Transcript Antiretroviral Update - New York and New Jersey AIDS

Antiretroviral Update
Spring 2008
Lisa M. Chirch, M.D.
Stony Brook University - CPHE
NY/NJ AIDS Education and Training Center
Objectives

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Review DHHS guidelines and most recent
changes / additions
Overview of recent significant clinical trial
results
Review currently approved, available
antiretroviral (ARV) medications and
known toxicities, idiosyncrasies
Report on new agents in the pipeline, or
under ongoing investigation in Phase II
and III trials
Case vignettes and discussion
Indications for initiating ARV therapy for the
chronically HIV-1 infected patient
Clinical Category
CD4+ cell count
Recommendation
AIDS-defining illness or
severe symptoms*
Any value
Treat
Asymptomatic
CD4 <200/mm3
Treat
Asymptomatic
CD4 >200, <350
Treat
Asymptomatic
CD4 >350
Discuss risks and
benefits, consider
patient comorbidities
and scenarios
* Initiation of ARV also recommended for individuals co-infected with Hepatitis B, HIV-associated
nephropathy, and pregnant women; Adapted from “Guidelines for the use of antiretroviral agents
in HIV-1 – infected adults and adolescents,” U.S. Dept. of Health and Human Services. 2008.
Predicted 6 month risk of AIDS according to
age, CD4, and viral load


Based on Poisson regression model: Phillips A, et
al. AIDS 2004 (CASCADE CollaborationConcerted Action on SeroConversion to AIDS
and Death in Europe:
www.ctu.mrc.ac.uk/cascade
Examples:
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35 year old with CD4 100, has 6 month risk of
progression to AIDS of 4.7% if viral load is 3,000;
9.3% if VL is 30,000; 18% if 300,000.
55 year old with CD4 of 150 has 4.7% risk if VL
3,000; 18.2% if VL 300,000.
55 year old with CD4 of 350 has 1.2% risk if VL
3,000, 3.6% if VL 100,000, 5% if VL 300,000.
Which of the following fixed dose combinations
(FDCs) are designated as preferred initial NRTI
options according to the most recent DHHS
guidelines?
D
...
an
d
)A
B
C/
3
TC
/3
T
BC
DV
/A
)Z
C
ZD
...
an
C
TD
an
d
C/
3
)A
B
B
)T
DF
/F
T
C
TC
an
d
ZD
20
...
V.
..
0% 0% 0% 0%
A
A) TDF/FTC and
ZDV/3TC
B) ABC/3TC and
TDF/FTC
C) ZDV/ABC/3TC and
TDF/FTC
D) ABC/3TC and
ZDV/3TC
Which of the following ARVs is
contraindicated in women with CD4 cell
counts above 250?
A) Efavirenz
B) Nelfinavir
C) Nevirapine
D) Didanosine
0%
0%
si
ne
e
an
o
D
)D
id
ira
)N
ev
B
)N
el
fin
a
pi
n
z
vi
re
n
)E
fa
A
0%
vi
r
0%
C
20
Which of the following regimens is not
recommended in women who are or may
become pregnant?
A) EFV/TDF/FTC
B) FPV/r plus
ABC/3TC
C) LPV/RTV plus
ZDV/3TC
D) All of the above
ve
ab
o
of
th
e
D
TV
PV
/R
)L
C
)A
ll
pl
us
BC
A
lu
s
PV
/r
p
)F
B
ZD
...
C
/3
T
TC
F/
F
/T
D
)E
FV
A
20
0% 0% 0% 0%
Preferred and Alternative ARVs in updated DHHS
Guidelines
Preferred
Alternative
NNRTI
PI
2 NRTI
Efavirenz
Atazanavir
+Ritonavir;
Fosamprenavir +
ritonavir (BID),
lopinavir/
ritonavir (BID)
Tenofovir/
Emtricitabine
Nevirapine
Atazanavir
Fosamprenavir
Fosamprenavir (QD)
Lopinavir/
ritonavir (QD)
Saquinavir/ritonavir
Abacavir/
Lamivudine (if
HLA*B5701
negative)
Zidovudine/
lamivudine
Didanosine +
lamivudine
Adapted from “Guidelines for the use of antiretroviral agents in HIV-1 – infected adults and
adolescents,” U.S. Dept. of Health and Human Services. 2008.
Rationale: recent data (KLEAN)

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Inclusion of boosted fosamprenavir in the “preferred”
list:
KLEAN: phase 3, open-label, multi-center, noninferiority study comparing the safety and efficacy of
ritonavir-boosted fosamprenavir to lopinavir/ritonavir,
both in combination with abacavir/lamivudine
878 treatment-naïve patients
At week 48, no significant differences between arms in
terms of virologic, immunologic, or metabolic
response; few adverse events in similar numbers
among 2 groups
Eron J et al. The Lancet. August 5, 2006; 368(9534):476-482.
BMS-089
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96-week randomized, open-label study
comparing the efficacy and safety of 400
mg atazanavir versus 300 mg of
atazanavir boosted with 100 mg of
ritonavir, both in combination with
lamivudine and stavudine.
199 naïve patients
Both arms had high rates of virologic
response and were well-tolerated
Malan E. et al. 13th CROI; Feb 5-8, 2006; Denver, Colorado. Abstract 107LB
BMS-089
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There were 10 virologic failures in the unboosted arm,
compared to only 3 in the ritonavir-boosted arm; 7
people in the unboosted arm developed resistance
mutations, primarily at the 184 codon, compared to
only 1 in the boosted arm.
Patients on ritonavir had higher rate of
hyperbilirubinemia
Changes in total cholesterol and triglyceride levels
were significantly higher in the ritonavir-boosted arm;
HDL also increased nearly identically in both arms.
Gilead 934
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Randomized, open-label, non-inferiority trial comparing
tenofovir, emtricitabine to zidovudine, lamivudine, both
in combination with Efavirenz.
517 naïve patients
At week 96 significantly more patients in tenofovir / FTC
arm achieved and maintained HIV RNA levels below 400
copies/mL, and had significantly greater limb fat by
DEXA.
The groups were similar in terms of patients achieving
HIV RNA < 50 copies/mL
Higher toxicity rates in zidovudine / lamivudine arm (esp.
anemia), may have contributed
Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and
efavirenz for HIV. Joel E. Gallant et al., for the Study 934 Group. The New
England Journal of Medicine. January 19, 2006;354(3):251-260.
Acceptable but inferior options


Nelfinavir
 Inferior virologic efficacy
 Pregnancy: good tolerability and
adequate PK data
Stavudine / lamivudine
 Significant toxicities: peripheral
neuropathy, lipoatrophy, lactic acidosis
and hepatic steatosis, pancreatitis
 Use if preferred or alternative dual NRTI
combination cannot be used
ARV components NOT recommended as initial
therapy
Darunavir
No data
DDI + Tenofovir
Potential for CD4 decline, virologic
failure, selection of resistance
mutations
Indinavir
Inconvenient dosing, fluid
requirement, nephrolithiasis
Tipranavir
No data
Enfuvirtide
No clinical trial experience;
injections
Zalcitabine + ZDV
Inferior virologic efficacy, higher
adverse effects
ARV Regimens not recommended at any time
ARV
Rationale
Exception
Monotherapy or dual-NRTI
regimens
Rapid development of
resistance, inferior antiviral
activity
Triple NRTI
High rate of early failure or
non-response
Atazanavir+indinavir
Additive hyperbilirubinemia
and nephrolithiasis
Amprenavir oral solution
Large amount of propylene
glycol
Didanosine + stavudine
Overlapping toxicity, eg
peripheral neuropathy,
pancreatitis, lactic acidosis
with hepatic steatosis
No other options, benefits
outweigh risks
Efavirenz in first trimester or
in women with child-bearing
potential
Teratogenic in primates
No other options, benefit
outweighs risk
Nevirapine initiation in naïve
women with CD4>250 or men
with CD4>400 cells/mm3
Potentially fatal hepatic
events
Benefits clearly outweighs risk
Trizivir®, and possibly
tenofovir + Combivir®
May 2007 update

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For HIV/HBV co-infected patients,
entecavir should not be used for the
treatment of HBV infection without
concomitant treatment for HIV.
Previous in vitro data showed no
significant activity against HIV-1; but
recent case-series of 3 patients reported
decline in HIV-RNA and emergence of
M184V mutations in one co-infected
patient on entecavir monotherapy.
Supplement to the Guidelines for the Use of Antiretroviral Agents in
HIV-1-infected Adults and Adolescents – October 2006.
Why Do Treatments Fail
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adherence
side effects – acute and longer-term
baseline resistance or cross-resistance
use of less potent antiretroviral regimens
sequential monotherapy
drug levels and drug interactions
tissue reservoir penetration
other, unknown reasons
M184V
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Arises rapidly on 3TC or FTC therapy
Continued antiviral activity in presence of drug
and mutation
decreased viral replication fitness
Presence of M184V slows the evolution of
thymidine analogue mutations (TAMs)
Increased susceptibility to ZDV, d4T, TDF
Modest decreased susceptibility to ddI and ABC
TAMs
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Emerge gradually with ongoing failure of
ZDV or d4T
Rare with ddI, TDF, ABC in absence of
thymidine analogue
Development of TAMs tends to follow
distinct pathways of mutation at either
codons 41 and 215, or at codons 67, 70,
219
McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes
DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.
K65R
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Selected by TDF and less frequently ABC
in the absence of thymidine analogue
Decreased susceptibility to TDF, ABC, and
ddI
Activity of TDF may be partially retained
with M184V present
Increases susceptibility to ZDV
McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes
DR. J Acquir Immune Defic Syndr. 2004; 36: 600-603.
L74V
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Selected by ABC or ddI in the absence of
a thymidine analogue
Decreases susceptibility to ABC and ddI
Does not decrease susceptibility to TDF or
thymidine analogues
McComsey G. AIDS Read. 2003; 37 Suppl 1: S36-43; Kuritskes DR. J
Acquir Immune Defic Syndr. 2004; 36: 600-603.
NNRTI mutations
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Long term virologic response to sequential
NNRTI use is poor, particularly when 2 or
more mutations are present
K103N, Y188L, or G190A mutations likely
prevent the clinical utility of all NNRTI’s
currently approved
Importance of most mutations depends on
the presence of Y181C, which has an
impact only in the presence of at least 1
other mutation (important for Etravirine)
Johnson VA et al. Topics in HIV Medicine 2007; 15(4): 119-125.
NNRTI hypersusceptibility
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Longer duration of NRTI use, prior use of
zidovudine, and abacavir or zidovudine
resistance have been associated with
enhanced susceptibility to NNRTIs
(defined as IC50 of >2.5-fold less than that
of wild-type reference strain)
Greater short term reductions in viral load
in patients with hypersusceptibility to
efavirenz, who received that drug as
salvage therapy
Hirsch M. CID 2003;37:113-128.
Protease gene mutations
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Major mutations
 Selected first in the presence of drug, or shown at the
virologic or biochemical level to lead to an alteration
in drug binding or an inhibition of viral replication
 Effect on drug susceptibility phenotype
Minor mutations
 Emerge later, by themselves do not have significant
effect on phenotype, but may improve replicative
fitness in the presence of major mutations
Presence of at least 2 key mutations (e.g., D30N, G48V,
I50V, V82A/F/T/S, I84V, and L90M) generally confers
broad cross-resistance to most currently available PIs
“boosting” with low dose ritonavir may result in higher
and more prolonged drug concentrations and greater
suppression of viral variants that contain a limited
number of mutations
Hirsch M. CID 2003;37:113-128.
Envelope gene mutations

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Entry of HIV-1 into cell involves attachment
mediated by gp120 binding to CD4, chemokine
coreceptor binding, and association of 2
trimeric helical coils (HR-1 and HR-2) located in
the ectodomain of gp41 into a 6-helix bundle
that brings virus and cell membranes closer
together, allowing fusion
T-20 (enfuvirtide) binds HR-1 and blocks
association with HR-2, inhibiting fusion and
viral entry
Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.
Entry inhibitors
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Mutations at gp41 codons 36-45 are associated
with an average 20-fold increase from baseline
IC50
CCR5 inhibitors: Maraviroc activity is limited to
patients with only R5-using virus detectable;
some cases of failure during therapy are
associated with outgrowth of X4 virus that preexists as a minority population below the level of
detection
Mutations in the gp120 molecule that allow the
virus to bind R5 receptors in the presence of
drug have been described
Johnson VA et al. Topics in HIV Medicine 2007; 15(4):119-125.
Integrase mutations

Raltegravir failure was associated with
integrase mutations in 2 distinct genetic
pathways defined by 2 or more mutations
including:

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A major mutation at either Q148H/K/R or
N155H, and
1 or more minor mutations
The potential for nephrotoxicity with
tenofovir is an important consideration in
patients who have
A) hyperpigmentation
B) severe anemia
C) baseline renal
insufficiency
D) none of the above
th
e
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in
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al
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0% 0% 0% 0%
Tenofovir – renal issues
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Several case reports noting development
of renal insufficiency in patients on
tenofovir, some without prior history of
renal dysfunction
Nephrotoxicity involving tubular
dysfunction with Fanconi syndrome noted
in toxicological studies, dose-limiting
toxicity in animal studies
Tenofovir – renal issues

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Two similar nucleotide analogues, cidofovir and
adefovir, have been associated with doselimiting, renal tubular cell toxicity in patients in
infectious hepatitis or cytomegalovirus infection
Renal toxicity is mediated by proximal tube
epithelial cells that express human renal organic
anion transporter (hOAT1) and actively uptake
these drugs
Figure 1.
Renal biopsy image by light microscopy showing acute tubular
injury with loss and irregularity of tubular epithelial cells (hematoxylin and
eosin strain; original magnification, ×100). Inset, prominent nuclear
enlargement with hyperchromatic and smudged chromatin (hematoxylin and
eosin stain; original magnification, ×400).
Tenofovir – renal issues

Package insert revision 2005: dose should be
adjusted for patients with creatinine clearance of
<50 mL/min.

Cockcroft-Gault equation:
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(140-age) x (lean body weight in kg) x 0.85 (females) / 72 x
plasma creatinine
CD4 and viral load seem not to be predictors of
renal toxicity
Patients on tenofovir should be monitored
closely for early signs of tubulopathy (glycosuria,
proteinuria, acidosis, mild creatinine increases)
every 2 weeks for the first 2 months; therapy
should be stopped if any signs of tubulopathy
develop
Karras et al. CID 2003; 36: 1070-1073; Zimmerman et al. CID 2006; 42: 28390.
More important clinical trials
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The SMART study
ACTG 5142
TITAN
SMART
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Strategies for Management of AntiRetroviral
Treatment
Randomized, prospective study: 33 countries,
80% in North America and Europe
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Median CD4 597, 72% had viral load <400 copies/mL
5,472 HIV-infected adults with CD4 >350
Control group took ART continuously “viral
suppression group”
“drug conservation group” took therapy episodically
(initiated when CD4 <250, stopped when >350)
El-Sadr W et al. N Engl J Med 2006; 355(22):2283-2296
SMART

Results:
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Trial halted by DSMB with a mean follow up time of
only 16 months
Greater risk of clinical disease progression events and
overall death in drug conservation group
Greater risk of serious renal, hepatic, and
cardiovascular events
Rather than protect patients, the withdrawal of
therapy increased risk of death from any cause,
including that of opportunistic infections.
Cardiovascular, hepatic, and renal disease, which are
often associated with ART, were greater in the
treatment interruption arm.
ACTG 5142
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Phase 3, randomized, open-label study
comparing three regimens:
lopinavir/ritonavir + 2 NRTI; Efavirenz vs.
2 NRTI; lopinavir/ritonavir + efavirenz
753 ART-Naive patients with viral load
>2,000
NRTIs were chosen by clinicians and
patients; initially only one provided at no
cost (extended-release stavudine…later
tenofovir was added)

Week 96
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ACTG 5142
Proportion of patients with VL < 50 copies/mL
statistically significantly greater in Efavirenz arm
Median increase in CD4 count was significantly higher
in the lopinavir arm
Those patients in the NRTI-sparing arm had
significantly higher fasting triglyceride levels (14%
grade 3, compared to 6% in lopinavir arm, 3% in
efavirenz arm); 45% moderate of severe laboratory
abnormality
No resistance to lopinavir was observed; however,
resistance to efavirenz was detected in nearly half of
patients who failed this regimen; NRTI resistance was
more common with virologic failure on efavirenz as
well
Riddler S. et al. New England Journal of Medicine, May 15, 2008.
Riddler S, et al. 96 week data from ACTG 5142
Virologic
success
(%)
Regimen
continuation
<200
copies
<50
copies
CD4
increase
Lopinavir
/r +
efavirenz
73
61
92
83
268
Lopinavir
/r + 2
NRTI
67
54
86
77
285
Efavirenz
+ 2 NRTI
76
60
93
89
241
TITAN
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Phase 3 study comparing darunavir/r and
lopinavir/r in patients with VL < 1000 copies/mL,
on stable but failing regimen for at least 12
weeks
604 patients randomized to open label
lopinavir/r or darunavir/r, both with optimized
background selected based on resistance testing
(T-20 and investigational drugs excluded)
Previous lopinavir therapy exclusion criteria
Data from week 48 present at IDSA 2007, San
Diego
TITAN

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Both PIs were well tolerated, only 7% discontinued due
to toxicity
Lipid level elevation similar between the groups; higher
incidence of diarrhea in lopinavir arm (42% vs. 32%),
rash in darunavir arm (16% vs. 7%)
Significantly more patients in darunavir arm achieved VL
<50; fewer patients in darunavir arm had virologic
failure (10% vs 22%), and had primary PI mutations
(21% vs. 36%)
**among patients with baseline lopinavir fold-change of
greater than 10-fold, only 28% achieved VL <50
(greater virologic failure driven by baseline phenotypic
resistance to lopinavir??)
TITAN – 48 weeks efficacy results
DRV/r
LPV/r
P value
VL<50
71
60
0.005
VL<400
77
67
<0.0001
CD4
increase
88
61
0.33
Adapted from Hardy WD et al. IDSA 2007; San Diego, CA. Abstract 1209.
Newly available ARVs

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MERIT
MOTIVATE
BENCHMRK
MERCK 004
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Integrase cross-resistance
Effects on lipid parameters
DUET
MERIT: Maraviroc vs Efavirenz in
Treatment-Naive Patients
Stratified by HIV-1 RNA < or  100,000
copies/mL and by Northern or Southern
Hemisphere
Antiretroviral-naive patients
infected with CCR5-tropic
HIV-1 and HIV-1 RNA
 2000 copies/mL
(N = 740)
Week 48 primary endpoint
Week 96
MVC 300 mg twice daily + ZDV/3TC
(n = 360)
EFV 600 mg once daily + ZDV/3TC
(n = 361)
MVC 300-mg once-daily arm discontinued early due to failure to demonstrate noninferiority to efavirenz at
end of phase IIB (Week 16)

Stringent noninferiority margin: -10% for lower bound of 1-sided 97.5% CI
Saag M, et al. IAS 2007. Abstract WESS104.
MERIT: Patients With VL < 50 Copies/mL
by baseline VL
 EFV patients more
likely to discontinue
due to AE
90
80
– Efficacy: 4.2%
 MVC patients more
likely to discontinue
due to lack of efficacy
– Overall: 26.9%
– AE: 4.2%
Patients, %
– Overall : 25.2%
– AE: 13.6%
EFV
100
71.6
70
69.6
MVC
66.6
59.6
60
50
40
30
20
10
0
n=
211
204
BL VL < 100,000
copies/mL
150
156
BL VL ≥ 100,000
copies/mL
– Efficacy: 11.9%
Saag M, et al. IAS 2007. Abstract WESS104.
MOTIVATE: Maraviroc in TreatmentExperienced Patients With R5 Virus




Randomized, double-blind, placebo-controlled, parallel phase IIb/III studies
44% failed screening with X4 or dual/mixed virus detected
Primary endpoint: mean change in HIV-1 RNA at Week 24
Based on MOTIVATE data FDA approved MVC in August 2007 for use in
treatment-experienced patients with R5-tropic virus only
2:2:1 randomization;
stratified by ENF use and VL
Patients infected with R5; HIV-1 RNA ≥ 5000
copies/mL; stable ART or no ART for ≥ 4 weeks;
previous ART experience with ≥ 1 agent (≥ 2 for
PIs) from 3 of the 4 antiretroviral drug classes
for ≥ 6 months or documented resistance to
members of 3 of 4 classes
(MOTIVATE 1: N = 601, Canada, US; MOTIVATE
2: N = 475,
Europe, Australia, US)
Week 24
planned interim analysis
MVC 150 mg or 300 mg* twice daily + OBR†
MVC 150 mg or 300 mg* once daily + OBR†
Placebo + OBR†
*Patients receiving PI (other than TPV) or DLV received 150 mg; all others received 300 mg. †OBR: 3-6 ARVs.
Nelson M, et al. CROI 2007. Abstract 104aLB.
Lalezari J, et al. CROI 2007. Abstract 104bLB.
Week 48
MOTIVATE 1 and 2: Combined Virologic
and Immunologic Efficacy

MVC + OBR associated with significantly greater virologic suppression than
placebo plus OBR in treatment-experienced patients
– Increased activity observed with de novo use of enfuvirtide, LPV/RTV
Outcome
Placebo+ OBR
MVC QD +
OBR
MVC
BID + OBR
VL<400
28
55‡
61‡
VL<50
23
44‡
45‡
Mean CD4 increase
57
109
106
*HIV-1 RNA value imputed as baseline if patient discontinued before 24 weeks.
†Patients with missing values were classified as failures unless they were responders at Weeks 20 and 32.
‡P = .0001 vs placebo group.
Gulick RM, et al. IAS 2007. Abstract WEPEB116LB.
Maraviroc dosing

With CYP3A inhibitors: 150 mg po BID




PIs (except tipranavir)
Ketoconzale, itraconazole, clarithromycin
With NRTIs, nevirapine, tipranavir /
ritonavir,enfuvirtide: 300 mg po BID
(recommended dose)
With CYP3A inducers: 600 mg (2 tabs) po BID





Efavirenz
Rifampin
Carbamazepine
Phenytoin
phenobarbital
Tropism testing

“Trofile”: co-receptor
tropism assay detects R5 vs. X4
virus


Monogram biosciences
HIV RNA > 1000
copies/mL required
Protocol 004: Raltegravir vs Efavirenz in
Treatment-Naive Patients

Treatment-naive patients (n = 198) with VL > 5000 copies/mL and CD4+
> 100 cells/mm3 randomized to one of 4 doses of RAL (100, 200, 400, 600 mg
BID) or EFV (600 mg QD) each with TDF + 3TC
Patient
Outcome, %
RAL 100
mg (n =
39)
RAL 200
mg
(n = 40)
RAL 400
mg
(n = 41)
RAL 600
mg
(n = 40)
EFV 600
mg
(n = 38)
VL < 400
copies/mL

Week 24
95
85
98
95
95

Week 48
97
85
98
90
87
VL < 50 copies/mL
Week 24
87
85
93
95
92
 Viral dynamics substudy: second-phase decay may be accelerated with RAL[2]
 Week 48
85
83
88
88
87

Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. Murray JM, et al. IAS 2007.
Abstract TUAB103.
Protocol 004: RAL Associated With
Fewer Lipid Effects vs EFV

RAL well tolerated with no dose-related toxicities


Dizziness, headache, and atypical dreams more frequent with EFV
Total cholesterol, LDL-cholesterol, triglycerides not
increased by RAL
Mean change
from baseline,
mg/L
RAL 100-600mg EFV 600mg QD
BID
P value
Total chol
-2.3
+20.7
<0.001
LDL
-7.5
+3.0
0.016
TG
-1.0
+49.5
0.068
*All RAL dose groups combined.
Markowitz M, et al. IAS 2007. Abstract TUAB104.
BENCHMRK





Double blind clinical trial: pts assigned to 200, 400 or
600 mg of MK-0518 BID along with OBT or placebo with
OBT
178 patients with at least one resistance mutation in
each of 3 drug classes, VL > 5,000, CD4 above 50
14% placebo group achieved VL<50 by week 24
65, 57, 67% achieved VL<50 taking 3 doses of MK-0518
Co-administration of T-20 boosted responses by about
20% in the MK-0518 arms
BENCHMRK 1 and 2: Raltegravir (MK0518) in Treatment-Experienced Pts

Randomized, double-blind, placebo-controlled, parallel phase III studies

Primary endpoints: HIV-1 RNA, CD4+ cell counts, and adverse events at
Week 16
Primary endpoints:
Week 16
HIV-infected,
triple-class resistant,
HIV-1 RNA > 1000 copies/mL
Raltegravir 400 mg twice daily + OBR*
BENCHMRK-1 (n = 232)
BENCHMRK-2 (n = 230)
BENCHMRK-1 (N = 350)
(Europe, Asia/Pacific, Peru)
BENCHMRK-2 (N = 349)
(North, South America)
*Selected investigational antiretrovirals permitted in OBR.
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
Planned duration:
Week 48
Placebo + OBR*
BENCHMRK-1 (n = 118)
BENCHMRK-2 (n = 119)
BENCHMRK 1 and 2:
VL < 400 copies/mL (ITT, NC = F)
Raltegravir + OBR
Patients With HIV-1 RNA
< 400 copies/mL (%)
100
Placebo + OBR
100
BENCHMRK-1
BENCHMRK-2
77%
80
77%
80
60
P < .001 at Week 16
60
P < .001 at Week 16
40
40
43%
41%
20
20
0
0
0 2 4
158
n=
230
12
16
Weeks
229
n=
118
118
81
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
n=
119
119
n=
232
8
12
16
Weeks
230
24
0 2 4
8
24
128
69
BENCHMRK 1 and 2:
VL < 50 copies/mL (ITT, NC = F)
Raltegravir + OBR
Patients with HIV-1 RNA
< 50 copies/mL (%)
100
100
BENCHMRK-1
80
Placebo + OBR
BENCHMRK-2
80
61%
62%
60
60
P < .001 at Week 16
P < .001 at Week 16
40
40
33%
20
36%
20
0
0
0 2 4
158
n=
230
12
16
Weeks
229
n=
118
118
81
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
n=
119
119
n=
232
8
12
16
Weeks
230
24
0 2 4
8
24
128
69
BENCHMRK 1 and 2: VL < 400 c/mL at
Wk 16 by Specific Agents in OBR
Raltegravir + OBR
n
447
230
Overall Efficacy Data
Placebo + OBR
79
43
Efficacy by Agents in OBR
Enfuvirtide
Darunavir
+
+
44
23
+
–
42
24
–
+
80
47
–
–
191
90
+ : First use in OBR
– : No use in OBR
98
87
90
63
90
55
29
0
Statistical analysis: virologic failure carried forward.
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
20
40
60
Patients (%)
74
80
100
Raltegravir and ?malignancies

Malignancy Conclusions
• In the original application, an imbalance in rates of
malignancies was noted. The malignancy types and rates in the
raltegravir group are those anticipated in a severely
immunodeficient HIV/AIDS population and are consistent with
reported rates in the literature. A history of malignancy prior to
enrollment was common and many of the malignancies in the
raltegravir group were likely present at time of study entry or
were recurrences of prior diagnosed malignancies.
• Based on an updated analysis of the same study cohorts, the
imbalance in rates of malignancies has not been sustained with
additional follow-up. This is consistent with the possibility that
the original imbalance was a function of small numbers of cases
and relatively imprecise estimates of rates.
• While the updated analysis is reassuring, the total amount of
safety follow-up is limited and additional data are needed.
Further follow-up is proposed in the Risk Management Plan.
Excerpted from Merck Briefing Document for FDA Hearing Sept 5, 2007
Raltegravir and malignancy

".....Overall, the rates and kinds of malignancies seen in
patients receiving raltegravir in the clinical development
program approximate the rates and kinds of
malignancies reported in the literature for patients with
HIV/AIDS....
....It is also noteworthy that in the patients receiving
raltegravir who ultimately developed a malignancy, the
median CD4 cell count was 122 cells/mm3 and all
patients with malignancy had a history of AIDS, a known
independent risk factor for malignancy. Most of the
malignancies encountered are associated with well
known risk factors for malignancy such as AIDS,
oncogenic viruses (papillomavirus infection, hepatitis B
virus infection), and tobacco.
Figure 19 displays Kaplan-Meier estimates of time to malignancies for the double-blind phase
of Protocols 004, 005, 018, and 019. Of note, no events occurred in the raltegravir arm after
month 4 in this analysis.
Figure 19
Kaplan-Meier Plot of Time to Malignancy-Double-Blind Phase
Phase II and III Studies
Original Application
Figure 20 displays Kaplan-Meier estimates of time to malignancies for the
double blind phase of Protocols 004, 005, 018 and 019 cumulatively seen over
18 months of therapy in this updated malignancy analysis. Figure 20
Kaplan-Meier Plot of Time to Malignancy-Double-Blind Phase
Phase II and III Studies
Cumulative Update as of 09-Jul-2007
Note: These data have not been reviewed by the FDA.
Integrase Inhibitor Resistance and
Cross-Resistance

Protocol 004: VF in 5 RAL recipients (3%)




3 had no detected integrase mutations
1 had N155H + M184M/I/V
1 had N155H + other mutations (V151I, D232D/N, G163G/R)
Separate report of 2 patients with VF on elvitegravir
(EVG)/RTV, with no VL response during first week after
switch to RAL


Suggests high level of cross-resistance between first 2 integrase
inhibitors
Patient 1 had N155H and 3 other integrase mutations at VF (VL:
840 copies/mL) on EVG/RTV


Regained viral suppression (< 50 copies/mL) after addition of DRV/RTV to RAL
Patient 2 had Q148R and 4 other integrase mutations at VF (VL:
10,700 copies/mL) on EVG/RTV

Failed to regain suppression after addition of DRV/RTV to RAL
Markowitz M, et al. IAS 2007. Abstract TUAB104. 2. DeJesus E , et al. IAS 2007. Abstract
TUPEB032 .
DUET-1 and -2: Etravirine + DRV/RTVContaining OBR Phase III Trials
Week 24‡
HIV-infected patients with virologic
failure on current HAART regimen,
history of ≥ 1 NNRTI resistance
mutations,
≥ 3 PI mutations,
HIV-1 RNA > 5000 copies/mL
ETR 200 mg BID*
+ DRV/RTV-containing OBR†
Placebo
+ DRV/RTV-containing OBR†
(DUET-1: N = 612 DUET-2: N = 591)
*New formulation equivalent to 800 mg BID with old formulation.
†Investigator-selected OBR to consist of DRV/RTV (600/100 mg/mL) + ≥ 2 NRTIs ±
enfuvirtide.
‡Planned Week 24 analysis: primary endpoint HIV-1 RNA < 50 copies/mL (TLOVR)
Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.
Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1.
Week 48
DUET-1 and -2: Virologic Response at
Week 24 (TLOVR Analysis)
VL < 50 copies/mL, %
100
80
DUET-1
DUET-2
P = .0003
ETR
Placebo
P = .005
62%
60
56%
44%
40
39%
20
0
P
ETR
P
ETR
Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.
Katlama C, et al. IAS 2007. Abstract WESS204.2. Mills A, et al. IAS 2007. Abstract WESS204.1.
DUET-1 and -2: BL ETR Mutations and
Virologic Response at Week 24
V90I
L100I
V106I
Y181C/I/V
A98G
K101E/P
V179D/F
G190A/S
 Presence of ≥ 3 ETR mutations
associated with response
similar to placebo + OBR
– 70% of patients had 0 or 1 ETR
resistance mutations at BL
Patients With HIV-1
RNA < 50 copies/mL (%)
 13 mutations associated with
ETR resistance
100
90
80
70
60
50
40
30
20
10
0
– 14% of patients had ≥ 3 ETR
resistance mutations at BL
0
1
2
3
4
5
No. of BL ETR Mutations
Patients (%)
Katlama C, et al. IAS 2007. Abstract WESS204.2.
40
30
16
8
5
1
Investigational ARVs
Vicriviroc – ACTG 5211
Elvitegravir
CCR5 monoclonal antibody – PRO 140
others
ACTG 5211: Phase II Trial of Vicriviroc in
Treatment-Experienced Patients
Stratified by enfuvirtide use and
baseline CD4+ count < or ≥ 50 cells/mm³
Antiretroviralexperienced patients
with HIV-1 RNA ≥ 5000
copies/mL and R5-only
virus on ritonavircontaining regimen
(N = 118)
Failing
regimen
Gulick R, et al. J Infect Dis 2007;196:304-312.
Day 14
Week 48
Placebo
(n = 28)
Vicriviroc 5 mg once daily
(n = 30)
Discontinued
Vicriviroc 10 mg once daily
(n = 30)
Vicriviroc 15 mg once daily
(n = 30)
OBR
(includes 100-800 mg Ritonavir)
ACTG 5211: Patients with HIV-1 RNA <
50 copies/mL at 24 and 48 Weeks

VCV + RTV-containing OBR associated with
sustained Placebo
antiviralVicriviroc
activity
at
Week
48
10 mg
Vicriviroc 15 mg
100
90
Patients, %
80
70
60
50
40
40
37
27
30
20
10
27
11
7
0
Week 24
Gulick R, et al. J Infect Dis 2007;196:304-312.
Week 48
ACTG 5211: Safety, Tolerability, and
Tropism on Failure


Incidence of grade 3/4 AEs comparable among arms (P ≥
.6)
10 patients developed malignancies (4 additional patients
since Week 24)


Vicriviroc: 8 patients

Non-Hodgkin’s lymphoma: n = 2
– Hodgkin’s disease: n = 2

Gastric adenocarcinoma: n = 1
– Squamous cell carcinoma: n = 1

Basal cell carcinoma: n = 1
– Kaposi sarcoma recurrence: n = 1
Placebo: 2 patients


Squamous cell carcinoma: n = 2
9 (35%) of 26 patients with VF on vicriviroc had dual/mixed
or X4 virus detected
Gulick R, et al. J Infect Dis 2007;196:304-312.
PRO 140 1302: Effects of a Single IV
Humanized CCR5 Antibody Infusion
PRO 140 0.5 mg/kg single IV infusion
(n = 10)
Patients with asymptomatic R5-tropic HIV-1
infection, HIV-1 RNA > 5000 copies/mL,
CD4+ cell count > 250 cells/mm3 (with nadir
> 200), and no antiretroviral therapy
for ≥ 3 months
PRO 140 2.0 mg/kg single IV infusion
(n = 10)
PRO 140 5.0 mg/kg single IV infusion
(n = 10)
(N = 39)
Mean Change in VL,
log10 copies/mL
0.5
59-day
follow-up
Placebo
(n = 9)
Placebo
0.5 mg/kg
2 mg/kg
5 mg/kg
0.0
-0.5
-1.0
‡
-1.5
†
‡
-2.0
0
‡
‡
10
†
*
*P ≤ .01
†P ≤ .001
‡P ≤ .0001
‡
‡
20
Saag MS, et al. IAS 2007. Abstract WESS201.
30
Study Day
40
50
60
The HLA-B*5701 genotype has been
shown to be a predictive risk factor for
A) poor CD4+ cell
response
B) ABC
hypersensitivity
C) insulin resistance
D) lipoatrophy
y
tr
op
h
)l
ip
oa
ce
re
s
ul
in
D
is
ta
n
ity
iti
v
)i
ns
C
hy
C
)A
B
B
A
)p
oo
r
CD
4+
pe
rs
e
ce
ll
20
ns
re
...
0% 0% 0% 0%
New testing available

HLA-B*5701 testing for Abacavir hypersensitivity
(HSR) – LabCorp, Quest; PCR on whole blood or
buccal swab to determine presence of HLAB5701 allele
 HSR observed in about 5% of patients in
clinical trials; 89% of cases occur in the first 6
weeks of therapy with ABC
 Most have multiple symptoms (fever, rash,
myalgias, arthralgias, etc…)
Ziagen package insert; GSK 2003; J Antimicrob Chemother. 2007;
59:591-593.
SHAPE: Retrospective Case-Control
Study
CASES
CONTROLS
Black and white subjects
with clinically suspected
ABC HSR (CS-HSR)
Black and white subjects
enrolled in KLEAN, ALOHA,
CNA30027, CNA30032
ABC
skin patch test
and HLA-B*5701
White: n = 130
Black: n = 69
Identify ABC-tolerant
subjects
White: n = 202
Black: n = 206
Skin patch test
positive
Skin patch test
negative
White: n = 42
Black: n = 5
White: n = 85
Black: n = 63
Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118,
Apr 2008
.
SHAPE: Sensitivity and Specificity of
HLA-B*5701
CS-HSR confirmed by HLA-B*5701
100%
100
Sensitivity of HLA-B*5701
96%
Specificity of HLA-B*5701
100%
99%
Sensitivity/Specificity of
HLA-B*5701, %
90
80
70
60
44%
50
40
14%
30
20
10
0
57/130
42/42
194/202
10/69
5/5
204/206
CS-HSR
Skin Test
Positive
Control
CS-HSR
Skin Test
Positive
Control
White
Black
Clinical Infectious Diseases. Volume 46, Issue 7, Page 1111–1118, Apr 2008
Case 1


46 year old male diagnosed in 2004; initial
CD4 400 cells/mm3; VL 55,000 copies/mL
2 years later CD4 decreased to 230, VL
increased to 150,000, and the patient opts
to begin ART:



Tenofovir / emtricitabine
Atazanavir 300mg + Ritonavir 100 mg
After 6 months his CD4 is 450, VL <50
Case 1


The patient reports good tolerance of
regimen and overall good health; he uses
loratadine and pseudoephedrine for
occasional bouts of seasonal rhinitis /
sinusitis
He also reports occasional overeating and
binge drinking, accompanied by rare
episodes of heartburn
Case 1


A few months later after having missed a
regular quarterly visit, the patient’s CD4 is
290 and VL 27,500; repeat testing
confirms
On questioning the patient reveals having
missed occasional doses of ritonavir, in an
attempt to reduce diarrhea and bloating,
and having initiated over the counter
omeprazole nearly daily, 20-40 mg
In addition to reinforcing the importance of
adherance to ritonavir, as well as the other drugs in
his ARV regimen, what next steps would you take?
sc
o
C
)a
dv
i
se
to
di
to
se
dv
i
)a
B
0%
di
sc
o
tie
pa
th
e
se
dv
i
)a
A
0%
nt
i..
.
nt
..
0%
nt
i..
.
A) advise the patient to avoid
omeprazole within 12
hours of taking
atazanavir
B) advise to discontinue
atazanavir and intensify
the regimen, increasing
the dose to 400 mg /day
C) advise to discontinue
omeprazole and order
resistance testing
20
Genotype reveals the following mutations:
RT: K65R, M184V, G190A
PI: I50L, G73S
Which regimen would you choose at this juncture?
A) new boosted PI +
NRTI
B) new boosted PI +
NRTI plus
enfuvirtide
C) NNRTI plus NRTIs
0%
0%
N
pl
us
RT
I
)N
N
C
ew
)n
B
A
)n
ew
bo
bo
os
te
os
te
d
d
PI
+
PI
+
...
...
20
RT
I
s
0%
Case 1


Genotype reveals likely lack of susceptibility to
approved NNRTIs (G190A); although he has not
been exposed to this class he may have
acquired the mutation at initial infection or
subsequent reinfection
Use of a fusion inhibitor is unnecessary in this
case to construct a regimen with at least 2,
ideally 3 active agents; reserving active agents
for future use is an important strategy in HIV
management
Based on resistance mutations, which
combination would you choose? (M184V,
K65R, G190A)
A) Tenofovir +
emtricitabine
B) Zidovudine +
lamivudine
C) Abacavir + lamivudine
D) Stavudine +
lamivudine
..
m
iv
.
la
vu
di
ne
vi
r+
D
)S
ta
ca
)A
ba
C
+
la
m
iv
u
i..
.
la
m
+
di
ne
id
ov
u
)Z
B
A
)T
en
o
fo
v
ir
+
em
tri
c
i..
.
20
...
0% 0% 0% 0%
Case 1



Genotype pattern suggests susceptibility
to abacavir, didanosine, and tenofovir
would most likely be reduced
The M184V may increase susceptibility to
zidovudine in the presence of 3TC or FTC
Stavudine likely remains phenotypically
active
Cased on recent clinical trial data, treatment
history, and genotype, which boosted PI would you
choose?
0%
rit
o
av
ir
/
av
)D
ar
un
C
B
)L
op
in
a
vi
r/
m
pr
en
os
a
)F
A
vi
r
na
v
r..
.
ir
/
20
0%
ir
0%
rit
on
a
A) Fosamprenavir /
ritonavir
B) Lopinavir /
ritonavir
C) Darunavir /
ritonavir
Case 1


All 3 choices are reasonable and have a good
likelihood of achieving undetectable HIV-1 RNA;
the patient has minimal PI resistance (I50L
confers resistance to atazanavir, G73S confers
broad PI resistance, but likely would have little
impact unaccompanied by another major PI
mutation)
Based on the results of TITAN,
darunavir/ritonavir out-performed
lopinavir/ritonavir at 48 weeks in less treatmentexperienced patients (31% naïve, 38% had
received 1 PI)
Case 1


POWER-1 demonstrated the superiority of
darunavir/ritonavir over investigatorselected comparator PIs in triple-class
experienced patients (in combination with
OBT)
KLEAN and CONTEXT demonstrated
efficacy and noninferiority of boosted
fosamprenavir in comparison with
lopinavir/ritonavir, in both naïve and
experienced patients, respectively
Case 2


50 year old male initially diagnosed in 1987, RF MSM;
initial CD4 800, nadir about 150. + history of Kaposi’s
sarcoma, recurrent molluscum, and esophageal
candidiasis
ART regimens:





1992-1995: zidovudine monotherapy; CD4 241
1995-1996: zidovudine + lamivudine; CD4 327, VL 100K
1996-1998: zidovudine + lamivudine + indinavir; CD4 708
1998-2003: didanosine+ ritonavir + saquinavir; CD4 580, VL
236K
2003-2004: lamivudine + didanosine + lopinavir / ritonavir; CD4
336, VL 111 K

Diagnosed with acute HBV infection, +sAg and eAg
Case 2

In 2004, virtual phenotype/genotype
shows:



RT: M184V, 41L, 210W, 215Y
PI: 54V, 71V, 82A
Data for atazanavir and fosamprenavir not yet
available
Based on this resistance pattern and the patient’s
history, what regimen would you choose at this
juncture?
A) Zidovudine / lamivudine
+ lopinavir / ritonavir
B) Tenofovir / emtricitabine
+ nevirapine
C) Tenofovir / emtricitabine
+ stavudine +
efavirenz
D) Tenofovir / emtricitabine
+ efavirenz +
fosamprenavir +
20
ritonavir
i..
.
ir
/
em
tr
ic
i..
.
D
)T
en
o
fo
v
ir
/
em
tr
ic
i..
.
C
)T
en
o
fo
v
ir
/
fo
v
en
o
)T
B
A
)Z
id
ov
u
di
ne
/l
em
tr
ic
am
iv
.
..
0% 0% 0% 0%
Case 2


He begins new regimen of tenofovir and FTC, +
boosted fosamprenavir, + efavirenz: CD4 >600;
VL <400 consistently for > 1 year.
The patient requests regimen simplification in
1/07 due to pill burden and fatigue, GI side
effects, and lipodystrophy. He attempts to enroll
in a local clinial trial examining the role of
rosiglitazone in HIV-related lipodystrophy.
What do you recommend now?
th
e
ve
ge
gi
ha
n
to
C
)c
e
gr
e
)a
B
0%
gi
m
..
th
e
in
...
ge
an
ch
a
e
)r
ef
us
A
0%
p.
..
0%
re
A) refuse a change in regimen,
reinforce the importance of
compliance
B) agree to give the patient a
“drug holiday” (structured
treatment interruption)
C) change the regimen to
tenofovir / emtricitabine /
efavirenz, which has just
20
become available
Case 2



The patient begins tenofovir /
emtricitabine / efavirenz.
3 months later he feels great, is tolerating
the drug extremely well, and his CD4
count is still 708 (35%)…
BUT…his viral load has climbed to
6437…now what?



A) continue his current regimen…the viral
load was probably a “blip” and will come
back down.
B) restart fosamprenavir and ritonavir.
C) repeat the viral load and order
resistance testing with plans to completely
change his regimen.
Case 2


Genotype/virtual phenotype performed in
April 2007 reveals the same NRTI
mutations as previously (M184V and
multiple TAMs); he now has the K103N,
and the same PI mutations as he had in
2003, with phenotypic sensitivity only to
saquinavir, tipranavir, and darunavir.
What happened?



A) although he reported 100%
compliance, he probably missed doses and
developed resistance to the NNRTIs
B) the lack of three fully active drugs put
more selection pressure on efavirenz,
bringing out an archived virus with the
K103N mutation, which he acquired either
at initial infection or later by reinfection
C) the geno/pheno from 2003 used a
different technique and was therefore
probably wrong
Case 2


The patient is concerned about his viral
rebound, and is willing to begin a new regimen.
Based on most recent geno/pheno the patient
begins tenofovir/emtricitabine, stavudine,
darunavir, and ritonavir. His regimen now
contains 3 drugs active against HIV and 2 active
against hepatitis B.
Although he is tolerating the regimen well, and
his viral load became undetectable after 6 weeks
(CD4 still about 700), he is now concerned
about increasing abdominal girth and wasting of
the extremities, which has been a chronic
problem, but he’s noticed it even more since
initiating the new regimen.
What might be a reasonable option for this
patient in the near future, assuming his viral
load remains undetectable?
ra
v
ir.
.
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ra
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ar
av
to
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de
ub
s
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C
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ub
s
tit
u
tit
u
te
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i
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0%
..
0%
h.
.
0%
A
A) add enfuvirtide to his
current regimen
B) substitute maraviroc for
darunavir / ritonavir
C) substitute raltegravir for
stavudine, with the
possibility of adding /
substituting etravirine at
a later date
20