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 re-initiating 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 2,000 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.


CONCLUSIONS
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.
Balduin
Melanie
M
Institute of Virology, University of Cologne, Fuerst-Pueckler Str. 56, D-50935 Cologne, Germany.
Sierra
Saleta
S
Däumer
Martin P
MP
Rockstroh
Jürgen K
JK
Oette
Mark
M
Fätkenheuer
Gerd
G
Kupfer
Bernd
B
Beerenwinkel
Niko
N
Hoffmann
Daniel
D
Selbig
Joachim
J
Pfister
Herbert J
HJ
Kaiser
Rolf
R
D044966:Anti-Retroviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D009154:Mutation; D011480:Protease Inhibitors / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D013045:Species Specificity; D016896:Treatment Outcome; D028761:Withholding Treatment
D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D011480:Protease Inhibitors; D012194:RNA-Directed DNA Polymerase