Improved interpretation of genotypic changes in the HIV-1 reverse transcriptase coding region that determine the virological response to didanosine.
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 x 2) + E44D/A/G + T69D/S/N/A + (L210W x 2) + T215Y or revertants + L228H/R - D123E/N/G/S, by use of which viruses were categorized as being susceptible (score < or =0), as having intermediate resistance (1-3), and as being resistant (> or =4) to didanosine. In the validation set, the adjusted mean difference in 12-week virological response was +0.34 log(10) 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.


CONCLUSIONS
The improved genotypic-resistance interpretation score can be applied to better guide the use of didanosine in treatment-experienced individuals.
De Luca
Andrea
A
Institute of Clinical Infectious Diseases, Catholic University, Roma, 00168, Italy. andrea.deluca@rm.unicatt.it
Giambenedetto
Simona Di
SD
Trotta
Maria Paola
MP
Colafigli
Manuela
M
Prosperi
Mattia
M
Ruiz
Lidia
L
Baxter
John
J
Clevenbergh
Philippe
P
Cauda
Roberto
R
Perno
Carlo-Federico
CF
Antinori
Andrea
A
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D003521:Cyclopropanes; D016049:Didanosine / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D054303:HIV Reverse Transcriptase / Q000187:drug effects / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019888:Nelfinavir / Q000494:pharmacology; D019829:Nevirapine / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016879:Salvage Therapy
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D011744:Pyrimidinones; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D061466:Lopinavir; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D019888:Nelfinavir; C098320:efavirenz; D016049:Didanosine