Predicting the unpredictable: Transmission of drug-resistant HIV

We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is high, and predict it will continue to rise. In contrast, we calculate that transmission of resistance is currently low, and predict it will remain low. We show that the epidemic of resistance is being generated mainly by the conversion of drug-sensitive cases to drug-resistant cases, and not by the transmission of resistant strains. We also show that transmission of resistant strains has not increased the overall number of new HIV infections. Our results indicate that transmission of resistant strains is, and will remain, a relatively minor public health problem.

[1]  P. Kissinger,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. , 1998, The New England journal of medicine.

[2]  E. Rosenberg,et al.  Reduced antiretroviral drug susceptibility among patients with primary HIV infection. , 1999, JAMA.

[3]  J. Catania,et al.  U.S. Priorities-HIV Prevention , 2000, Science.

[4]  S. Little Is transmitted drug resistance in HIV on the rise? , 2001, BMJ : British Medical Journal.

[5]  Hadi Dowlatabadi,et al.  Sensitivity and Uncertainty Analysis of Complex Models of Disease Transmission: an HIV Model, as an Example , 1994 .

[6]  A. Mocroft,et al.  Predictors of virological success and ensuing failure in HIV-positive patients starting highly active antiretroviral therapy in Europe: results from the EuroSIDA study. , 2000, Archives of internal medicine.

[7]  J. Gallant,et al.  Strategies for long-term success in the treatment of HIV infection. , 2000, JAMA.

[8]  F. Brun-Vézinet,et al.  A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team. , 1998, The New England journal of medicine.

[9]  J. Kahn,et al.  Sexual transmission of an HIV-1 variant resistant to multiple reverse-transcriptase and protease inhibitors. , 1998, The New England journal of medicine.

[10]  J. C. Helton,et al.  Statistical Analyses of Scatterplots to Identify Important Factors in Large-Scale Simulations, 1: Review and Comparison of Techniques , 1999 .

[11]  H. Gershengorn,et al.  A tale of two futures: HIV and antiretroviral therapy in San Francisco. , 2000, Science.

[12]  R. Hogg,et al.  Improved survival among HIV-infected individuals following initiation of antiretroviral therapy. , 1998, JAMA.

[13]  Katia Koelle,et al.  Antibiotic resistance—to treat... , 1999, Nature Medicine.

[14]  J. Gerberding,et al.  Understanding, predicting and controlling the emergence of drug-resistant tuberculosis: a theoretical framework , 1998, Journal of Molecular Medicine.

[15]  S. Blower,et al.  Live attenuated HIV vaccines: Predicting the tradeoff between efficacy and safety , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Blower,et al.  Control Strategies for Tuberculosis Epidemics: New Models for Old Problems , 1996, Science.

[17]  S. Yerly,et al.  Transmission of antiretroviral-drug-resistant HIV-1 variants , 1999, The Lancet.

[18]  R. Grant,et al.  Impaired replication of protease inhibitor-resistant HIV-1 in human thymus , 2001, Nature Medicine.

[19]  E. H. Kaplan,et al.  Public Health Consequences of Screening Patients for Adherence to Highly Active Antiretroviral Therapy , 2001, Journal of acquired immune deficiency syndromes.

[20]  M. Battegay,et al.  Reasons for discontinuation of first highly active antiretroviral therapy in a cohort of proteinase inhibitor-naive HIV-infected patients. , 2001, Journal of acquired immune deficiency syndromes.

[21]  M A Wainberg,et al.  Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use , 2000, AIDS.

[22]  To treat or not to treat? , 1998, Nature Medicine.

[23]  J. Montaner,et al.  Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine , 2001, AIDS.

[24]  S. Blower,et al.  Predicting and preventing the emergence of antiviral drug resistance in HSV-2 , 1998, Nature Medicine.

[25]  S. Blower,et al.  The intrinsic transmission dynamics of tuberculosis epidemics , 1995, Nature Medicine.

[26]  V. Calvez,et al.  Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team). , 2000, JAMA.

[27]  S. Blower Calculating the consequences: HAART and risky sex. , 2001, AIDS.

[28]  M Egger,et al.  AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. , 1999, JAMA.

[29]  S. Hammer,et al.  Patterns of plasma human immunodeficiency virus type 1 RNA response to antiretroviral therapy. , 2001, The Journal of infectious diseases.

[30]  A Muñoz,et al.  Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. , 1998, JAMA.

[31]  G. Satten,et al.  Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. , 1998, The New England journal of medicine.

[32]  R. Coutinho,et al.  Large diurnal variation in CD4 cell count and T‐cell function among drug users: implications for clinical practice and epidemiological studies , 1992, AIDS.

[33]  B. Gazzard,et al.  1998 revision to the British HIV Association guidelines for antiretroviral treatment of HIV seropositive individuals , 1998, The Lancet.

[34]  Christopher Dye,et al.  Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. , 2001, The New England journal of medicine.

[35]  M. Hirsch,et al.  Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens. , 2000, JAMA.

[36]  T. Quinn,et al.  Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. , 2000, The New England journal of medicine.

[37]  W. Henley,et al.  Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases , 2001, AIDS.