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

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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 under 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 in 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 patients 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.