Background: This Phase IIb study explored the antiviral
activity and safety of the investigational CCR5 antago-
nist aplaviroc (APL) in antiretroviral-naive patients
harbouring R5-tropic virus.
Methods: One hundred and forty-seven patients were
randomized 2:2:1 to one of two APL dosing regimens or
efavirenz (EFV). All dosage arms were administered twice
daily and in combination with lamivudine/zidovudine
(3TC/ZDV; Combivir, COM). Efficacy, safety, and
pharmacokinetic parameters were assessed.
Results: This study was prematurely terminated due to
APL-associated idiosyncratic hepatotoxicity. The primary
endpoint of the study was the proportion of patients
with plasma HIV-1 RNA <400 copies/ml who remained on
randomized treatment through week 12. Of the 147
patients enrolled, 145 patients received one dose of
treatment and were included in the intention-to-treat
population. The proportion of patients with HIV-1 RNA
<400 copies/ml at week 12 was 53%, 50% and 66% in
the APL 600 mg twice daily, APL 800 mg twice daily, and
EFV arms, respectively. Common clinical adverse events
(AEs) were diarrhoea, nausea, fatigue and headache. APL
demonstrated non-linear pharmacokinetics with high
interpatient variability. In addition to the hepatic find-
ings, there was an apparent dose–response relationship
in the incidence of diarrhoea.
Conclusions: Whereas target plasma concentrations of APL
were achieved, the antiviral activity of APL as the third
agent in a triple drug regimen did not appear to be compa-
rable to EFV in this treatment-naive patient population.
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 Clumeck4, Jihad Slim5, Deb McCarty6,
Helen Steel7, Jörg-Peter Kleim7, Tab Bonny8and Judith Millard6on 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: JSCurrier@mednet.ucla.edu
Although highly active antiretroviral therapy
(HAART) results in a profound and sustained reduc-
tion in plasma HIV-1 RNA in many individuals, the
side effects of currently available antiretrovirals
(including toxicity, dyslipidaemia and body dysmor-
phic changes) and the emergence of multidrug-resistant
viral strains continue to represent major challenges for
the management of HIV infection. As such, new targets
for therapy (such as inhibitors of the chemokine recep-
tors CCR5 and CXCR4) could provide improvements
in the care of HIV-infected individuals.
CCR5 antagonists are active against viral isolates
that use the CCR5 coreceptor for viral entry. CCR5-
tropic (R5-tropic) virus has been found to be present in
at least 50% of viruses in both antiretroviral therapy
(ART)-naive and -experienced, HIV-1-infected patients
in several studies [1–6]. There is considerable interest
in the potential utility of CCR5 antagonists when used
in potent combinations with other antiretroviral drugs.
Aplaviroc (APL) is a CCR5 antagonist being
developed for the treatment of HIV-1 infection in
combination with other ART regimens. In vitro data
© 2008 International Medical Press 1359-6535
Antiviral Therapy 13:297–306
showed that APL was highly specific for the CCR5
receptor and inhibited R5-tropic HIV-1 replication at
low to subnanomolar concentrations . Multiple
passage experiments (>48 weeks) using R5-tropic
HIV-1 from both laboratory-derived and clinical
isolates demonstrated that reduced susceptibility to
APL was slow to develop in vitro [8,9]. Data from a
single and repeat dose-escalation study in HIV-nega-
tive healthy adult patients suggested that APL was
well-tolerated at individual doses up to 800 mg .
Of note, 24 h after a single dose, when plasma drug
concentrations were undetectable, significant CCR5
receptor occupancy by APL (median percentage of
68–88% across the doses studied) was still observed.
Furthermore, at 12 h after final dose administration
during the multiple-dose phase, receptor occupancy by
APL exceeded 97% . A 10-day APL monotherapy
study completed in HIV-1-infected adults demon-
strated acceptable short-term safety. A mean 1.66 log10
copies/ml at nadir decrease in viral load from baseline
was observed in the highest dosage arm (600 mg twice
daily), demonstrating potent antiviral activity .
The antiviral efficacy observed with APL in this
monotherapy study compared favourably with the short-
term efficacy of other potent antiretrovirals in ART-naive
HIV-1-infected patients. Short-term monotherapy studies
evaluating nucleoside reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase inhibitors
(NNRTIs) and protease inhibitors (PIs) have also
demonstrated a 1.5–2.0 log10copies/ml decrease in viral
load from baseline [12–14]. Therefore, the short-term
antiviral potency demonstrated with the CCR5 antago-
nist APL supported the investigation of its addition as a
third agent to a standard-of-care dual NRTI backbone in
ASCENT (A Study of Combivir and Entry Inhibitor
in Naive Treatment – CCR102881) was a randomized
clinical trial designed to define an APL dosage regimen
that could be potentially evaluated in subsequent
Phase III trials.
HIV-1-infected, antiretroviral-naive male and female
patients aged ≥13 years (or ≥18 where required by local
regulatory agencies) with a screening plasma HIV-1
RNA ≥10,000 copies/ml, CD4+T-cell count ≥100
cells/mm3and R5-tropic virus, as determined by the
PhenoSense HIV Entry™ assay, (Monogram Biosciences,
South San Francisco, CA, USA) were eligible for study
enrolment. Furthermore, patients could not have major
NRTI or NNRTI mutations based on the mutation list
defined by the International AIDS Society , which
were determined by the GeneSeq™ assay (Monogram
Biosciences). The study was conducted from 14 January
2005 until 15 September 2005.
Study design and treatment regimens
This Phase IIb, randomized, partially double-blinded,
multicentre, parallel-group, dose-ranging study was
conducted at 33 centres in the United States, four
centres in Canada and 24 sites in the European Union.
Patients were randomized 2:2:1 to one of the two
double-blinded APL dosage regimens (APL 600 mg
twice daily or APL 800 mg twice daily) or an efavirenz
(EFV) control regimen; all regimens were administered
in combination with lamivudine (3TC) and zidovudine
(ZDV), which were dispensed as one fixed-dose combi-
nation tablet of Combivir®. APL was administered as
200 mg tablets. Randomization was stratified
according to each patient’s plasma HIV-1 RNA level at
screening (<100,000 copies/ml versus ≥100,000
copies/ml). Originally designed to be a 96-week study,
ASCENT was stopped prematurely due to the occur-
rence of treatment-emergent idiosyncratic hepatotoxicity
in some patients participating in this and a parallel Phase
IIb study . Thus, most patients were evaluated over
a 12-week treatment period only.
Study assessments and monitoring
Patients enrolled in the study were evaluated at screening,
days 1 (baseline, BL), 3, 5, and 10, and weeks 2, 4 and
every 4 weeks thereafter. An additional follow-up visit
was to be made within 4 weeks following the withdrawal
visit for resolution of any ongoing adverse events (AEs)
and new serious AEs (SAEs). Screening evaluations
included informed consent, demographics (which
included Centers of Disease Control and Prevention
[CDC] classification), medical history, physical examina-
tion, triplicate electrocardiograms with heart rate, and
determination of HIV-1 coreceptor tropism and reverse
transcriptase (RT) genotype. Clinical evaluations of AEs
and SAEs were also performed at screening, BL, weeks 2,
4 and every 4 weeks thereafter through to week 24, and
every 8 weeks thereafter through to withdrawal.
Laboratory testing performed at a central laboratory
included complete blood count with lymphocyte subset
determination, serum chemistry panel and plasma HIV-1
RNA by PCR. In addition, hepatitis B surface antigen and
hepatitis C serology were performed for all patients at the
baseline visit. Clinical and laboratory AEs were graded
according to the 2004 DAIDS toxicity grading scale .
Efficacy was evaluated by measuring plasma HIV-1 RNA
in blood samples (by both the Roche [Van Nuys, CA]
COBAS Monitor Amplicor Standard PCR Assay [lower
limit of detection 400 copies/ml] and the Roche [Heston,
UK] PCR UltraSensitive Assay [lower limit of detection
50 copies/ml]). Lymphocyte subsets were assessed by
flow cytometry. CDC-associated conditions and clinical
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© 2008 International Medical Press
Accepted for publication 19 November 2007