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Antiviral Activity and Safety of Aplaviroc with Lamivudine/Zidovudine in HIV-Infected, Therapy-Naive Patients: the ASCENT (CCR102881) Study

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Antiviral Activity and Safety of Aplaviroc with Lamivudine/Zidovudine in HIV-Infected, Therapy-Naive Patients: the ASCENT (CCR102881) Study Currier 25/3/08 14:22 Page 297 Antiviral Therapy 13:297–306 Original article Antiviral activity and safety of aplaviroc with lamivudine/zidovudine in HIV-infected, therapy-naive patients: the ASCENT (CCR102881) study Judith Currier1*, Adriano Lazzarin2, Louis Sloan3, Nathan Clumeck 4, Jihad Slim5, Deb McCarty 6, Helen Steel 7, Jörg-Peter Kleim7, Tab Bonny 8 and Judith Millard 6 on behalf of the ASCENT study team 1UCLA Center for Care, Los Angeles, CA, United States 2San Raffaele Vita-Salute University, Milan, Italy 3North Texas Disease Consultants, Dallas, TX, USA 4St Pierre University Hospital, Brussels, Belgium 5St. Michael’s Medical Center, Newark, NJ, USA 6GlaxoSmithKline, Research Triangle Park, NC, USA 7GlaxoSmithKline, Greenford, United Kingdom 8W. L. Gore and Associates, Flagstaff, AZ, USA *Corresponding author: E-mail: [email protected] Background: This Phase IIb study explored the antiviral patients enrolled, 145 patients received one dose of activity and safety of the investigational CCR5 antago- treatment and were included in the intention-to-treat nist aplaviroc (APL) in antiretroviral-naive patients population. The proportion of patients with HIV-1 RNA harbouring R5-tropic virus. <400 copies/ml at week 12 was 53%, 50% and 66% in Methods: One hundred and forty-seven patients were the APL 600 mg twice daily, APL 800 mg twice daily, and randomized 2:2:1 to one of two APL dosing regimens or EFV arms, respectively. Common clinical adverse events efavirenz (EFV). All dosage arms were administered twice (AEs) were diarrhoea, nausea, fatigue and headache. APL daily and in combination with lamivudine/zidovudine demonstrated non-linear pharmacokinetics with high (3TC/ZDV; Combivir, COM). Efficacy, safety, and interpatient variability. In addition to the hepatic find- pharmacokinetic parameters were assessed. ings, there was an apparent dose–response relationship Results: This study was prematurely terminated due to in the incidence of diarrhoea. APL-associated idiosyncratic hepatotoxicity. The primary Conclusions: Whereas target plasma concentrations of APL endpoint of the study was the proportion of patients were achieved, the antiviral activity of APL as the third with plasma HIV-1 RNA <400 copies/ml who remained on agent in a triple drug regimen did not appear to be compa- randomized treatment through week 12. Of the 147 rable to EFV in this treatment-naive patient population. Introduction Although highly active antiretroviral therapy CCR5 antagonists are active against viral isolates (HAART) results in a profound and sustained reduc- that use the CCR5 coreceptor for viral entry. CCR5- tion in plasma HIV-1 RNA in many individuals, the tropic (R5-tropic) virus has been found to be present in side effects of currently available antiretrovirals at least 50% of viruses in both antiretroviral therapy (including toxicity, dyslipidaemia and body dysmor- (ART)-naive and -experienced, HIV-1-infected patients phic changes) and the emergence of multidrug-resistant in several studies [1–6]. There is considerable interest viral strains continue to represent major challenges for in the potential utility of CCR5 antagonists when used the management of HIV infection. As such, new targets in potent combinations with other antiretroviral drugs. for therapy (such as inhibitors of the chemokine recep- Aplaviroc (APL) is a CCR5 antagonist being tors CCR5 and CXCR4) could provide improvements developed for the treatment of HIV-1 infection in in the care of HIV-infected individuals. combination with other ART regimens. In vitro data © 2008 International Medical Press 1359-6535 297 Currier 25/3/08 14:22 Page 298 J Currier et al. showed that APL was highly specific for the CCR5 Biosciences). The study was conducted from 14 January receptor and inhibited R5-tropic HIV-1 replication at 2005 until 15 September 2005. low to subnanomolar concentrations [7]. Multiple passage experiments (>48 weeks) using R5-tropic Study design and treatment regimens HIV-1 from both laboratory-derived and clinical This Phase IIb, randomized, partially double-blinded, isolates demonstrated that reduced susceptibility to multicentre, parallel-group, dose-ranging study was APL was slow to develop in vitro [8,9]. Data from a conducted at 33 centres in the United States, four single and repeat dose-escalation study in HIV-nega- centres in Canada and 24 sites in the European Union. tive healthy adult patients suggested that APL was Patients were randomized 2:2:1 to one of the two well-tolerated at individual doses up to 800 mg [10]. double-blinded APL dosage regimens (APL 600 mg Of note, 24 h after a single dose, when plasma drug twice daily or APL 800 mg twice daily) or an efavirenz concentrations were undetectable, significant CCR5 (EFV) control regimen; all regimens were administered receptor occupancy by APL (median percentage of in combination with lamivudine (3TC) and zidovudine 68–88% across the doses studied) was still observed. (ZDV), which were dispensed as one fixed-dose combi- Furthermore, at 12 h after final dose administration nation tablet of Combivir®. APL was administered as during the multiple-dose phase, receptor occupancy by 200 mg tablets. Randomization was stratified APL exceeded 97% [10]. A 10-day APL monotherapy according to each patient’s plasma HIV-1 RNA level at study completed in HIV-1-infected adults demon- screening (<100,000 copies/ml versus ≥100,000 strated acceptable short-term safety. A mean 1.66 log10 copies/ml). Originally designed to be a 96-week study, copies/ml at nadir decrease in viral load from baseline ASCENT was stopped prematurely due to the occur- was observed in the highest dosage arm (600 mg twice rence of treatment-emergent idiosyncratic hepatotoxicity daily), demonstrating potent antiviral activity [11]. in some patients participating in this and a parallel Phase The antiviral efficacy observed with APL in this IIb study [16]. Thus, most patients were evaluated over monotherapy study compared favourably with the short- a 12-week treatment period only. term efficacy of other potent antiretrovirals in ART-naive HIV-1-infected patients. Short-term monotherapy studies Study assessments and monitoring evaluating nucleoside reverse transcriptase inhibitors Patients enrolled in the study were evaluated at screening, (NRTIs), non-nucleoside reverse transcriptase inhibitors days 1 (baseline, BL), 3, 5, and 10, and weeks 2, 4 and (NNRTIs) and protease inhibitors (PIs) have also every 4 weeks thereafter. An additional follow-up visit demonstrated a 1.5–2.0 log10 copies/ml decrease in viral was to be made within 4 weeks following the withdrawal load from baseline [12–14]. Therefore, the short-term visit for resolution of any ongoing adverse events (AEs) antiviral potency demonstrated with the CCR5 antago- and new serious AEs (SAEs). Screening evaluations nist APL supported the investigation of its addition as a included informed consent, demographics (which third agent to a standard-of-care dual NRTI backbone in included Centers of Disease Control and Prevention ART-naive patients. [CDC] classification), medical history, physical examina- ASCENT (A Study of Combivir and Entry Inhibitor tion, triplicate electrocardiograms with heart rate, and in Naive Treatment – CCR102881) was a randomized determination of HIV-1 coreceptor tropism and reverse clinical trial designed to define an APL dosage regimen transcriptase (RT) genotype. Clinical evaluations of AEs that could be potentially evaluated in subsequent and SAEs were also performed at screening, BL, weeks 2, Phase III trials. 4 and every 4 weeks thereafter through to week 24, and every 8 weeks thereafter through to withdrawal. Methods Laboratory testing performed at a central laboratory included complete blood count with lymphocyte subset Study participants determination, serum chemistry panel and plasma HIV-1 HIV-1-infected, antiretroviral-naive male and female RNA by PCR. In addition, hepatitis B surface antigen and patients aged ≥13 years (or ≥18 where required by local hepatitis C serology were performed for all patients at the regulatory agencies) with a screening plasma HIV-1 baseline visit. Clinical and laboratory AEs were graded RNA ≥10,000 copies/ml, CD4+ T-cell count ≥100 according to the 2004 DAIDS toxicity grading scale [17]. cells/mm3 and R5-tropic virus, as determined by the Efficacy was evaluated by measuring plasma HIV-1 RNA PhenoSense HIV Entry™ assay, (Monogram Biosciences, in blood samples (by both the Roche [Van Nuys, CA] South San Francisco, CA, USA) were eligible for study COBAS Monitor Amplicor Standard PCR Assay [lower enrolment. Furthermore, patients could not have major limit of detection 400 copies/ml] and the Roche [Heston, NRTI or NNRTI mutations based on the mutation list UK] PCR UltraSensitive Assay [lower limit of detection defined by the International AIDS Society [15], which 50 copies/ml]). Lymphocyte subsets were assessed by were determined by the GeneSeq™ assay (Monogram flow cytometry. CDC-associated conditions and clinical 298 © 2008 International Medical Press Currier 25/3/08 14:22 Page 299 Antiviral activity and safety of aplaviroc: ASCENT study disease progression were also monitored. New or Pharmacokinetic/pharmacodynamic analysis recurrent category C clinical disease progression events Serial plasma samples for APL, 3TC and ZDV were confirmed by an independent reviewer. Safety was pharmacokinetic (PK) evaluations were collected from assessed by monitoring of clinical AEs and SAEs, clin- a subset of patients at week 12 and the concentrations
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