Salvage therapy with abacavir in HIV-1-infected patients with previously documented M184V mutation: a possibility of NRTI recycling.
We evaluated in an open-label, randomized, controlled, pilot trial if the re-emergence of previously selected resistant strains, harbouring M184V mutation, could be modulated by the use of different drug associations as components of the new antiretroviral regimens. In addition, we assessed the clinical relevance of this mutation on the management of heavily pretreated HIV-infected patients. The primary end-point of the study was the reselection of M184V mutation. Secondary end-points were the variation over time of HIV RNA plasma levels and CD4 cell counts and the progression of HIV disease. The primary population for efficacy analysis was the intention-to-treat exposed population. After a run-in phase consisting in a new treatment regimen excluding either lamivudine (3TC) or abacavir (ABC) so as to clear the previously documented M184V mutation, 18 patients with an HIV RNA plasma level greater than 10000 copies/ml were randomized to receive an antiretroviral drug regimen (at least three drugs) including either ABC or the association of ABC+3TC. All patients were naive to ABC. The M184V mutation reappeared in 1/9 patients in the ABC group and in 8/9 patients in the ABC+3TC group (P<0.003, 95% CI: 0.5-1). In the ABC group we observed a rapid decrement of viral load that was maintained throughout all the study period (P<0.05). On the contrary, in the ABC+3TC group, after a transient decrement at 2 months, a progressive increment towards baseline values was observed. The proportion of patients with a viral load reduction of at least 0.5 logs at 12 months was significantly higher in the ABC group: 8/9 patients vs 3/9 (P=0.05, 95% CI: 0.2-0.92). Similarly, from an immunological point-of-view, the increase at all time points (since randomization) in CD4 cell count was statistically significant in the ABC group (P<0.01), while no difference was observed in the ABC+3TC group. The possibility of a successful use of ABC in salvage regimens opens alternative therapeutic options for heavily pretreated patients with previously documented M184V mutation. Further studies should clarify whether this is true for other drugs of the nucleoside analogues class.
Maggiolo
Franco
F
Division of Infectious Diseases, Ospedali Riuniti, Bergamo, Italy. franco31556@hotmail.com
Callegaro
Annapaola
A
Arici
Claudio
C
Quinzan
Giampaolo
G
Gregis
Giampietro
G
Ripamonti
Diego
D
Tebaldi
Alessandra
A
Goglio
Antonio
A
Suter
Fredy
F
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D015497:HIV-1 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D010865:Pilot Projects; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016879:Salvage Therapy; D019562:Viral Load; D000099227:Abacavir
D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D000099227:Abacavir