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Drug Resistance Outcomes at 48 Weeks in the OK04 Trial: A Comparative Trial of Single-drug Maintenance Therapy with Lopinavir/Ritonavir vs Triple Therapy with LPV/r
Jose Arribas*1, F Pulido2, R Delgado2, E Cabrero3, J Pasquau4, J Portilla5, P Miralles6, A Ocampo7, C Cepeda2, M Norton8, and OK04 Study Group
1Hosp La Paz, Madrid, Spain; 2Hosp 12 de Octubre, Madrid, Spain; 3Abbott Labs, Madrid, Spain; 4Hosp Virgen de las Nieves, Granada, Spain; 5Hosp Gen, Alicante, Spain; 6Hosp Gregorio Maranon, Spain; 7Hosp Xeral Cies, Vigo, Spain; and 8Abbott Labs, Chicago, IL, US
Background: OK04 is an ongoing 144-week,
randomized, open-label, non-inferiority trial comparing lopinavir/ritonavir
(LPV/r) + 2 nucleosides (duotherapy), with LPV/r monotherapy. Patients were eligible for OK04 if their HIV-1
RNA was suppressed to <50 for ≥6 months and no previous virologic failure while receiving protease inhibitor (PI)
therapy.
Methods: Population genotyping (ViroSeq V2) was performed in real time on all plasma
samples from patients with HIV-1 RNA >500.
Results: We randomized 198 patients, n = 100 to monotherapy
and n = 98 to duotherapy.
Through week 48, 15 subjects (26 episodes of viral load
>500) qualified for genotypic testing, 11 (11%) in the monotherapy
arm, 4 (4%) in the duotherapy arm. Protease
inhibitor (PI) -associated mutations were detected in 3 subjects, 2 of 11 in monotherapy (2% of patients on monotherapy),
1 of 4 in duotherapy (1% of patients on duotherapy, p =
0.56). All 3 subjects exhibited >1 episode of viral load >500. Reverse
transcriptase (RT) mutations were detected in 2 subjects, 1 in monotherapy and 1 in duotherapy.
At week 16, subject #VN04 on monotherapy
showed protease (PR) mutations 10F and 46I. Virtual phenotype showed 1.5-fold
resistance to LPV/r. Subject #VN04 had a h/o 33 months of prior ART treatment (zidovudine [AZT] + lamivudine [3TC]
+ nevirapine [NVP], zidovudine
[AZT] + didanosine [ddI] + LPV/r,
abacavir [ABC] + ddI+LPV/r)
and after virological failure was switched to tenofovir (TDF) + stavudine (d4T)
+ saquinavir (SQV) + RTV and re-suppressed to <50.
At week 48, subject #XC02 on monotherapy showed PR
mutations 54V, 77I, and 82A. Virtual phenotype showed 7.1-fold resistance to
LPV/r. Subject #XC02 had a h/o 142 months of prior ART treatment (AZT, AZT + ddI, d4T + 3TC + NFV, ddI + EFV +
indinavir [IDV] + RTV, ddI +
LPV/r + EFV, AZT + ABC + 3TC, ddI + TDF + LPV/r) and
after virological failure switched to TDF/emtricitabine (FTC) + SQV + RTV and re-suppressed to
<50. At week 24, subject #DO05 on duotherapy
showed mutations 41L, 74V, 184V, 210W, 211K, 215Y (RT) and 54V, 63P, 71V, 82A
(PR). Virtual phenotype showed 7.2-fold resistance to LPV/r. Subject #DO5 had a h/o 132 months of prior ART treatment (AZT, ddI, d4T + 3TC + RTV, d4T + 3TC + LPV/r.) and after virological failure was lost to follow-up. At week 36
subject #DO34 on monotherapy had an isolated viral
load >500 copies/mL and showed only RT mutations
41L, 74V, 210W, and 215Y. Subject #DO34 had a h/o 114
months of prior ART treatment (AZT, ddI, d4T + 3TC + LPV/r).
Conclusions: The incidence of PI
resistance at 48 weeks was 2% for monotherapy and 1%
for duotherapy. Most subjects who qualified for
resistance testing were not found to have PI-associated resistance mutations.
The 2 subjects who showed resistance mutations on LPV/r monotherapy were able
to re-suppress after being switched to a SQV-based regimen. Archived RT
mutations could be detected at rebound in 1 patient receiving LPV/r monotherapy.
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