Pilot, Randomized Study Assessing Safety, Tolerability and Efficacy of Simplified LPV/r Maintenance Therapy in HIV Patients on the 1st PI-Based Regimen

Abstract

ObjectivesTo compare the efficacy and safety of an individualized treatment-simplification strategy consisting of switching from a highly-active anti-retroviral treatment (HAART) with a ritonavir-boosted protease inhibitor (PI/r) and 2 nucleoside reverse-transcriptase inhibitors (NRTIs) to lopinavir/ritonavir (LPV/r) monotherapy, with intensification by 2 NRTIs if necessary, to that of continuing their HAART.MethodsThis is a one-year, randomized, open-label, multi-center study in virologically-suppressed HIV-1-infected adults on their first PI/r-containing treatment, randomized to either LPV/r-monotherapy or continue their current treatment. Treatment efficacy was determined by plasma HIV-1 RNA viral load (VL), time-to-virologic rebound, patient-reported outcomes (PROs) and CD4+T-cell-count changes. Safety was assessed with the incidence of treatment-emergent adverse events (AE).ResultsForty-one patients were randomized to LPV/r and 39 to continue their HAART. No statistically-significant differences between the two study groups in demographics and baseline characteristics were observed. At day-360, 71(39:LPV/r;32:HAART) patients completed treatment, while 9(2:LPV/r;7:HAART) discontinued. In a Last Observation Carried Forward Intent-to-Treat analysis, 40(98%) patients on LPV/r and 37(95%) on HAART had VL<200copies/mL (P = 0.61). Time-to-virologic rebound, changes in PROs, CD4+ T-cell-count and VL from baseline, also exhibited no statistically-significant between-group differences. Most frequent AEs were diarrhea (19%), headache (18%) and influenza (16%). Four (10%) patients on LPV/r were intensified with 2 NRTIs, all regaining virologic control. Eight serious AEs were reported by 5(2:LPV/r;3:HAART) patients.ConclusionAt day-360, virologic efficacy and safety of LPV/r appears comparable to that of a PI+2NRTIs HAART. These results suggest that our individualized, simplified maintenance strategy with LPV/r-monotherapy and protocol-mandated NRTI re-introduction upon viral rebound, in virologically-suppressed patients merits further prospective long-term evaluation.Trial RegistrationClinicalTrials.gov NCT00159224

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

“…Moreover, in contrast to previous studies, patients with a history of VF while on a PI-based regimen were enrolled, and there was no previous period in which tolerance to LPVr was determined before the start of monotherapy. Despite these facts, the virological efficacy was similar to that observed in clinical trials of mtLPVr (6,7,(9)(10)(11)(12)(13). It is noteworthy to mention that neither a history of VF on an unboosted or ritonavir-boosted PI-containing regimen nor the presence of minor resistance mutations to LPVr nor the once-daily administration of LPVr had negative influences on the virological outcome.…”

“…Notwithstanding, a considerable proportion of patients maintained an undetectable viremia on lopinavirritonavir maintenance monotherapy (mtLPVr) and could benefit from a simpler regimen without nucleoside analogues or other antiretroviral drugs. Moreover, lack of adherence has been indicated as the main reason for virological failure (VF) in different studies (6)(7)(8)(9)(10)(11)(12)(13).…”

Durability of Lopinavir/Ritonavir Monotherapy in Individuals with Viral Load ≦50 Copies/Ml in an Observational Setting

“…Median CD4 + T-cell count at nadir was 215 cell/mm 3 (IQR 116-336). In 50 participants (22%), CD4 + T-cell count at nadir was ≤100 cells/mm 3 + T-cell count was ≤350 cells/mm 3 ; duration of viral suppression <50 copies/ml before switch was of 47 months (IQR 20-73). A total of 52 (23%) individuals previously failed virologically to a PI-based regimen (Table 1).…”

“…It has been evaluated in a number of clinical trials including also HCV-coinfected individuals [1][2][3][4], but currently there are still no conclusive data on the efficacy and toxicity of such a regimen in daily clinical practice.…”

What to do Next? Second-line Antiretroviral Therapy

“…Simplification to PI/r monotherapy in fully suppressed patients might avoid the long-term effects of the NRTIs. Although initially considered a promising strategy, some studies showed a higher rate of low-level viremia (up to 12 % of participants) resulting in the need of reintroducing NRTIs [63][64][65]. The addition of 3TC to a PI/r was proposed in order to increase dual therapy efficacy [66].…”