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17th International HIV Drug Resistance Workshop10-14 June 2008, Sitges, Spain |
VIROLOGICAL RESPONSE AND RESISTANCE IN MULTI-EXPERIENCED PATIENTS TREATED WITH RALTEGRAVIR
Antivir Ther. 2008; 13(Suppl. 3):A20 (abstract no. 18)
F Ceccherini-Silberstein1,2, D Armenia1, R D’Arrigo2, V Micheli3, L Fabeni1, P Meraviglia3 , A Capetti3, M Zaccarelli2, MP Trotta2, P Narciso2, A Antinori2 and CF Perno1,2
1University of Rome Tor Vergata, Rome, Italy 2INMI “L Spallanzani”, Rome, Italy 3Hospital Sacco, Milan, Italy
BACKGROUND: Raltegravir is a novel and potent integrase inhibitor that showed very promising results in clinical trials. Data about the efficacy of raltegravir in uncontrolled studies, as well as the dynamics of resistance mutations, have yet to be defined. The objective was to study the potential correlations between virological response and the development of short-term resistance.
METHODS: HIV-1-infected treatment-experienced patients with triple-class resistant virus who received raltegravir plus optimized background therapy (OBT) were analyzed. Integrase genotyping together with CD4+ T-cell count and plasma HIV-1 RNA were assessed at baseline and at weeks 4–24.
RESULTS: Fifty-two patients received raltegravir plus OBT. At baseline, median HIV-1 RNA was 4.67 log copies/ml and median CD4+ T-cell count was 127 cells/mm3. At 7–19 days after raltegravir-based therapy, a very sharp decrease of HIV-1 RNA (median reduction -2.03 log copies/ml) was found. After 4 weeks, the median HIV-1 RNA reduction was -2.43 log copies/ml and 50% of patients reached <50 copies/ml. Median CD4+ T-cell count increase was 71 cells/mm3 (P=0.007). At week 12, <50 HIV-1 RNA copies/ml was achieved in 64% of available patients and maintained to the end of observation period. Baseline sequences showed only secondary integrase mutations, such as L74I (1.9%), T97A (1.9%), S119G (3.8%), M154I (17.3%), K156N (11.5%), V165I (20.1%), V201I (40.3%) and I203M (1.9%). Integrase sequences of 16 patients after 18–60 days of raltegravir-based therapy (median HIV-1 RNA 92 copies/ml) were successfully obtained. Of interest, 4/5 that did not reach <50 copies/ml at 12 weeks developed primary mutations, while the same occurred in only 1/11 that achieved <50 copies/ml (P=0.013). One patient added G140S+Q148Q mutations. Three patients presented the N155H mutation, all having the V165I secondary mutation at baseline, while one patient presented the Y143R mutation, having T97A at baseline. This suggests that different patterns of mutations conferring resistance to raltegravir can be related to selected polymorphisms present at baseline.
CONCLUSIONS: Raltegravir showed an extraordinary potent antiretroviral and immunological efficacy in the large majority of multi-experienced patients. In a minority of patients, a rapid resistance to raltegravir emerged and correlated with later virological outcome, thus confirming the importance of associating this new integrase inhibitor to other active drugs to maintain long-term efficacy.
2008-06-10
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