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Session 92 Poster Abstracts
Emergence of Resistance to Specific Drugs and Drug Combinations
Wednesday, 1:30 - 3:30 pm
Poster Hall


662
Relative Superiority of an Initial Antiretroviral Strategy Is Not Determined only by Frequency of Emergence of HIV Drug Resistance and Cross-resistance
V Johnson1, R Shafer2, L Smeaton3, V DeGruttola3, M Winters2, J Hazelwood1, L Sutton4, B Griffin3, S Snyder5, M Hirsch6, T Merigan2, M Wantman3, G Robbins6, R D'Aquila*4, and The Adult ACTG 384 Protocol Team
1Birmingham VA Med. Ctr and Univ. of Alabama at Birmingham Sch. of Med., USA; 2Stanford Univ. Med. Ctr., CA, USA; 3Statistical and Data Analysis Ctr. (SDAC), Harvard Sch. of Publ. Hlth., Boston, MA, USA; 4Vanderbilt Univ. Sch. of Med., Nashville, TN, USA; 5Social and Sci. Systems, Inc., Silver Spring, MD, USA; and 6Massachusetts Gen. Hosp. and Harvard Med. Sch., Boston, MA

Background:  ACTG 384 was a randomized, partially double-blinded trial comparing sequential 3-drug vs. initial 4 drug regimens. Results showed a strong interaction between choices of dual nucleosides and EFV vs NFV and supported that initial ZDV+3TC+EFV (arm C) could be a standard. These analyses:  determined baseline resistance; identified mutations selected; and compared resistance frequencies across arms at virologic failure to test if resistance was less frequent in arm with lowest failure rate.

 

Arm

# Randomized

Step 1

# Failed Step 1

Step 2

A

155

ddI+d4T+EFV

69

ZDV+3TC+NFV

B

155

ddI+d4T+NFV

77

ZDV+3TC+EFV

C

155

ZDV+3TC+EFV

31

ddI+d4T+NFV

D

155

ZDV+3TC+NFV

66

ddI+d4T+EFV

E

178

ddI+d4T+NFV+EFV

57

(no step 2)

F

182

ZDV+3TC+NFV+EFV

41

(no step 2)

 

Methods:  Sequencing not done for RNA <1000 copies/mL (10%). Three labs generated 1211 sequences (Bayer TruGene, Rules v7) from 1359 baseline and virologic failure specimens; sequencing failures were rare (0.8%). Significance level of chi square analyses adjusted for multiple comparisons (Bonferroni, p <0.003).

Results:  Baseline resistance was rare (1%). Failing ddI+d4T selected RT 65R and 74V with equally low frequencies (4%), but did not select RT 184V. TAM were rare (about 3%) in every arm. In comparisons of percentage resistance at virologic failure using all randomized subjects as denominator, arm A had more failures with any acquired resistance (25.1%) than did arm C (10%, p = 0.0005) and each 4-drug arm (p <0.003). Arm C did not differ from 4-drug arms. In analyses of percentage resistance at virologic failure using only subjects with step 1 virologic failure as denominator, arm B demonstrated less frequent resistance (28.6%) than arm A (56.5%, p = 0.0006) and no other differences were seen among arms. Similar results were seen for cumulative failures (e.g., at step 1 or both steps) and within each drug class.

Conclusions:  HIV drug resistance emergence does not fully explain the superiority of ZDV+3TC+EFV, or the interaction between nucleosides and EFV vs NFV, observed in ACTG 384. Many virologic failures on each arm lacked detectable virus resistance. The regimen with the least frequent resistance emergence among virologic failures (initial ddI+d4T+NFV, arm B) was not the arm with the lowest regimen failure rate (initial ZDV+3TC+EFV, arm C). Other mechanisms for initial regimen virologic failure require further investigation. RT 65R, but not 184V, may emerge after d4T+ddI therapy.

 

Keywords: antiretroviral drug resistance; initial HIV treatment; randomized clinical trial