Programme Supplement [International Conference on AIDS (16th: 2006: Toronto, Canada)]

Late Breaker Abstracts

this setting. Earlier detection and treatment of patients may limit
development of resistance.
THLBO214
Potent antiretroviral effect of MK-0518, a novel HIV-1
integrase inhibitor, as part of combination ART in treatment
-naive HIV-1 infected patients
M. Markowitz', B.-Y. Nguyen2, F. Gotuzzo3, F. Mendo4, W.
Ratanasuwan5, C. Kovacs6, J. Zhao', L. Gilde2, R. Isaacs2, H.
Teppler2. 'The Rockefeller University, Aaron Diamond AIDS
Research Center, New York, United States, 'Merck Research
Laboratories, Clinical Research, West Point, United States,
3Hospital Nacional Cayetano Heredia, Lima, Peru, 4Hospital
Nacional Edgardo Rebagliati, Lima, Peru, 5Siriraj Hospital, Mahidol
University, Bangkok, Thailand, 6Canadian Immunological Research
Collaborative, Toronto, Canada, 7Merck Research Laboratories,
Clinical Statistics, West Point, United States
Background: Phase II study evaluating MK-0518, a novel
HIV integrase inhibitor, vs efavirenz, combined with tenofovir/
lamivudine (TFV/3TC), in ART-naive HIV-infected patients (pts)
with HIV-1 RNA >5000 copies/mL and CD4 cells >100i/uL. p
Methods: Multicenter, double-blind, randomized 2-part study
evaluating MK-0518 (100, 200, 400, or 600mg p.o. b.i.d) vs
efavirenz (600 mg qd) both with TFV/3TC. Pts entered this study
(Part 2) after 10 days monotherapy (Part 1) or were newly enrolled,
and monitored for safety, tolerability, and efficacy.
Results: 197 pts were enrolled and treated. At this preliminary
analysis 85 had wK 16 data. Enrolled pts were of mean age 36
years, 80% male, 69% non-white, and 34% had AIDS. Mean
baseline HIV RNA ranged from 4.6 - 4.8 log10 copies/mL per
treatment group. Proportions of pts achieving HIV RNA <400 or
<50 copies/mL (observed) at wk 16 are shown:
HIV RNA levels % (95% CI)
Treatmentt (mg) N <400 copies/uL <50 copies/uL

Background: Maraviroc (MVC) is a CCR5 antagonist active against
R5 but not X4 or dual-tropic (R5/X4) HIV-1 in vitro. Patients with
"dual-tropic" HIV generally are infected with a mixture of virus
populations comprising R5, X4, and R5/X4 variants. This study was
performed to determine the safety and efficacy of MVC, added to
an optimised regimen (OBT) versus OBT alone, in patients with
dual/mixed-tropic (D/M) infection.
Methods: A4001029 is an ongoing, double-blind, placebocontrolled trial. Subjects on a stable antiretroviral regimen, with
non-R5 virus, HIV-1 RNA >5,000 c/mL and triple class experience
and/or dual class resistant virus were randomized to one of three
groups: OBT +/- MVC QD or BID. The primary endpoint was the
change from baseline to 24 weeks in viral load (VL) for patients
with D/M virus at screening, using an intent-to-treat analysis.
Results: Of 186 subjects with non-R5 virus randomized and
treated, 167 had D/M virus at screening. Median baseline CD4
count was <50 cells/pL and mean baseline VL was >5log10 c/mL
for each treatment group. VL change from baseline to week 24
was similar for the MVC QD (-0.91 log10) and placebo groups (0.97 log10) but slightly greater for the MVC BID group (-1.20 log10).
Mean CD4 change was greater for the MVC groups: +60 and +62
cells/ L, for QD and BID, respectively compared to +35 cells/ L for
placebo. Grade 3/4 adverse events, discontinuations and deaths
occurred with similar frequency in all three groups. Therewe re no
cases of lymphoma or adenocarcinoma.
Conclusions: MVC was safe and well tolerated in this advanced
population with documented D/M HIV-1 infection. While superiority
of either MVC dose added on to OBT, versus OBT alone, was not
achieved, there was no evidence of virological or immunological
decline. In fact, a greaterCD4 increase occurred in both MVC groups
versus the placebo group, which requires further investigation.
THLB0216
A phase I study to explore the safety, tolerability, and
pharmacokinetics of Fosalvudine Tidoxil in patients infected
with HIV-1
Cahn P.1, Reuss F.2, Rolon M.3, Wit F.4, Boehm E.2, Lange
J.5. 1Fundacion Huesped, Buenos Aires, Argentina, 2Heidelberg
Pharma GmbH, Hamburg, Germany, 3Hospital Juan Fernandez,
Buenos Aires, Argentina, 4IATEC, Amsterdam, Netherlands,
5IATEC/Academic Medical Center, Amsterdam, Netherlands
Background: The nucleoside analogue Alovudine (FLT) has potent
anti-HIV activity and considerable toxicity. Fosalvudine Tidoxil is a
pro-drug of FLT covalently linked with a lipid-moiety. Compared to
the parent compound the toxicity of Fosalvudine is expected to be
significantly lower because of altered pharmacokinetic properties.
Furthermore, a continuous slow cell-associated release of the FLTmonophosphate is expected to result in effective concentrations
of the antiviral drug for a longer time-span, compatible with oncedaily oral administration. This study evaluates the safety, tolerance
and pharmacokinetics of Fosalvudine in HIV-1-infected patients.
Methods: This is a single-dose, open-label, phase-I, singlecenter study. Twenty-four ART-naive HIV-1-infected patients in 4
consecutive dose-groups of six patients received one single oral
dose of 5, 10, 20, or 40mg Fosalvudine with 7 days of follow-up.
Results: No clinically significant clinical or laboratory adverse
events occurred. Fosalvudine became detectable in plasma 2 hours
after intake of 5mg and 1 hour after intake of 10, 30 or 40mg.
Fosalvudine was still detectable in all patients of all dose-groups
24 hours after intake. Pharmacokinetic parameters of Fosalvudine
Tidoxil by non-compartmental analysis (median and range):

Late Breaker
Abstracts

MK-0518 b.i.d. 100 18 89 (65, 99)
MK-0518 b.i.d. 200 18 100 (82, 100)
MK-0518 b.i.d. 300 17 94 (71, 100)
MK-0518 b.i.d. 400 17 100 (81, 100)
Efavirenz qd 600 15 93 (68, 100)

88 (64, 99)*
100 (82, 100)
94 (71, 100)
94 (70, 100)*
86 (57, 98)*

Programme..........................................................................................................................................
Contributor
Index

(t With TFV/3TC; *One pt pending UltraSensitive results excluded)
All groups showed >2.2 log10 decline in HIV RNA and similar
increased CD4 cells (75-135/uL). Drug-related clinical adverse
experiences (AEs) were generally similar in all groups; nausea,
dizziness and headache were most common. Laboratory AEs were
infrequent; one pt discontinued due to elevated AST in the MK0518 600mg group. There were no drug related serious AEs. Full
wk 24 data will be presented.
Conclusions: In this preliminary analysis, MK-0518 with TFV/3TC
at all doses studied had potent antiretroviral activity and was
generally well-tolerated in ART-naive pts.
THLBO215
Safety and efficacy of Maraviroc (MVC), a novel CCR5
antagonist, when used in combination with optimized
background therapy (OBT)forthetreatmentofantiretroviralexperienced subjects infected with dual/mixed-tropic HIV1: 24-week results of a phase 2b exploratory trial
H. Mayers, E. van der Ryst2, M. Saag3, B. Clotet4, G. Fatkenheuer5,
N. Clumeck6, K. Turner2, ].M. Goodrich'. 'Pfizer Global Research and
Development, New London, United States, 2Pfizer Global Research
and Development, Sandwich, United Kingdom, 3University of
Alabama, Birmingham, United States, 4University Hospital Germans
Trias i Pujol, Barcelona, Spain, 5University of Cologne, Cologne,
Germany, 6St Pierre University Hospital, Brussels, Belgium

Fosalvudine
Tidoxil
AUCinf (hr*ug/
L)
T1/2 (hr)
Tmax (hr)
Cmax (ug/L)
Accumulation
index

5mg
452
(295-916)
4.18
(3.73-7.76)
6.00
(6.00-6.00)
65.6
(43.9-141)
1.019045

10mg
581
(454-1300)
4.67
(4.49-5.02)
6.0
(6.00-8.00)
61.8
(44.4-203)
1.029205

20mg
1670
(644-1930)
5.63
(4.42-6.63)
7.00
(6.00-10.0)
181
(54.2-293)
1.054951

40mg
3960
(2730-7580)
7.01
(6.43-8.58)
7.00
(4.00-8.00)
489
(283-666)
1.102767

XVI INTERNATIONAL AIDS CONFERENCE * 13-18 AUGUST 2006 * TORONTO CANADA * PROGRAMME SUPPLEMENT