Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group.

Abacavir (1592U89) is a nucleoside inhibitor of human immunodeficiency virus (HIV) type 1 reverse transcriptase (RT). Resistance to abacavir was studied with abacavir alone and with abacavir in combination with other nucleoside analogues in cell culture, in virus isolates from zidovudine/lamivudine clinical trials, and in the first dose-escalating 12-week clinical trial (CNA2001) to evaluate abacavir clinical potency. Abacavir alone in vitro selected for mutations at HIV RT codons K65R, L74V, Y115F, and M184V. However, abacavir combined with zidovudine selected against virus with the M184V mutation. Abacavir therapy in vivo resulted in large decreases in HIV load (>1 log), even in 1 subject who had the M184V mutation at baseline. A total of 51% of subjects showed new mutations at any of codons K65R, L74V, and M184V after abacavir monotherapy, compared with 11% who received zidovudine/abacavir. Small changes (2- to 4-fold) in abacavir susceptibility were detected. On stopping therapy, reselection of the pretherapy sequence occurred within 4 weeks.

[1]  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.

[2]  P. Harrigan,et al.  Dual resistance to zidovudine and lamivudine in patients treated with zidovudine-lamivudine combination therapy: association with therapy failure. , 1998, The Journal of infectious diseases.

[3]  J W Mulder,et al.  Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group. , 1996, The Journal of infectious diseases.

[4]  E. Garvey,et al.  Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89 , 1997, Antimicrobial agents and chemotherapy.

[5]  S. Hammer,et al.  A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team. , 1996, The New England journal of medicine.

[6]  J. Condra.  Virological and clinical implications of resistance to HIV-1 protease inhibitors. , 1998, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[7]  S D Kemp,et al.  Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Harrigan,et al.  Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients : A randomized controlled comparison with zidovudine monotherapy , 1996 .

[9]  S D Kemp,et al.  Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. , 1995, Science.

[10]  S D Kemp,et al.  Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. , 1991, Science.

[11]  B. Larder,et al.  Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates , 1994, Antimicrobial Agents and Chemotherapy.

[12]  M. Wainberg,et al.  The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2',3'-dideoxyinosine and 2',3'-dideoxycytidine confers high-level resistance to the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine , 1993, Antimicrobial Agents and Chemotherapy.

[13]  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.

[14]  Tom de Groot,et al.  Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. , 1997, The Journal of infectious diseases.

[15]  D. Richman,et al.  Susceptibilities of zidovudine-susceptible and -resistant human immunodeficiency virus isolates to antiviral agents determined by using a quantitative plaque reduction assay , 1990, Antimicrobial Agents and Chemotherapy.

[16]  P. Harrigan,et al.  Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility , 1996, Journal of virology.

[17]  M. Tisdale,et al.  Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89 , 1997, Antimicrobial agents and chemotherapy.

[18]  J. Sninsky,et al.  Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC). , 1995, The Journal of infectious diseases.

[19]  P. Harrigan,et al.  Relative Replicative Fitness of Zidovudine-Resistant Human Immunodeficiency Virus Type 1 Isolates In Vitro , 1998, Journal of Virology.

[20]  J. Montaner,et al.  Development of HIV‐1 resistance to (−)2′‐deoxy‐3′‐thiacytidine in patients with AIDS or advanced AIDS‐related complex , 1995, AIDS.

[21]  E A Emini,et al.  Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. , 1997, The New England journal of medicine.

[22]  R. Schooley,et al.  Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV‐infected adults , 1998, AIDS.

[23]  J Desmyter,et al.  Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. , 1988, Journal of virological methods.

[24]  L. Boone,et al.  1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity , 1997, Antimicrobial agents and chemotherapy.

[25]  B. Larder,et al.  Quantitative detection of HIV-1 drug resistance mutations by automated DNA sequencing , 1993, Nature.

[26]  J. Darbyshire,et al.  Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals , 1996, The Lancet.

[27]  John W. Mellors,et al.  Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma , 1996, Science.

[28]  D. Kuritzkes,et al.  Drug resistance and virologic response in NUCA 3001, a randomized trial of lamivudine (3TC) versus zidovudine (ZDV) versus ZDV plus 3TC in previously untreated patients , 1996, AIDS.