Multiple sites in HIV-1 reverse transcriptase associated with virological response to combination therapy

Objective: To determine whether analysis of sequence variation in reverse t ranscriptase at baseline can explain differences in response to combination antiretroviral therapy. Methods: Amino acid sequences of reverse transcriptase obtained from baseli ne isolates from 55 patients included in a trial of zidovudine and didanosi ne versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship betw een numbers and identity of mutations at baseline and virological response after 8 and 48 weeks. Results: Numbers of baseline zidovudine resistance mutations were predictiv e of short-term response (week 8). Amino acid identity-at position 215 expl ained > 20% of the variation in response at week 8, but less at week 48. Mu ltiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model i ncorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explain ed > 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 combin ation therapy has revealed effects of baseline amino acidmutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in th e short term and may require more complex analysis. (C) 2000 Lippincott Wil liams & Wilkins.