Improved Interpretation of Genotypic Changes in the HIV-1 Reverse Transcriptase Coding Region That Determine the Virological Response to Didanosine

• Published in: The Journal of infectious diseases 2007-12, Vol.196 (11), p.1645-1653
• Main Authors: De Luca, Andrea, Di Giambenedetto, Simona, Trotta, Maria Paola, Colafigli, Manuela, Prosperi, Mattia, Ruiz, Lidia, Baxter, John, Clevenbergh, Philippe, Cauda, Roberto, Perno, Carlo-Federico, Antinori, Andrea
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Adult; AIDS; Anti-HIV Agents - pharmacology; Antiretrovirals; Benzoxazines - pharmacology; Biological and medical sciences; Codons; Didanosine - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Genetic mutation; Genotype; HIV; HIV 1; HIV Reverse Transcriptase - drug effects; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; HIV/AIDS; Human immunodeficiency virus 1; Humans; Lopinavir; Male; Microbiology; Middle Aged; Miscellaneous; Mutation; Nelfinavir - pharmacology; Nevirapine - pharmacology; Pyrimidinones - pharmacology; Reverse Transcriptase Inhibitors - pharmacology; RNA; RNA, Viral - analysis; Salvage Therapy; Viral load; Virology; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/522231

Background. Consensus on the interpretation of mutations in the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) gene that predict the response to didanosine treatment is needed. Methods. Baseline HIV-1 RT genotypes and 12-week virological outcomes for patients undergoing didanosine-containing salvage regimens were extracted from prospective studies. Existing didanosine genotypic-resistance interpretation rules were validated in the entire-patient data set. Mutations were given weighted positive or negative scores according to their coefficient of correlation with virological response in a derivation set. The score resulting from the algebraic sum of the mutations was then validated in an independent data set. Results. A total of 485 patients were analyzed. The didanosine-resistance scores derived from the Jaguar and Gesca studies predicted virological outcome. The best correlation with response was found with the derived score (M41L × 2) + E44D/A/G + T69D/S/N/A + (L210W × 2) + T215Y or revertants + L228H/R — D123E/N/G/S, by use of which viruses were categorized as being susceptible (score ⩽0), as having intermediate resistance (1–3), and as being resistant (⩾4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log10 copies/mL (95% confidence interval, +0.11 to +0.57; P = .004) per higher resistance category. Correlation with virological response constantly outperformed that obtained with the previous interpretation. Conclusion. The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.