Clonal resistance analyses of HIV type-1 after failure of therapy with didanosine, lamivudine and tenofovir

• Published in: Antiviral therapy 2010-01, Vol.15 (3), p.437-441
• Main Authors: Barnas, Douglas, Koontz, Dianna, Bazmi, Holly, Bixby, Christian, Jemsek, Joseph, Mellors, John W
• Format: Article
• Language: English
• Subjects: Adenine - administration & dosage; Adenine - analogs & derivatives; Adenine - pharmacology; Adenine - therapeutic use; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Didanosine - administration & dosage; Didanosine - pharmacology; Didanosine - therapeutic use; Drug Resistance, Viral - genetics; Drug Therapy, Combination; Genome, Viral - genetics; Genotype; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Lamivudine - administration & dosage; Lamivudine - pharmacology; Lamivudine - therapeutic use; Medical sciences; Mutation; Organophosphonates - administration & dosage; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Pharmacology. Drug treatments; Phenotype; Recombination, Genetic; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use; Sequence Analysis, DNA; Tenofovir; Treatment Failure; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 1359-6535; 2040-2058
• DOI: 10.3851/IMP1539

Background The rapid failure of initial therapy with combinations of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) that exclude zidovudine has not been fully explained by standard virus population analyses of HIV type-1 (HIV-1) drug resistance. We therefore investigated HIV-1 genotype and phenotype at the single genome level in samples from patients on a failing regimen of tenofovir (TNV), didanosine (ddI) and lamivudine (3TC). Methods Single genome sequencing was performed on 9 failure samples containing both K65R and M184V mutations by standard genotype, either as wild-type/mutant mixtures (6/9) or as mutant only (3/9). Recombinant clones with different combinations of observed mutations were generated and tested for NRTI susceptibility. Results Of the 204 single genome sequences analysed, 50% were K65R/M184V double mutants, 38% were M184V single mutants, 10% were M184I single mutants and only 1% (2 sequences) were K65R single mutants. Phenotypic testing of recombinant clones showed a significant increase in resistance for double mutants: mean fold resistance to abacavir, ddI and TNV was 6.5, 4.3 and 1.6 for K65R/M184V double mutants versus 2.5, 1.9 and 0.6 for M184V single mutants, respectively (P