Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy.
OBJECTIVE
To determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy.


METHODS
Amino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks.


RESULTS
Numbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 601 + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks.


CONCLUSIONS
Use of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.
Precious
H M
HM
Centre for HIV Research, University of Edinburgh, Scotland.
Günthard
H F
HF
Wong
J K
JK
D'Aquila
R T
RT
Johnson
V A
VA
Kuritzkes
D R
DR
Richman
D D
DD
Leigh Brown
A J
AJ
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000821:virology*; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D004311:Double-Blind Method; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D019829:Nevirapine / Q000627:therapeutic use; D010919:Placebos; D017354:Point Mutation; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D020539:Sequence Analysis, Protein; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D010919:Placebos; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine; D054303:HIV Reverse Transcriptase