RESUMO
OBJECTIVE: To compare the efficacy, safety, and anti-inflammatory effects of cenicriviroc (CVC), an oral, once-daily C-C chemokine receptor types 5 and 2 antagonist, with those of efavirenz (EFV) in treatment-naive, HIV-1-infected adults. DESIGN: A 48-week, randomized, double-blind, double-dummy phase 2b trial at 43 institutions (USA and Puerto Rico). METHODS: Study participants (HIV-1 RNA ≥1000 copies/ml, CD4 cell count ≥200 cells/µl, C-C chemokine receptor type 5-tropic virus) were randomized 2â:â2â:â1 to CVC 100âmg (CVC100), CVC 200âmg (CVC200), or EFV 600âmg, each administered with emtricitabine/tenofovir disoproxil fumarate. Key end points were virologic success (HIV-1 RNA <50 copies/ml) at week 24 (primary) and week 48 (secondary), safety/tolerability at weeks 24 and 48. Study sites and patients remained blinded until week 48. RESULTS: A total of 143 patients were randomized (CVC100, nâ=â59; CVC200, nâ=â56; EFV, nâ=â28). Virologic success was obtained at week 24 in 76, 73, and 71% of study participants for CVC100, CVC200, and EFV, respectively (all Pâ>â0.05 versus EFV), and at week 48 in 68, 64, and 50%, respectively (all Pâ>â0.05 versus EFV). Resistance mutations emerged in five and zero CVC and EFV-treated study participants, respectively. Virologic nonresponse and nucleoside reverse transcriptase inhibitor resistance decreased when CVC minimum plasma concentration was at least 47.8âng/ml. Treatment-related adverse events of at least grade 2 and discontinuations because of adverse events were less frequent in CVC-treated study participants. Total and low-density lipoprotein cholesterol decreased with CVC, but increased with EFV. C-C chemokine ligand type 2 (CCL2) (aka monocyte chemotactic protein-1) increased in a dose-dependent manner, whereas soluble CD14 levels decreased with CVC. CONCLUSION: CVC showed efficacy and favorable safety in treatment-naive HIV-1-infected study participants, supporting selection of CVC200 for phase 3 studies. TRIAL REGISTRATION: NCT01338883.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Imidazóis/administração & dosagem , Receptores CXCR5/antagonistas & inibidores , Tropismo Viral , Adulto , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Ciclopropanos , Método Duplo-Cego , Feminino , Genótipo , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Imidazóis/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Porto Rico , Receptores de HIV/antagonistas & inibidores , Sulfóxidos , Resultado do Tratamento , Estados Unidos , Carga Viral , Adulto JovemRESUMO
BACKGROUND: Vicriviroc, a novel HIV CCR5 antagonist, demonstrated significant efficacy and favorable tolerability in phase II trials in treatment-experienced subjects, supporting further evaluation in phase III studies. METHODS: Two identical double-blind, placebo (PBO)-controlled trials in CCR5-tropic HIV-infected subjects with documented resistance to two antiretroviral classes were conducted. Subjects were randomized to vicriviroc 30 mg QD (N = 571) or PBO (N = 286) with open-label optimized background therapy (OBT) containing ≥2 fully active antiretroviral drugs. The primary endpoint was percentage of subjects with <50 copies/mL HIV RNA at 48 weeks. It was analyzed in a logistic regression with treatment (vicriviroc + OBT/PBO + OBT), use of enfuvirtide in baseline OBT (yes/no), and baseline HIV RNA (≤100,000/>100,000 copies/mL) as covariates. In addition, a pre-planned analysis to examine other efficacy and safety endpoints was conducted. RESULTS: Baseline characteristics of the pooled mITT population (vicriviroc, n = 486; PBO, n = 235) included mean HIV RNA of 4.6 log(10) copies/mL and mean CD4 count of 257 cells/µL. Approximately 60% of subjects received ≥3 active drugs in the OBT. The percentage of subjects with <50 copies/mL HIV RNA was not significantly different between vicriviroc and PBO at week 48 (64% vs 62%, p = 0.6). However, in subjects receiving ≤2 active drugs in their OBT, the proportion achieving <50 copies/mL HIV RNA was higher in those receiving vicriviroc compared with PBO (70% vs 55%, p = 0.02). CONCLUSIONS: The studies failed to show significant efficacy gains when vicriviroc was added to OBT. However, given the efficacy results of earlier vicriviroc trials and other CCR5 antagonist, studies are needed to define the role of this class of drugs in the treatment of HIV. Clinical trial identifier: http://www.clinicaltrial.gov/: VICTOR-E3 (NCT00523211) and VICTOR-E4 (NCT00474370).
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Receptores CCR5/metabolismo , Receptores de HIV/metabolismo , Adulto , Método Duplo-Cego , Feminino , Infecções por HIV/virologia , HIV-1/isolamento & purificação , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , RNA Viral/sangue , Resultado do Tratamento , Carga Viral , Viremia/virologiaRESUMO
OBJECTIVES: To compare the safety and antiviral activity of once (QD) or twice (BID) daily lopinavir/ritonavir (LPV/r) in combination with investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in treatment-experienced subjects. METHODS: Subjects failing treatment with HIV-1 RNA > 1000 copies per milliliter received LPV/r tablets 800/200 mg QD (n = 300) or 400/100 mg BID (n = 299) with investigator-chosen nucleoside/nucleotide reverse transcriptase inhibitors. Efficacy was determined by the intent-to-treat time to loss of virologic response (ITT-TLOVR) algorithm. Safety, tolerability, adherence, impact of baseline protease mutations on virologic response, and emergence of resistance on therapy were assessed. RESULTS: Demographics were comparable across groups. By intent-to-treat time to loss of virologic response, 166 QD subjects (55.3%) and 155 BID subjects (51.8%) were responders at week 48 (P = 0.413), with similar mean increases in CD4 T-cell count. QD subjects demonstrated better adherence than BID subjects. The occurrence of treatment-related moderate/severe adverse events was comparable for all events except nausea, which was reported more frequently among BID-treated subjects. Emergence of new protease resistance mutations on treatment was similarly infrequent in both groups. CONCLUSION: LPV/r dosed QD resulted in increased treatment adherence and was as efficacious as BID LPV/r while providing similar safety, tolerability, and limited resistance evolution.