Evolution of HIV resistance during treatment interruption in experienced patients and after restarting a new therapy

Background: To analyse the evolution of resistance patterns in patients undergoing treatment interruption (TI) and reinitiating highly active anti-retroviral therapy (HAART). Methods: HIV-RT and -PR gene-sequences were analysed in 14 patients (>5 failing prior drugs) before and during TI and tinder a new HAART. Genotypes were interpreted using two bioinformatics systems. Additionally, virus load (VL) and CD4(+)-T-cell counts were measured. Results: Six patients (42%) achieved sustained undetectable VL up to one year after TI (responders), while 8 (57%) maintained VL of more than 2000 copies/mL (non-responders). Different patterns of resistance-mutations evolution were detected. During TI loss of all Mutations was observed in three patients, a reduction of mutations was detected in seven patients, and no alteration was seen ill four patients. In the responders, 87.5% of protease inhibitor (PI)-resistance mutations waned during TI and remained undetectable under the new treatment. In contrast, in the non-responder group most PI-resistance mutations continued noticeable under the new therapy. Loss of primary PI-resistance mutations and the presence of one fully active PI in the new regimen significantly correlated with Success of subsequent treatment (p = 0.028). In two patient, new reverse transcriptase associated mutations were detected during TI, G190A (NNRTI mutation) and K70R (NRTI mutation). Appearance of K70R could be explained by a reverse direction of a previously described pathway of thymidin analogues mutation resistance development, while G190A could be due to prolonged subinhibitory drug levels after cessation of NNRTIs. Conclusion: In the evolution of HAART-resistance, different patterns were observed in responders and non-responders during but not before TI. Absence of PI-resistance associated mutations during and after TI and administration of a predicted fully active PI for the new therapy correlated with success. Newly detected mutations during TI may indicate reversibility of previously described mutational pathways. (c) 2005 Elsevier B.V. All rights reserved.