Assessing resistance costs of antiretroviral therapies via measures of future drug options.

The emergence of drug-resistant human immunodeficiency virus (HIV) type 1 in the setting of antiretroviral therapy failure limits the number of drugs available for use in subsequent therapy regimens. To quantify the relative HIV-1-resistance costs associated with various antiretroviral therapy strategies, we developed 2 related measures of future drug options (FDOs) by use of rule-based genotype-interpretation systems. The FDO1 metric assesses the number of drug classes that remain useful; the FDO2 metric assesses the number of drug classes that remain useful and the number of active drugs within each class. Application of these methods is illustrated with data from a randomized study of 3 therapy regimens in nucleoside analog-experienced patients. Each therapy regimen resulted in a unique pattern of drug-resistance (and cross-resistance) mutations. The regimen with the highest virologic failure rate preserved greater future drug options. Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights.

[1]  The Two‐Sample Problem with Induced Dependent Censorship , 1999, Biometrics.

[2]  A. Telenti,et al.  Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: a prospective cohort study , 1999, The Lancet.

[3]  Mark Dybul,et al.  Guidelines for Using Antiretroviral Agents among HIV-Infected Adults and Adolescents: The Panel on Clinical Practices for Treatment of HIV* , 2002, Annals of Internal Medicine.

[4]  A. Carr.  For Personal Use. Only Reproduce with Permission from the Lancet Publishing Group. the Study of Adverse Events in Clinical Trials , 2022 .

[5]  M A Fischl,et al.  A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. , 1997, The New England journal of medicine.

[6]  Manuel Battegay,et al.  Impact of new antiretroviral combination therapies in HIV infected patients in Switzerland: prospective multicentre study , 1997, BMJ.

[7]  D. Ho,et al.  Ordered accumulation of mutations in HIV protease confers resistance to ritonavir , 1996, Nature Medicine.

[8]  H. Fleury,et al.  Predictors of long-term increase in CD4(+) cell counts in human immunodeficiency virus-infected patients receiving a protease inhibitor-containing antiretroviral regimen. , 2002, The Journal of infectious diseases.

[9]  A. Perelson,et al.  Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. , 1999, The New England journal of medicine.

[10]  D. Katzenstein,et al.  Randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: AIDS Clinical Trials Group Study 359. , 2000, The Journal of infectious diseases.

[11]  B. G. Rao,et al.  Structural and Kinetic Analyses of the Protease from an Amprenavir-Resistant Human Immunodeficiency Virus Type 1 Mutant Rendered Resistant to Saquinavir and Resensitized to Amprenavir , 2000, Journal of Virology.

[12]  Michael S Saag,et al.  Antiretroviral treatment for adult HIV infection in 2002: updated recommendations of the International AIDS Society-USA Panel. , 2002, JAMA.

[13]  D. Richman,et al.  Simultaneous vs sequential initiation of therapy with indinavir, zidovudine, and lamivudine for HIV-1 infection: 100-week follow-up. , 1998, JAMA.

[14]  S. Hammer,et al.  The Relation between Baseline HIV Drug Resistance and Response to Antiretroviral Therapy: Re-Analysis of Retrospective and Prospective Studies Using a Standardized Data Analysis Plan , 2000, Antiviral therapy.

[15]  S. Hammer,et al.  Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. , 2001, The New England journal of medicine.

[16]  Anastasios A. Tsiatis,et al.  Estimating medical costs with censored data , 2000 .

[17]  D. Kuritzkes,et al.  Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial , 2000, AIDS.

[18]  R. Haubrich,et al.  Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors , 2001, AIDS.

[19]  D. Katzenstein,et al.  Antiretroviral treatment in resource-poor settings: clinical research priorities , 2002, The Lancet.

[20]  Brendan A. Larder,et al.  Extent of Cross-Resistance between Agents Used To Treat Human Immunodeficiency Virus Type 1 Infection in Clinically Derived Isolates , 2002, Antimicrobial Agents and Chemotherapy.

[21]  L. Naeger,et al.  Increased Drug Susceptibility of HIV-1 Reverse Transcriptase Mutants Containing M184V and Zidovudine-Associated Mutations: Analysis of Enzyme Processivity, Chain-Terminator Removal and Viral Replication , 2000, Antiviral therapy.

[22]  P. Tebas,et al.  Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. , 1999, AIDS.

[23]  R. Grant,et al.  Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. , 2000, The Journal of infectious diseases.

[24]  B. Clotet,et al.  Selection of drug-resistant HIV-1 mutants in response to repeated structured treatment interruptions , 2002, AIDS.

[25]  M. Segal,et al.  Evolution of Phenotypic Drug Susceptibility and Viral Replication Capacity during Long-Term Virologic Failure of Protease Inhibitor Therapy in Human Immunodeficiency Virus-Infected Adults , 2002, Journal of Virology.

[26]  Bg Gazzard and.  British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy. , 2005, HIV medicine.

[27]  Victor DeGruttola,et al.  Dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. , 2002, JAMA.

[28]  Lee Bacheler,et al.  Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs , 2003, AIDS.

[29]  Matthew J. Gonzales,et al.  Human Immunodeficiency Virus Reverse Transcriptase and Protease Sequence Database: an expanded data model integrating natural language text and sequence analysis programs , 2001, Nucleic Acids Res..

[30]  Hongwei Zhao,et al.  ESTIMATING MEAN QUALITY ADJUSTED LIFETIME WITH CENSORED DATA , 2002 .

[31]  M. Hughes,et al.  Monitoring Plasma HIV-1 RNA Levels in Addition to CD4+ Lymphocyte Count Improves Assessment of Antiretroviral Therapeutic Response , 1997, Annals of Internal Medicine.

[32]  S. Hammer,et al.  Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. , 2000, JAMA.

[33]  R. Siliciano,et al.  HIV-1 drug resistance profiles in children and adults with viral load of <50 copies/ml receiving combination therapy. , 2001, JAMA.

[34]  D. Richman,et al.  Comparative analysis of HIV type 1 genotypic resistance across antiretroviral trial treatment regimens. , 2000, AIDS research and human retroviruses.

[35]  B. Clotet,et al.  M184V is associated with a low incidence of thymidine analogue mutations and low phenotypic resistance to zidovudine and stavudine. , 2002, AIDS.

[36]  R Hoh,et al.  Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. , 2001, The New England journal of medicine.

[37]  R. Chaisson,et al.  Highly Active Antiretroviral Therapy in a Large Urban Clinic: Risk Factors for Virologic Failure and Adverse Drug Reactions , 1999, Annals of Internal Medicine.

[38]  D. Ho,et al.  Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. , 2000, The Journal of clinical investigation.