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Emergence of Drug Resistance Mutations During Treatment Interruption in Patients with Undetectable Viral Loads
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Reported by Jules Levin
14th Intl HIV Drug Resistance Wksp
June 7-11, 2005
Quebec City, Canada
MA Winters1*, D Weng-Cherng2, K Henry3, P Tebas4, H Valdez5, M Wantman2, and DA Katzenstein1 for the ACTG A5102 Study Team
1Stanford University, Stanford, CA, 2Harvard School of Public Health, Boston, MA, and 3University of Minnesota, Minneapolis, MN,
4University of Pennsylvania, Pittsburgh, PA, 5Boehringer-Ingelheim Pharmaceuticals, Ridgebury, CT
INTRODUCTION
Treatment interruption (TI) can evaluate or alleviate side-effects of continuous antretorviral therapy (ARV). However, TI may select for drug resistance
mutations (DRM), depending on regimen, virologic, and host factors. The objective of this study was to identify and characterize the emergence and
persistence of DRM in patients with undetectable viral loads who undergo TI.
METHODS
ACTG A5102 was a randomized trial to study the effect of HAART + IL-2 on CD4 cell counts in patients undergoing a TI. Primary results of the study will be published elsewhere (submitted). In this study, subjects on a HAART regimen (NNRTI + 2 NRTI, PI + 2NRTI, or 3 NRTI) with HIV RNA less than 200 copies/ml and CD4 cell counts greater than 500 cells/ml were entered into the study. After
16 weeks of continued HAART ± IL-2, the TI was initiated and viral load testing (Ultrasensitive Roche Amplicor Monitor) was performed at 2, 4, 8 weeks, and every 4 weeks thereafter. Proviral DNA levels were measured using a Roche PCR-based assay. Genotypes were determined using an in-house genotyping assay at Stanford University at virus breakthrough, defined as the first TI time point where plasma HIV RNA was >500 copies/ml.
RESULTS
--All 46 subjects developed HIV RNA levels greater than 500 copies/ml: 20 (43%) at week 2, 16 (35%) at week 4, and 10 (22%) at week 8.
--DRM in baseline PBMC and breakthrough plasma were available from 41 subjects: twenty subjects had received NNRTI-based HAART, 17 had received PI based HAART, and 4 had received 3TC/ABC/ZDV [table 1]
--Eleven of 41(27%) subjects had PI, NRTI, and/or NNRTI DRM at breakthrough, 3/20 on NNRTI-based HAART, 8/17 on PI-based HAART, and 0/4 on triple NRTI (p= 0.057, Fisher's Exact test). [table 4]
--Ten of 11 DRM-subjects had breakthrough at Week 2, significantly earlier than patients without DRM at breakthrough (p = 0.0019, Wilcoxon test) [table 3]
--The presence of DRM in baseline PBMC DNA was associated with DRM in breakthrough plasma (5/5 with baseline PBMC DRM vs. 6/36 without baseline PBMC DRM, p=0.0006, Fisher's Exact test) [table 2]
--Subjects with DRM in breakthrough plasma RNA showed a more rapid CD4 cell decline during the TI compared to patients without DRM at breakthrough (p <0.0001) [figure 1]
AUTHOR CONCLUSIONS
A more rapid return of detectable viral load during TI was observed in subjects with DRM-containing strains.
The presence of DRM in PBMC DNA before the TI was associated with, but not required, for emergence of DRM containing strains at breakthrough.
Subjects with breakthough DRM-containing strains had a more rapid fall in CD4 cell counts compared to patients with wildtype strains.
Evaluating patients 2 weeks after beginning a TI for viral load and genotype may be useful in determining whether the TI should be continued.
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