Acad. Sci. USA 96(20), 10958–10961.
Combination Therapy, a Simple FactSheet from the AIDS Treatment Data Network. http://www.aegis.com/factshts/network/simple/combo.html. Retrieved 1 December 2005.
Daluge, S.M., Good, S.S., Faletto, M.B., Miller, W.H., St Clair, M.H., Boone, L.R., Tisdale, M., Parry, N.R., Reardon, J.E., Dornsife, R.E., Averett, D.R., Krenitsky, T.A., 1997. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob. Agents Chemother. 41(5), 1082–1093.
Dorman, K.S., Kaplan, A.H., Lange, K., Sinsheimer, J.S., 2000. Mutation takes no vacation: can structured treatment interruptions increase the risk of drug-resistant HIV-1? J. Acquir Immune Defic. Syndr. 25(5), 398–402.
Dybul, M., 2002. Structured treatment interruption: approaches and risks. Curr. Infect. Dis. Rep. 4(2), 175–180.
Eldred, L., Cheever, L., 1998. Update on adherence to HIV therapy. Hopkins HIV Rep. 10(1), 10–11.
Finzi, D., Blankson, J., Siliciano, J.D., Margolick, J.B., Chadwick, K., Pierson, T., Smith, K., Lisziewicz, J., Lori, F., Flexner, C., Quinn, T.C., Chaisson, R.E., Rosenberg, E., Walker, B., Gange, S., Gallant, J., Siliciano, R.F., 1999. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1. even in patients on effective combination therapy. Nat. Med. 5, 512–517.
Fister, K.R., Lenhart, S., McNally, J.S., 1998. Optimizing chemotherapy in an HIV model. Electr. J. Diff. Eq. 32, 1–12.
Grabar, S., Pradier, C., Le Corfec, E., Lancar, R., Allavena, C., Bentata, M., Berlureau, P., Dupont, C., Fabbro-Peray, P., Poizot-Martin, I., Costagliola, D., 2000. Factors associated with clinical and virological failure in patients receiving a triple therapy including a protease inhibitor. AIDS 14(2), 141–149.
Gulick, R.M., 2002. Structured treatment interruption in patients infected with HIV: a new approach to therapy? Drugs 62(2), 245–253.
Hatano, H., Miller, K.D., Yoder, C.P., Yanovski, J.A., Sebring, N.G., Jones, E.C., Davey, R.T.J., 2000. Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy. AIDS 14(13), 1935–1942.
HIV ePharmacotherapy Network Home Page. http://hiv.buffalo.edu. Retrieved 22 September 2005.
Howard, A.A., Arnsten, J.H., Lo, Y., Vlahov, D., Rich, J.D., Schuman, P., Stone, V.E., Smith, D.K.F., Schoenbaum, E.E.F.T.H.S.G., 2002. A prospective study of adherence and viral load in a large multi-center cohort of HIV-infected women. AIDS 16(16), 2175–2182.
Jefferys, R., 2006. SMART stops stopping. TAGline 13(1), 1–4.
Julg, B., Goebel, F.D., 2006. Treatment interruption in HIV therapy: a SMART strategy? Infection 34(3), 186–188.
Kaech, S.M., Wherry, E.J., Ahmed, R., 2002. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2(4), 251–262.
Karlin, S., Taylor, H.M., 1975. A First Course in Stochastic Processes. Academic, New York.
Kathleen, J.R., 2000. Barriers to and facilitators of HIV-positive patients’ adherence to antiretroviral treatment regimens. AIDS Patient Care STDs 14(3), 155–168.
Kirschner, D., Webb, G.F., 1996. A model for treatment strategy in the chemotherapy of AIDS. Bull. Math. Biol. 58(2), 367–390.
Kirschner, D., Lenhart, S., Serbin, S., 1997. Optimal control of the chemotherapy of HIV. J. Math. Biol. 35(7), 775–792.
Komarova, N.L., Barnes, E., Klenerman, P., Wodarz, D., 2003. Boosting immunity by antiviral drug therapy: a simple relationship among timing, efficacy, and success. Proc. Natl. Acad. Sci. USA 100(4), 1855–1860.
Krakovska, O., Wahl, L.M., 2007a. Costs versus benefits: best possible and best practical treatment regimens for HIV. J. Math. Biol. 54(3), 385–406.
Krakovska, O., Wahl, L.M., 2007b. Optimal drug treatment regimens for HIV depend on adherence. J. Theor. Biol. 246(3), 499–509.
Lisziewicz, J., Lori, F., 2002. Structured treatment interruptions in HIV/AIDS therapy. Microbes Infect. 4(2), 207–214.
Liverpool HIV Pharmacology Group (LHPG) Website. http://www.hiv-druginteractions.org/. Retrieved 5 December 2005.
Lohse, N., Obel, N., Kronborg, G., Laursen, A., Pedersen, C., Larsen, C.S., Kvinesdal, B., Sorensen, H.T., Gerstoft, J., 2005. Declining risk of triple-class antiretroviral drug failure in danish HIV-infected individuals. AIDS 19(8), 815–822.
Lori, F., Lisziewicz, J., 2001. Structured treatment interruptions for the management of HIV infection. JAMA 286(23), 2981–2987.
Macnab, K.A., Gill, M.J., Sutherland, L.R., Murphy, A., Brant, R., 1996. Zidovudine absorption and small intestinal function in HIV seropositive patients. J. Antimicrob. Chemother. 37(4), 825–829.
Markowitz, M., Louie, M., Hurley, A., Sun, E., Di Mascio, M., Perelson, A.S., Ho, D.D., 2003. A novel antiviral intervention results in more accurate assessment of human immunodeficiency virus type 1 replication dynamics and T-cell decay in vivo. J. Virol. 77, 5037–5038.
Martin-Carbonero, L., Soriano, V., Valencia, E., Garcia-Samaniego, J., Lopez, M., Gonzalez-Lahoz, J., 2001. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res. Hum. Retroviruses 17(16), 1467–1471.
Martinez-Picado, J., Negredo, E., Ruiz, L., Shintani, A., Fumaz, C.R., Zala, C., Domingo, P., Vilaro, J., Llibre, J.M., Viciana, P., Hertogs, K., Boucher, C., D’Aquila, R.T., Clotet, B., SWATCH Study Team, 2003. Alternation of antiretroviral drug regimens for HIV infection. a randomized, controlled trial. Ann. Intern. Med. 139(2), 81–89.
Mocroft, A., Ledergerber, B., Viard, J.P., Staszewski, S., Murphy, M., Chiesi, A., Horban, A., Hansen, A.B., Phillips, A.N., Lundgren, J.D., EuroSIDA Study Group, 2004. Time to virological failure of 3 classes of antiretrovirals after initiation of highly active antiretroviral therapy: results from the EuroSIDA study group. J. Infect. Dis. 190(11), 1947–1956.
Montaner, L.J., 2001. Structured treatment interruptions to control HIV-1 and limit drug exposure. Trends Immunol. 22(2), 92–96.
Murphy, R.L., Sommadossi, J.P., Lamson, M., Hall, D.B., Myers, M., Dusek, A., 1999. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with Human Immunodeficiency Virus type 1. J. Infect. Dis. 179(5), 1116–1123.
NIAD Division of AIDS (DAIDS) Home Page. http://www.niaid.nih.gov/daids/. Retrieved 22 September 2005.
Nowak, M.A., May, R.M., 2000. Virus Dynamics: Mathematical Principles of Immunology and Virology. Oxford University Press, Oxford. Chap. 10.
Pai, N.P., Tulsky, J.P., Lawrence, J., Colford, J.M.J., Reingold, A.L., Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. Cochrane Database Syst. Rev. 4 (2005). DOI: 10.1002/14651858.CD005482.
Perelson, A.S., Nelson, P.W., 1999. Mathematical analysis of HIV-1 dynamics in vivo. SIAM Rev. 41(1), 3–44.
Pfizer Inc. Home Page. http://www.pfizer.ca/. Retrieved 22 September 2005.
Phillips, A.N., Staszewski, S., Weber, R., Kirk, O., Francioli, P., Miller, V., Vernazza, P., Lundgren, J.D., Ledergerber, B., Swiss HIV Cohort Study, Frakfurt HIV Clinic Cohort, EuroSIDA Study Group, 2001. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load. JAMA 286(20), 2560–2567.
Phillips, A.N., Dunn, D., Sabin, C., Pozniak, A., Matthias, R., Geretti, A.M., Clarke, J., Churchill, D., Williams, I., Hill, T., Green, H., Porter, K., Scullard, G., Johnson, M., Easterbrook, P., Gilson, R., Fisher, M., Loveday, C., Gazzard, B., Pillay, D., UK Collaborative Group on HIV Drug Resistance, UK CHIC Study Group, 2005. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS 19(5), 487–494.
Ramratnam, B., Mittler, J.E., Zhang, L., Boden, D., Hurley, A., Fang, F., Macken, C.A., Perelson, A.S., Markowitz, M., Ho, D.D., 2000. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat. Med. 6(1), 82–85.
Ribeiro, R.M., Bonhoeffer, S.N.M., 1998. The frequency of resistant mutant virus before antiviral therapy. AIDS 12(5), 461–465.
Ribeiro, R.M., Mohri, H., Ho, D.D., Perelson, A.S., 2002. In vivo dynamics of t cell activation, proliferation, and death in HIV-1 infection: why are CD4+ but not CD8+ T cells depleted? Proc. Natl. Acad. Sci. USA 99(24), 15572–15577.
RxList, The Internet Drug Index Home Page. http://www.rxlist.com/. Retrieved 15 October 2005.
Siegel, K., Schrimshaw, E.W., Raveis, V.H., 2000. Accounts for non-adherence to antiviral combination therapies among older HIV-infected adults. Psychol. Heal. Med. 5(1), 29–42.
The Immunodeficiency Clinic—University Health Network Home Page. http://www.tthhivclinic.com/. Retrieved 15 October 2005.
van Heeswijk, R.P., Veldkamp, A.I., Mulder, J.W., Meenhorst, P.L., Wit, F.W., Lange, J.M., Danner, S.A., Foudraine, N.A., Kwakkelstein, M.O., Reiss, P., Beijnen, J.H., Hoetelmans, R.M., 2000. The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1 infected individuals. AIDS 14(8), F77–F82.
Viani, R.M., Gutteberg, T.J., Lathey, J.L., Spector, S.A., 1999. Lactoferrin inhibits HIV-1 replication in vitro and exhibits synergy when combined with zidovudine. AIDS 13(10), 1273–1274.
Wahl, L.M., Nowak, M.A., 2000. Adherence and resistance: Predictions for therapy outcome. Proc. Biol. Sci. 267(1445), 835–843.
Walensky, R.P., Goldie, S.J., Sax, P.E., Weinstein, M.C., Paltiel, A.D., Kimmel, A.D., Seage, G.R.R., Losina, E., Zhang, H., Islam, R., Freedberg, K.A., 2002. Treatment for primary HIV infection: projecting outcomes of immediate, interrupted, or delayed therapy. J. Acquir Immune Defic. Syndr. 31, 27–37.
Walmsley, S., Loutfy, M., 2002. Can structured treatment interruptions (STIs) be used as a strategy to decrease total drug requirements and toxicity in HIV infection? J. Int. Assoc. Phys. AIDS Care (Chic. Ill.) 1(3), 95–103.
Wodarz, D., Page, K.M., Arnaout, R.A., Thomsen, A.R., Lifson, J.D., Nowak, M.A., 2000. A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment. Philos. Trans. Roy. Soc. Lond. B Biol. Sci. 355(1395), 329–343.
Zhang, L., Ramratnam, B., Tenner-Racz, K., He, Y., Vesanen, M., Lewin, S., Talal, A., Racz, P., Perelson, A.S., Korber, B.T., Markowitz, M., Ho, D.D., 1999. Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N. Engl. J. Med. 340(21), 1605–1913.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
Krakovska, O., Wahl, L.M. Drug-Sparing Regimens for HIV Combination Therapy: Benefits Predicted for “Drug Coasting”. Bull. Math. Biol. 69, 2627–2647 (2007). https://doi.org/10.1007/s11538-007-9234-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11538-007-9234-9