Antiviral activity and safety of aplaviroc, a CCR5 antagonist, in combination with lopinavir/ritonavir in HIV‐infected, therapy‐naïve patients: results of the EPIC study (CCR100136)^*

Abstract

This phase IIb study explored the antiviral activity and safety of the investigational CC chemokine receptor 5 (CCR5) antagonist aplaviroc (APL) in antiretroviral-naïve patients harbouring R5-or R5X4-tropic virus. MethodsA total of 191 patients were randomized 2:2:2:1 to one of three APL dosing regimens or to lamivudine (3TC)/zidovudine (ZDV) twice daily (bid), each in combination with lopinavir/ritonavir (LPV/r) 400 mg/100 mg bid. Efficacy, safety and pharmacokinetic parameters were assessed. ResultsThis study was terminated prematurely because of APL-associated idiosyncratic hepatotoxicity. A total of 141 patients initiated treatment early enough to have been able to complete 12 weeks on treatment [modified intent-to-treat (M-ITT) population]; of these, 133 completed the 12-week treatment phase. The proportion of subjects in the M-ITT population with HIV-1 RNA o400 copies/mL at week 12 was 50, 48, 54 and 75% in the APL 200 mg bid, APL 400 mg bid, APL 800 mg once a day (qd) and 3TC/ZDV arms, respectively. Similar responses were seen in the few subjects harbouring R5X4-tropic virus (n 5 17). Common clinical adverse events (AEs) were diarrhoea, nausea, fatigue and headache. APL demonstrated nonlinear pharmacokinetics with high interpatient variability. ConclusionsWhile target plasma concentrations of APL were achieved, the antiviral activity of APL 1 LPV/r did not appear to be comparable to that of 3TC/ZDV 1 LPV/r. IntroductionUnlike currently available agents which inhibit HIV after infection of the target cell, aplaviroc (APL; 873140), a novel spirodiketopiperazine CC chemokine receptor 5 (CCR5) antagonist, inhibits HIV entry into cells, blocking a critical step in the fusion process [1]. For this reason, CCR5 is an attractive potential target for the treatment of HIV infection [2,3].APL demonstrated significant anti-HIV activity in in vitro and severe combined immunodeficiency (SCID) mouse studies [4,5]. In a phase I/II randomized dose-ranging study of APL monotherapy in R5-tropic antiretroviral (ARV)-naïve (n 5 19) and ARV-experienced (n 5 21) patients, 10 days of APL led to dose-dependent decreases in HIV-1 *Data were presented in part at the 10th European AIDS Conference, Dublin, Ireland,[17][18][19][20] DOI: 10.1111/j.1468-1293.2008.00660.x HIV Medicine (2009 (RTV). In a drug interaction study in healthy volunteers, repeat-dose coadministration of APL with lopinavir/ritonavir (LPV/r) increased the plasma APL area under the curve (AUC) by 7.7-fold without significant changes in LPV or RTV plasma exposure [8]. The combination of APL and LPV/r was well tolerated over the 7-day dosing interval of this study.Triple-drug antiretroviral therapy (ART) regimens that contain LPV/r are potent, durable and associated with a high barrier to genetic resistance when used in ARV-naïve patients [9,10]. In a pilot study, Gathe et al. reported that LPV/r may be effective as monotherapy in some ARV-naïve patients [11]. Thus, the nucleoside-sparing, two-drug combination of APL with LPV/r merited study in HIVinfected pati...

CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

“…Similarly, a low incidence of malignancies was reported in treatment-naive MERIT patients who received maraviroc with a Combivir backbone [14]. Finally, there was no evidence of treatmentrelated malignancies in the terminated aplaviroc clinical development programme [3,4]. Taken together, these data are reassuring and suggest that the antagonism of CCR5 does not give rise to classwide signature toxicities over the durations of treatment studied thus far.…”

“…For example, a retrospective analysis of A4001029 identified a greater short-term virological response (approximately twofold at week 12) among maraviroc patients with <10% CXCR4-using virus at screening, by ultra-deep sequencing, than those with >10% [93]. Furthermore, in the EPIC study of aplaviroc [3], week 12 viral load reductions among 11 evaluable patients with DM virus at screening visit ranged from -1.89 to -3.49 log 10 copies/ml, suggesting that some patients experienced rapid virological declines despite detectable CXCR4-using virus [3]. Although these reports suggest that some patients with DM virus might respond to treatment with a CCR5 antagonist, the clinical relevance of these observations remains unclear given the small sample sizes, the short duration of follow-up involved and the lack of a clinically validated algorithm to distinguish 'susceptible' from 'non-susceptible' DM samples.…”

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

“…Pharmacokinetic studies on patient P5 showed that serum APL levels at week 4 of treatment were near the mean for patients in the corresponding dosing arm, as were trough levels. 48 These data indicate that noncompliance is unlikely to be responsible for the absence of evidence of selective pressure on the env gene for P5. The pretreatment ability of HIV Envs isolated from P5 to utilize the drug-bound form of the receptor likely abrogated any selective pressure on env that the drug may have exerted.…”

Virologic Failure in Therapy-Naïve Subjects on Aplaviroc plus Lopinavir-Ritonavir: Detection of Aplaviroc Resistance Requires Clonal Analysis of Envelope

“…ART-naïve subjects (n ϭ 191) were enrolled in CCR100136; the full clinical data set is described elsewhere (40). The presence of only R5 tropism was not a requirement for enrollment in CCR100136; plasma was taken from 173 subjects that tested as R5-tropic and 18 as DM-tropic at enrollment.…”

“…CCR100136, a larger phase IIb study, was designed to evaluate a novel two-drug regimen comprising several doses of APL administered in combination with a boosted protease inhibitor (PI) (lopinavir-ritonavir [LPV-r]; Kaletra) in treatment-naïve subjects with either R5-or DM-tropic virus (40).…”