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Antiretroviral Update Spring 2008

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Title: Antiretroviral Update Spring 2008


1
Antiretroviral UpdateSpring 2008
  • Lisa M. Chirch, M.D.
  • Stony Brook University - CPHE
  • NY/NJ AIDS Education and Training Center

2
Objectives
  • 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

3
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 lt200/mm3 Treat
Asymptomatic CD4 gt200, lt350 Treat
Asymptomatic CD4 gt350 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.
4
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 Collaboration- Concerted
    Action on SeroConversion to AIDS and Death in
    Europe www.ctu.mrc.ac.uk/cascade
  • Examples
  • 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.

5
Which of the following fixed dose combinations
(FDCs) are designated as preferred initial NRTI
options according to the most recent DHHS
guidelines?
  • 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

6
Which of the following ARVs is contraindicated in
women with CD4 cell counts above 250?
  • A) Efavirenz
  • B) Nelfinavir
  • C) Nevirapine
  • D) Didanosine

7
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

8
Preferred and Alternative ARVs in updated DHHS
Guidelines
NNRTI PI 2 NRTI
Preferred Efavirenz Atazanavir Ritonavir Fosamprenavir ritonavir (BID), lopinavir/ ritonavir (BID) Tenofovir/ Emtricitabine Abacavir/ Lamivudine (if HLAB5701 negative)
Alternative Nevirapine Atazanavir Fosamprenavir Fosamprenavir (QD) Lopinavir/ ritonavir (QD) Saquinavir/ritonavir 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.
9
Rationale recent data (KLEAN)
  • Inclusion of boosted fosamprenavir in the
    preferred list
  • KLEAN phase 3, open-label, multi-center,
    non-inferiority 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.
10
BMS-089
  • 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
11
BMS-089
  • 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.

12
Gilead 934
  • 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 lt 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,
2006354(3)251-260.
13
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

14
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
15
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 Trizivir, and possibly tenofovir Combivir
Atazanavirindinavir 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 CD4gt250 or men with CD4gt400 cells/mm3 Potentially fatal hepatic events Benefits clearly outweighs risk
16
May 2007 update
  • 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.
17
Why Do Treatments Fail
  • 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

18
M184V
  • 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

19
TAMs
  • 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.
20
K65R
  • 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.
21
L74V
  • 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.
22
NNRTI mutations
  • 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 NNRTIs 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.
23
NNRTI hypersusceptibility
  • 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 gt2.5-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 200337113-128.
24
Protease gene mutations
  • 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 200337113-128.
25
Envelope gene mutations
  • 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.
26
Entry inhibitors
  • 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
    pre-exists 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.
27
Integrase mutations
  • Raltegravir failure was associated with integrase
    mutations in 2 distinct genetic pathways defined
    by 2 or more mutations including
  • A major mutation at either Q148H/K/R or N155H,
    and
  • 1 or more minor mutations

28
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

29
Tenofovir renal issues
  • 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

30
Tenofovir renal issues
  • Two similar nucleotide analogues, cidofovir and
    adefovir, have been associated with
    dose-limiting, 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

31
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).
32
Tenofovir renal issues
  • Package insert revision 2005 dose should be
    adjusted for patients with creatinine clearance
    of lt50 mL/min.
  • Cockcroft-Gault equation
  • (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 42 283-90.
33
More important clinical trials
  • The SMART study
  • ACTG 5142
  • TITAN

34
SMART
  • Strategies for Management of AntiRetroviral
    Treatment
  • Randomized, prospective study 33 countries, 80
    in North America and Europe
  • Median CD4 597, 72 had viral load lt400 copies/mL
  • 5,472 HIV-infected adults with CD4 gt350
  • Control group took ART continuously viral
    suppression group
  • drug conservation group took therapy
    episodically (initiated when CD4 lt250, stopped
    when gt350)

El-Sadr W et al. N Engl J Med 2006
355(22)2283-2296
35
SMART
  • Results
  • 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.

36
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37
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38
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39
ACTG 5142
  • 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 gt2,000
  • NRTIs were chosen by clinicians and patients
    initially only one provided at no cost
    (extended-release stavudinelater tenofovir was
    added)

40
ACTG 5142
  • Week 96
  • Proportion of patients with VL lt 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.
41
Riddler S, et al. 96 week data from ACTG 5142
Virologic success () Regimen contin-uation lt200 copies lt50 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
42
TITAN
  • Phase 3 study comparing darunavir/r and
    lopinavir/r in patients with VL lt 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

43
TITAN
  • 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 lt50 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 lt50 (greater virologic failure driven
    by baseline phenotypic resistance to lopinavir??)

44
TITAN 48 weeks efficacy results
DRV/r LPV/r P value
VLlt50 71 60 0.005
VLlt400 77 67 lt0.0001
CD4 increase 88 61 0.33
Adapted from Hardy WD et al. IDSA 2007 San
Diego, CA. Abstract 1209.
45
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46
Newly available ARVs
  • MERIT
  • MOTIVATE
  • BENCHMRK
  • MERCK 004
  • Integrase cross-resistance
  • Effects on lipid parameters
  • DUET

47
MERIT Maraviroc vs Efavirenz in Treatment-Naive
Patients
Stratified by HIV-1 RNA lt or ? 100,000 copies/mL
and by Northern or Southern Hemisphere
Week 48 primary endpoint
Week 96
MVC 300 mg twice daily ZDV/3TC (n 360)
Antiretroviral-naive patients infected with
CCR5-tropic HIV-1 and HIV-1 RNA ? 2000
copies/mL (N 740)
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.
48
MERIT Patients With VL lt 50 Copies/mL by
baseline VL
  • EFV patients more likely to discontinue due to AE
  • Overall 25.2
  • AE 13.6
  • Efficacy 4.2
  • MVC patients more likely to discontinue due to
    lack of efficacy
  • Overall 26.9
  • AE 4.2
  • Efficacy 11.9

MVC
EFV
100
90
80
71.6
69.6
66.6
70
59.6
60
50
Patients,
40
30
20
10
0
n
211
204
150
156
BL VL lt 100,000 copies/mL
BL VL 100,000 copies/mL
Saag M, et al. IAS 2007. Abstract WESS104.
49
MOTIVATE Maraviroc in Treatment-Experienced
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
  • 221 randomization
  • stratified by ENF use and VL

Week 24 planned interim analysis
Week 48
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)
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.
50
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
VLlt400 28 55 61
VLlt50 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.
51
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

52
Tropism testing
  • Trofile co-receptor tropism assay - detects
    R5 vs. X4 virus
  • Monogram biosciences
  • HIV RNA gt 1000 copies/mL required

53
Protocol 004 Raltegravir vs Efavirenz in
Treatment-Naive Patients
  • Treatment-naive patients (n 198) with VL gt 5000
    copies/mL and CD4 gt 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 lt 400 copies/mL
Week 24 95 85 98 95 95
Week 48 97 85 98 90 87
VL lt 50 copies/mL
Week 24 87 85 93 95 92
Week 48 85 83 88 88 87
  • Viral dynamics substudy second-phase decay may
    be accelerated with RAL2

Markowitz M, et al. IAS 2007. Abstract TUAB104.
2. Murray JM, et al. IAS 2007. Abstract TUAB103.
54
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 BID EFV 600mg QD P value
Total chol -2.3 20.7 lt0.001
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.
55
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 gt 5,000,
    CD4 above 50
  • 14 placebo group achieved VLlt50 by week 24
  • 65, 57, 67 achieved VLlt50 taking 3 doses of
    MK-0518
  • Co-administration of T-20 boosted responses by
    about 20 in the MK-0518 arms

56
BENCHMRK 1 and 2 Raltegravir (MK-0518) 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

Planned duration Week 48
Primary endpoints Week 16
HIV-infected, triple-class resistant, HIV-1 RNA
gt 1000 copies/mL BENCHMRK-1 (N 350) (Europe,
Asia/Pacific, Peru) BENCHMRK-2 (N 349) (North,
South America)
Raltegravir 400 mg twice daily OBR BENCHMRK-1
(n 232) BENCHMRK-2 (n 230)
Placebo OBR BENCHMRK-1 (n 118) BENCHMRK-2 (n
119)
Selected investigational antiretrovirals
permitted in OBR.
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
57
BENCHMRK 1 and 2 VL lt 400 copies/mL (ITT, NC
F)
Raltegravir OBR
Placebo OBR
BENCHMRK-2
BENCHMRK-1
100
100
77
77
80
80
P lt .001 at Week 16
P lt .001 at Week 16
60
60
Patients With HIV-1 RNA lt 400 copies/mL ()
40
40
43
41
20
20
0
0
0
2
4
8
12
16
24
0
2
4
8
12
16
24
Weeks
Weeks
230
158
232
n
128
229
230
n
81
118
118
n
69
119
119
n
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
58
BENCHMRK 1 and 2 VL lt 50 copies/mL (ITT, NC F)
Raltegravir OBR
Placebo OBR
BENCHMRK-2
BENCHMRK-1
100
100
80
80
61
62
60
60
Patients with HIV-1 RNA lt 50 copies/mL ()
P lt .001 at Week 16
P lt .001 at Week 16
40
40
36
33
20
20
0
0
0
2
4
8
12
16
24
0
2
4
8
12
16
24
Weeks
Weeks
230
158
232
n
229
128
230
n
81
118
118
n
69
119
119
n
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
59
BENCHMRK 1 and 2 VL lt 400 c/mL at Wk 16 by
Specific Agents in OBR
Raltegravir OBR
n
Placebo OBR
Overall Efficacy Data
447
79
230
43
Efficacy by Agents in OBR
Enfuvirtide
Darunavir
44
98


23
87
42


90
24
63
80


90
47
55
191


74
90
29
First use in OBR No use in OBR
0
20
40
60
80
100
Patients ()
Statistical analysis virologic failure carried
forward.
Cooper D, et al. CROI 2007. Abstract 105aLB.
Steigbigel R, et al. CROI 2007. Abstract 105bLB.
60
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
61
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.

62
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
19Kaplan-Meier Plot of Time to
Malignancy-Double-Blind PhasePhase II and III
StudiesOriginal Application
63
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 20Kaplan-Meier Plot
of Time to Malignancy-Double-Blind PhasePhase II
and III StudiesCumulative Update as of
09-Jul-2007Note These data have not been
reviewed by the FDA.
64
(No Transcript)
65
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 (lt 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
.
66
DUET-1 and -2 Etravirine DRV/RTV-Containing
OBR Phase III Trials
Week 48
Week 24
HIV-infected patients with virologic failure on
current HAART regimen, history of 1 NNRTI
resistance mutations, 3 PI mutations, HIV-1
RNA gt 5000 copies/mL (DUET-1 N 612 DUET-2 N
591)
ETR 200 mg BID DRV/RTV-containing OBR
Placebo DRV/RTV-containing OBR
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 lt 50 copies/mL (TLOVR)
Madruga JV, et al. Lancet. 200737029-38.
Lazzarin A, et al. Lancet. 200737039-48.Katlama
C, et al. IAS 2007. Abstract WESS204.2. Mills A,
et al. IAS 2007. Abstract WESS204.1.
67
DUET-1 and -2 Virologic Response at Week 24
(TLOVR Analysis)
100
DUET-1
DUET-2
ETR
Placebo
P .0003
80
P .005
62
60
56
44
VL lt 50 copies/mL,
39
40
20
0
P
ETR
P
ETR
Madruga JV, et al. Lancet. 200737029-38.
Lazzarin A, et al. Lancet. 200737039-48.Katlama
C, et al. IAS 2007. Abstract WESS204.2. Mills A,
et al. IAS 2007. Abstract WESS204.1.
68
DUET-1 and -2 BL ETR Mutations and Virologic
Response at Week 24
  • 13 mutations associated with ETR resistance
  • V90I A98G
  • L100I K101E/P
  • V106I V179D/F
  • Y181C/I/V 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
  • 14 of patients had 3 ETR resistance mutations
    at BL

100
90
80
70
60
Patients With HIV-1 RNA lt 50 copies/mL ()
50
40
30
20
10
0
0
1
2
3
4
5
No. of BL ETR Mutations
Patients ()
40
30
16
8
5
1
Katlama C, et al. IAS 2007. Abstract WESS204.2.
69
Investigational ARVs
  • Vicriviroc ACTG 5211
  • Elvitegravir
  • CCR5 monoclonal antibody PRO 140
  • others

70
ACTG 5211 Phase II Trial of Vicriviroc in
Treatment-Experienced Patients
Stratified by enfuvirtide use and baseline CD4
count lt or 50 cells/mm³
Day 14
Week 48
Placebo(n 28)
Antiretroviral-experienced patients with HIV-1
RNA 5000 copies/mL and R5-only virus on
ritonavir-containing regimen (N 118)
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)
Failing regimen
Gulick R, et al. J Infect Dis 2007196304-312.
71
ACTG 5211 Patients with HIV-1 RNA lt 50 copies/mL
at 24 and 48 Weeks
  • VCV RTV-containing OBR associated with
    sustained antiviral activity at Week 48

Placebo
Vicriviroc 10 mg
Vicriviroc 15 mg
100
90
80
70
60
Patients,
50
40
37
40
27
27
30
20
11
7
10
0
Week 24
Week 48
Gulick R, et al. J Infect Dis 2007196304-312.
72
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-Hodgkins lymphoma n 2 Hodgkins
    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 2007196304-312.
73
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 gt 5000 copies/mL, CD4 cell
count gt 250 cells/mm3 (with nadir gt 200), and no
antiretroviral therapy for 3 months (N 39)
PRO 140 2.0 mg/kg single IV infusion (n 10)
59-day follow-up
PRO 140 5.0 mg/kg single IV infusion (n 10)
Placebo (n 9)
0.5
0.0
-0.5
Mean Change in VL, log10 copies/mL
-1.0
P .01 P .001 P .0001
-1.5
-2.0
0
10
20
30
40
50
60
Study Day
Saag MS, et al. IAS 2007. Abstract WESS201.
74
The HLA-B5701 genotype has been shown to be a
predictive risk factor for
  • A) poor CD4 cell response
  • B) ABC hypersensitivity
  • C) insulin resistance
  • D) lipoatrophy

75
New testing available
  • HLA-B5701 testing for Abacavir hypersensitivity
    (HSR) LabCorp, Quest PCR on whole blood or
    buccal swab to determine presence of HLA-B5701
    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 59591-593.
76
SHAPE Retrospective Case-Control Study
CASES
CONTROLS
Black and white subjects with clinically
suspectedABC HSR (CS-HSR)
Black and white subjects enrolled in KLEAN,
ALOHA,CNA30027, CNA30032
ABCskin patch test and HLA-B5701
Identify ABC-tolerantsubjects
White n 130 Black n 69
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 11111118, Apr 2008 .
77
SHAPE Sensitivity and Specificity of HLA-B5701
CS-HSR confirmed by HLA-B5701
Sensitivity of HLA-B5701
Specificity of HLA-B5701
100
99
100
96
100
90
80
70
44
60
Sensitivity/Specificity of HLA-B5701,
50
40
14
30
20
10
57/130
42/42
194/202
10/69
5/5
204/206
0
Skin Test Positive
CS-HSR
Skin Test Positive
CS-HSR
Control
Control
White
Black
Clinical Infectious Diseases. Volume 46, Issue 7,
Page 11111118, Apr 2008
78
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 lt50

79
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

80
Case 1
  • A few months later after having missed a regular
    quarterly visit, the patients 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

81
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?
  • 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

82
Genotype reveals the following mutationsRT
K65R, M184V, G190API I50L, G73SWhich regimen
would you choose at this juncture?
  • A) new boosted PI NRTI
  • B) new boosted PI NRTI plus enfuvirtide
  • C) NNRTI plus NRTIs

83
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

84
Based on resistance mutations, which combination
would you choose? (M184V, K65R, G190A)
  • A) Tenofovir emtricitabine
  • B) Zidovudine lamivudine
  • C) Abacavir lamivudine
  • D) Stavudine lamivudine

85
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

86
Cased on recent clinical trial data, treatment
history, and genotype, which boosted PI would you
choose?
  • A) Fosamprenavir / ritonavir
  • B) Lopinavir / ritonavir
  • C) Darunavir / ritonavir

87
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 treatment-experienced patients (31 naïve,
    38 had received 1 PI)

88
Case 1
  • POWER-1 demonstrated the superiority of
    darunavir/ritonavir over investigator-selected
    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

89
Case 2
  • 50 year old male initially diagnosed in 1987, RF
    MSM initial CD4 800, nadir about 150. history
    of Kaposis 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

90
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

91
Based on this resistance pattern and the
patients 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 ritonavir

92
Case 2
  • He begins new regimen of tenofovir and FTC,
    boosted fosamprenavir, efavirenz CD4 gt600 VL
    lt400 consistently for gt 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.

93
What do you recommend now?
  • 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 become
    available

94
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)
  • BUThis viral load has climbed to 6437now what?

95
  • A) continue his current regimenthe 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.

96
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?

97
  • 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

98
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 hes noticed it even more since initiating
    the new regimen.

99
What might be a reasonable option for this
patient in the near future, assuming his viral
load remains undetectable?
  • 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
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