Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy.

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor-containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P= .04, chi(2) test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30-3.75; P= .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy.

[1]  K. Tashima,et al.  Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. , 1999, The New England journal of medicine.

[2]  J. Pagano,et al.  Long-term persistence of zidovudine resistance mutations in plasma isolates of human immunodeficiency virus type 1 of dideoxyinosine-treated patients removed from zidovudine therapy. , 1994, The Journal of infectious diseases.

[3]  R. Colonno,et al.  Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Remco,et al.  pol gene diversity of five human immunodeficiency virus type 1 subtypes: evidence for naturally occurring mutations that contribute to drug resistance, limited recombination patterns, and common ancestry for subtypes B and D , 1997, Journal of virology.

[5]  J. Rockstroh,et al.  Reply: Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients. , 1997, AIDS.

[6]  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.

[7]  S D Kemp,et al.  Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). , 1989, Science.

[8]  M. Mouroux,et al.  Polymorphism of the Human Immunodeficiency Virus Type 1 (HIV-1) Protease Gene and Response of HIV-1-Infected Patients to a Protease Inhibitor , 1999, Journal of Clinical Microbiology.

[9]  S. Little.  Transmission and Prevalence of HIV Resistance among Treatment-Naive Subjects , 2000, Antiviral therapy.

[10]  M. Kazatchkine,et al.  Efficacy of a five-drug combination including ritonavir, saquinavir and efavirenz in patients who failed on a conventional triple-drug regimen: phenotypic resistance to protease inhibitors predicts outcome of therapy. , 1999, AIDS.

[11]  E. Arnold,et al.  Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  H. B. Schock,et al.  Mutational Anatomy of an HIV-1 Protease Variant Conferring Cross-resistance to Protease Inhibitors in Clinical Trials , 1996, The Journal of Biological Chemistry.

[13]  J. Martinez-Picado,et al.  Replicative Fitness of Protease Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1 , 1999, Journal of Virology.

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

[15]  H. Mitsuya,et al.  Comparative Fitness of Multi-Dideoxynucleoside-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) in an In Vitro Competitive HIV-1 Replication Assay , 1999, Journal of Virology.

[16]  B. Efron,et al.  Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor-experienced persons. , 1999, The Journal of infectious diseases.

[17]  JD Lundgren,et al.  Changing patterns of mortality across Europe in patients infected with HIV-1 , 1998, The Lancet.

[18]  P. McCullagh,et al.  Generalized Linear Models , 1992 .

[19]  J. Montaner,et al.  A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study. , 1998, JAMA.

[20]  B Wise,et al.  Antiretroviral therapy in adults. , 1996, Journal of the American Academy of Nurse Practitioners.

[21]  D V Glidden,et al.  Baseline human immunodeficiency virus type 1 phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel-capsule saquinavir in AIDS clinical trials group protocol 333. , 2000, The Journal of infectious diseases.

[22]  B. Larder,et al.  Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. , 1992, The Journal of infectious diseases.

[23]  T. Merigan,et al.  A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy , 2000 .

[24]  Robert Shafer,et al.  HIV-1 Genotypic Resistance Patterns Predict Response to saquinavirritonavir Therapy in Patients in Whom Previous Protease Inhibitor Therapy Had Failed , 1999, Annals of Internal Medicine.

[25]  D. Katzenstein,et al.  Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. , 1994, The Journal of infectious diseases.

[26]  M. Moroni,et al.  Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naïve patients , 2000, AIDS.

[27]  D. R. Kuritzkes,et al.  Genotypic and Phenotypic Characterization of Human Immunodeficiency Virus Type 1 Variants Isolated from Patients Treated with the Protease Inhibitor Nelfinavir , 1998, Antimicrobial Agents and Chemotherapy.

[28]  T. Merigan,et al.  Multiple Concurrent Reverse Transcriptase and Protease Mutations and Multidrug Resistance of HIV-1 Isolates from Heavily Treated Patients , 1998, Annals of Internal Medicine.

[29]  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.

[30]  D. Venzon,et al.  Altered drug sensitivity, fitness, and evolution of human immunodeficiency virus type 1 with pol gene mutations conferring multi-dideoxynucleoside resistance. , 1998, The Journal of infectious diseases.

[31]  J. Ioannidis,et al.  Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. , 1998, The New England journal of medicine.

[32]  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.

[33]  P. Harrigan,et al.  Baseline HIV drug resistance profile predicts response to ritonavir-saquinavir protease inhibitor therapy in a community setting. , 1999, AIDS.

[34]  J. Fitzgibbon,et al.  Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine , 1992, Antimicrobial Agents and Chemotherapy.

[35]  M. Wainberg,et al.  High-level resistance to (-) enantiomeric 2'-deoxy-3'-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase , 1993, Antimicrobial Agents and Chemotherapy.

[36]  T. Merigan,et al.  Clinical cross-resistance between the HIV-1 protease inhibitors saquinavir and indinavir and correlations with genotypic mutations. , 1999, AIDS.

[37]  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.

[38]  M. Lederman,et al.  Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine-lamivudine-ritonavir: genotypic analysis of human immunodeficiency virus type 1 isolates from AIDS clinical trials group protocol 315.ACTG Protocol 315 Team. , 2000, The Journal of infectious diseases.

[39]  M A Fischl,et al.  Antiretroviral Therapy in Adults Updated Recommendations of the International AIDS Society–USA Panel , 2000 .

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

[41]  J. Condra,et al.  In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors , 1995, Nature.

[42]  D. Richman,et al.  HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. , 1989, Science.

[43]  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.

[44]  B. Larder,et al.  Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. , 1992, Proceedings of the National Academy of Sciences of the United States of America.