Important Updates From Recent HIV Conferences

1
Important Updates From Recent HIV Conferences

• Donna E. Sweet, MD, MACP
• Professor of Medicine
• The University of Kansas School of Medicine -
  Wichita

2
Disclosure of Financial RelationshipsThis
speaker has the following significant financial
relationships with commercial entities to
disclose

• Speakers Bureau for BMS, Abbott, Gilead, Pfizer,
  Merck, GSK, Orthobiotech, and Roche

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
3
Message from Toronto Deliver AIDS Treatment and
Prevention

• Growth of the pandemic continues to outpace the
  broad and expanding efforts to control it

4
Time to Deliver

• 4.1 people were newly infected with HIV in 2005
• 2.8 million AIDS-related deaths
• The majority of the estimated 38.6 million people
  living with HIV do not know that they are
  infected
• Stigma and discrimination related to HIV remain
  major issues throughout the world

5
(No Transcript)
6
Presented in Toronto HIV Treatment is
Feasible in all Countries

• The best price for a first line regimen of
  generic antiretroviral drugs in low-income
  countries is now
• about 130 a year for adults (down from 285 in
  2004)
• Less than 200 a year for children
• However, the average cost of first line regimens
  remains higher than this
• Second - line regimens may cost 1500 or more per
  year

7
Providing Antiretroviral Therapy in low-middle
income countries

• June 2006 1.65 million people in low-middle
  income countries were receiving antiretroviral
  therapy
• Including about a million in Sub-Saharan Africa
• And between 60,000 and 100,000 children
• In some countries, therapy is provided to more
  than 25 of those in need
• It is improving in others

8
But not in all

• Uganda decreased from 51 (12/2005) to 35 in
  6/2006
• Although the number being treated in Uganda has
  grown, the estimated number who require treatment
  has increased faster

9
Shortages of Health Care Workers

• The provision of HIV treatment is compromised by
  profound shortages of skilled health workers and
  dysfunctional and inefficient health care systems
• Frustrated by low salaries and poor working
  conditions, physicians and nurses leave their
  countries

10
Shortages of Health Care Workers

• No improvement in financing or medical products
  can make a lasting difference to peoples lives
  until the crisis in the health workforce is
  solved. - Anders Norstrom, Acting
  director-general of WHO

11
Prevention is Essential to Expanding Treatment

• Financing for AIDS programs in low- and
  middle-income countries is estimated at 8.9
  billion in 2006
• but the estimated need is 14.9 billion
• 2008 it will be 22.1 billion
• The number of people receiving antiretroviral
  drugs has been increasing by about 450,000 per
  year
• About 10 people become infected for each person
  who begins treatment

12
Data from the HIM CohortAbstract TUPE)434
Previous use of non-occupational post-exposure
prophylaxis against HIV (NPEP) and subsequent HIV
infection in homosexual men

• Non-occupational post-exposure prophylaxis (NPEP)
  is increasingly being used to prevent HIV
• In Sydney, guidelines recommending NPEP have been
  in place since 1998 and community awareness of
  availability is high

13
Data from the HIM Cohort Abstract TUPE)434
Previous use of non-occupational post-exposure
prophylaxis against HIV (NPEP) and subsequent HIV
infection in homosexual men

• Conclusions
• Non-occupational post-exposure prophylaxis use is
  relatively frequent in homosexual men in
  Australia
• Those who have previously received NPEP continue
  to report high levels of risk behavior and have
  higher rates of HIV infection.

14
Data from the HIM Cohort Abstract TUPE)434
Previous use of non-occupational post-exposure
prophylaxis against HIV (NPEP) and subsequent HIV
infection in homosexual men

• These findings highlight the need for further HIV
  prevention interventions targeted to homosexual
  men who receive NPEP

15
Prevention Developments Microbicidals in
Development

• That could be applied to the vagina or rectum
• That could deliver antiretroviral medications
  through a ring placed inside the vagina
  convenient and could release drugs for many days

16
South African Lifespans Cut Short by AIDS

• South Africas average life expectancy has
  declined by 13 years since 1990, from 64 to 51
  years, due to HIV/AIDS.
• 49 y.o. males
• 53 y.o. females
• New HIV infections are soaring among females aged
  15 to 24
• Combined with declining trends in fertility,
  HIV/AIDS is expected to lead to a decline in
  children over the next 10 years.

Source IAPAC Monthly, December 2006, page 455
17
South Africa Decline in Life Expectancy
A 15 year old

• 1990 29 chance of dying before the age of 60

• 2006 56 chance of dying before the age of 60

18
HIV Risk Halved by Circumcision

• NIH announced evidence from two large trials in
  Africa indicating that
• circumcision reduces a mans risk of contracting
  HIV from heterosexual sex by half

Source IAPAC Monthly, December 2006, page 455
19
Adult Circumcision Reduces HIV Risk by Half

• 2 current randomized, controlled trials were
  conducted
• Conducted in
• Kisumu, Kenya
• Rakai, Uganda
• Heterosexual transmission is primary route of
  infection
• Men were randomly assigned to circumcision
  performed by trained medical professionals in
  community health clinics or to a wait group

• JAMA, January 17, 2007 Vol 297, No 3, Page 254

20
Adult Circumcision Reduces HIV Risk by Half

• Kenya
• 2784 HIV negative men ages 15 t0 49 years old
• 47 uncircumcised men became infected
• 22 circumcised men became infected
• Transmission was reduced by 53
• Uganda
• 4996 HIV negative men ages 15 to 49 years old
• 43 uncircumcised men became infected
• 22 circumcised men became infected
• HIV acquisition was reduced by 48

• JAMA, January 17, 2007 Vol 297, No 3, Page 254

21
Immunologically Discordant ART Response Increased
Disease Progression Risk

• HIV-positive patients whose ART succeeds in
  suppressing viral load to undetectable levels,
  but who nevertheless fail to experience an
  increase in their CD4 count above 200 cells/mm3,
  remain at high risk of progression to AIDS and
  death in the first year of treatment

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

22
Immunologically Discordant ART Response Increased
Disease Progression Risk

• Canadian study of patients with two consecutive
  viral loads under 50 copies/mL.
• Divided into two groups of those according to
• CD4 count response to ART
• CD4 count that had increased to at least 200
• Rates of progression and death were measured
  between the two groups

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

23
Immunologically Discordant ART Response Increased
Disease Progression Risk

• Patients whose CD4 counts did not increase to at
  least 200 cells/mm3 a year after commencing
  virologically effective ART had a hazard ratio of
  progression to AIDS or death of 3.94 compared to
  patients whose CD4 count increased to above 200
  cells/mm3.

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

24
ART Naïve and Already Resistant

• 16 of antiretroviral therapy (ART)-naïve
  patients enrolling in GlaxoSmithKline (GSK)
  sponsored clinical trials in the United States
  last year already had resistance to at least one
  antiretroviral drug
• The frequency of resistance has almost tripled
  since 2000
• Almost 2/3 of those with resistance in 2005
  showed resistance to an NNRTI.

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006, GSK company researchers

25
Resistance Patterns Studied

• 2,035 ART-naïve patients who enrolled in
  GSK-sponsored studies in the U.S. between 2000
  and 2005
• 84 Male
• 48 white
• 36 African American
• Median CD4 count of 252
• Exposure data on 1,529 of these
• 67 gay men
• 35 heterosexual
• 5 injecting drug use
• 2 blood transfusion

• Source Reported by GSK company researchers.
  IAPAC Monthly, October 2006

26
Resistance Patterns Studied (two different
classification systems used for analysis)

• NNRTI resistance prevalence grew from 2 in 2000
  to between 10 and 11 in 2005
• NRTI resistance prevalence grew from 4 - 5 in
  2000 to 7 - 8 in 2005
• PI resistance showed less of a trend toward
  increase and remained below 5 throughout the
  period
• The likelihood of participants showing resistance
  patterns increased over the time between 2000 and
  2005
• The likelihood of having either NRTI or NNRTI
  mutations significantly increased over time

27
Resistance Patterns Studied (two different
classification systems used for analysis)

• Looking at specific demographics of study
  participants, multivariate analysis showed no
  significant differences between gay men and
  heterosexuals in the risk of resistance
• Heterosexuals appeared to have lower risk of
  acquiring PI resistance
• Lower risk of resistance among African American
  men and women compared to whites
• Overall 40 less
• NRTI resistance 53 less

28
Resistance Patterns Studied (two different
classification systems used for analysis)

• A greater risk of resistance in later years among
  people with lower viral load was noted
• Higher CD4 count did not show a similar
  relationship so it is not able to be determined
  if this is a marker for more recent infection

29
Clinical Studies of Antiretroviral Therapy
30
MO3-613 Study LPV/r SGC as single-drug
maintenance vs. 2 nucs EFV
31
HOPS Cohort Incidence of MI and lipid-lowering
agent use by year
32
GEMINI SQV/RTV vs LPV/RTV in Treatment-Naive
Patients

• Prospective, phase IIIb, open-label study
• Primary endpoint percent of patients with VL 50 c/mL at Week 48

Week 24 interim analysis of first 150 patients
Week 48
SQV/RTV 1000/100 mg BID TDF/FTC (n 167)
Treatment-naive patients CD4 count 350
cells/mm3 VL 10,000 copies/mL (N 337)
LPV/RTV SGC 400/100 mg BID TDF/FTC (n 170)
Slim J, et al. Glasgow 2006. Abstract PL2.5.
33
GEMINI Viral Suppression With SQV/RTV vs LPV/RTV
at Week 24 (ITT)

• No significant difference between SQV/RTV and
  LPV/RTV at any time point
• No acquisition of PI mutations at failure in
  either arm

100

83.6
P .637
80.6
80
75.3
P .427
69.4
60
Patients ()
40

SQV/RTV (n 72)
20
LPV/RTV (n 73)
0
0
2
4
8
12
16
20
24
Weeks
Slim J, et al. Glasgow 2006. Abstract PL2.5.
34
GEMINI Change in Lipids at Week 24
P .02
SQV/RTV
LPV/RTV
88
250
P .18
29
21
200
29
P .78
150
Mean Lipid Values (mg/dL)
12
10
100
P .60
9
9
50
0
BL
BL
BL
BL
Week 24
Week 24
Week 24
Week 24
TC
LDL
HDL
Triglycerides
Slim J, et al. Glasgow 2006. Abstract PL2.5.
35
GEMINI Patients Over NCEP Levels With SQV/RTV vs
LPV/RTV
Fasting TC 200 mg/dL ( 5.20 mmol/L)
Fasting TG 400 mg/dL ( 4.52 mmol/L)
SQV/RTV
P .036
50
LPV/RTV
38
40
30
Proportion of Patients ()
P .009
21
17
20
13
13
10
4
1
0
0
Baseline
Week 24
Baseline
Week 24
Slim J, et al. Glasgow 2006. Abstract 2.5.
36
SOLO 180-Week Follow on FPV/RTV Once Daily

• APV 30005 international, uncontrolled follow-up
  trial of patients who had received 48 weeks of
  FPV/RTV 1400/200 mg QD in SOLO trial (N 213)
• Results similar between those with baseline HIV
  RNA 100,000 and 100,000
• Onset of grade 2-4 AEs primarily before Week 48
• 29 patients failed therapy only 2 exhibited APV
  resistance mutations I54M, V32I, L33F, I47V
• 37 patients withdrew, primarily due to life
  events

Viral Suppression at Week 180
95
100
89
80
66
62
60
Patients AchievingViral Suppression ()
40
20
0
ITT MD F
Observed
Bellos N, et al. Glasgow 2006. Poster P13.
37
REDUCE FPV/RTV 1400/100 mg vs 1400/200 mg at
Week 24
Viral Suppression at Week 24 ITT, MF

• Randomized, open-label, 96-week pilot study of
  treatment-naive patients (N 115)
• FPV/RTV 1400/200 mg QD (n 57) vs 1400/100 mg
  QD (n 58), each with ABC/3TC QD
• Endpoints
• patients
• patients with drug-related discontinuations at
  Week 48
• Differences in efficacy may reflect differences
  in baseline VL between arms

RTV 100
RTV 200
(P .051)
(P .009)
100
90
88
75
80
67
60
Patients Achieving Virologic Suppression ()
40
20
0


Hicks C, et al. Glasgow 2006. Poster P2.
38
REDUCE Lipid Levels FPV/RTV 1400/100 mg vs
1400/200 mg at Wk 24
Baseline
Week 24
LDL Cholesterol
HDL Cholesterol
Total Cholesterol
Triglycerides
250
125
118
114
205
104
199
200
101
100
166
175
166
170
150
75
Lipid Levels (mg/dL)
120
120
100
48
50
45
39
37
50
25
0
0
100
200
100
200
100
200
100
200
Hicks C, et al. Glasgow 2006. Poster P2.
39
BI 1182.33 TPV/RTV vs LPV/RTV in Naive Patients
Week 48
TPV/RTV 500/100 mg BID TDF 3TC (n 187)

• Treatment naive
• VL 5000 c/mL
• CD4
• DAIDS grade 1
• Prior AIDS event must be resolved
• Patient on stable treatment for 2 weeks before
  screening
• (N 558)

TPV/RTV 500/200 mg BID TDF 3TC (n 186)
LPV/RTV 400/100 mg BID TDF 3TC (n 185)

• Primary endpoint percent with VL at 2 consecutive visits without prior viral
  rebound or change in antiretroviral therapy

Cooper D, et al. Glasgow 2006. Abstract P13.4.
40
BI 1182.33 VL vs LPV/RTV (ITT)

• Primary analysis demonstrated noninferiority for
  the TPV/RTV arms compared with the LPV/RTV arm at
  Week 48

• However, post hoc Week 48 efficacy analysis
  performed after all patients completed Week 60
  (and, therefore, had confirmed Week 48 VL showed
• TPV/RTV 500/200 mg BID noninferior to LPV/RTV
• TPV/RTV 500/100 mg BID no longer noninferior

100
80
69.2
65.8
66.7
60
Patients With VL
40
20
TPV/RTV 200
TPV/RTV 100
LPV/RTV
Cooper D, et al. Glasgow 2006. Abstract P13.4.
41
BI 1182.33 Adverse Events With TPV/RTV vs LPV/RTV

• Percent of patients with grade 3 or 4 lipid
  elevations at Week 48 similar among arms
• Based on AST/ALT elevations, study of TPV/RTV 200
  in naive patients ended
• 20 with Grade 3/4 AST/ALT elevations at Day 672

Cooper D, et al. Glasgow 2006. Abstract P13.4.
42
TMC125-C227 Etravirine vs PI in
NNRTI-Experienced Patients

• Etravirine (TMC-125, ETV) next-generation NNRTI
  with activity against many NNRTI-resistant
  variants
• TMC125-C227 exploratory phase II trial of
  HIV-positive, PI-naive patients with 1 NNRTI
  resistance mutation and VL 1000 copies/mL. ETV
  arm closed after DMSB review
• Randomized to
• Etravirine 800 mg BID 2 NRTIs (n 59 at early
  study closure)
• Investigator-selected PI 2 NRTIs (n 57 at
  early study closure)
• NRTIs selected using phenotypic resistance
  testing
• Majority of study population from
  resource-limited nationsmajor centers South
  Africa (n 48), Brazil (n 27), Thailand (n
  18), Argentina (n 8) other patients from
  Spain, Russia, UK, Mexico

Woodfall B, et al. Glasgow 2006. Abstract PL5.6.
43
TMC125-C227 Etravirine vs PI in
NNRTI-Experienced Patients (contd)

• Unexpectedly large numbers of baseline resistance
  mutations in this first-line failure population
  may reflect resource-limited settings
• Between 1 and 7 detectable baseline NRTI
  resistance mutations
• 37 of ETV group and 35 of PI group recycled 1
  NRTI
• 9 of ETV group and 12 of PI group recycled 1
  NRTI
• Between 0 and 4 detectable baseline NNRTI
  resistance mutations
• Median EFV fold change 129.8
• Median NVP fold change 88.0
• Median ETV fold change 2.0
• Higher number of NRTI mutations also associated
  with higher number of NNRTI mutations

Woodfall B, et al. Glasgow 2006. Abstract PL5.6.
44
TMC125-C227 Etravirine vs PI in
NNRTI-Experienced Patients (contd)

• VL declined by 1.3 log10 copies/mL in ETV arm at
  Week 8 but then rebounded, vs continual VL
  decline in PI arm
• Lack of sustained response to ETV probably
  related to high level of baseline NRTI
  resistance, ie, insufficient activity in OBR
• Better responses in ETV patients with fewer TAMs
  and/or M184V
• After adjusting for level of NRTI and NNRTI
  resistance, virologic response to ETV was
  independent of detection of Y181C or K103N at
  baseline
• In some countries, patients may have been on
  nonsuppressive NRTI NNRTI regimens for
  prolonged periods prior to study entry
• Reinforces importance of a timely change of
  regimen at virologic failure to minimize
  accumulation of resistance mutations

Woodfall B, et al. Glasgow 2006. Abstract PL5.6.
45
Effect of BL Resistance on Response to DRV/RTV in
POWER 1, 2, 3

• Understanding PI resistance is complex
  phenotypic resistance testing is useful but too
  costly in many situations
• In POWER 1, 2, and 3, baseline fold change was
  strongest predictor of Week 24 response by
  unadjusted analysis
• 11 mutations associated with reduced response
• V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S,
  L76V, I84V, and L89V
• 73 of patients had 2 of these mutations

Mutations in color indicate those that occurred
with failure.
DeMeyer S, et al. Glasgow 2006. Poster P196.
46
Predictive Value of DRV Mutations Confirmed in
Clinical Isolates

• Panel of 9668 HIV-1 clinical isolates submitted
  for routine resistance testing used to validate
  predictive value of DRV resistance-associated
  mutations

DRV Susceptibility
FC 10
FC 10
100
80
60
Isolates ()
40
20
0
3 710
0 5401
1 1423
2 1178
4 449
5 294
6 113
7 66
8 13
9 1
Number of DRV Resistance-Associated Mutations
Clinical Isolates n
V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S,
L76V, I84V, and L89V
DeMeyer S, et al. Glasgow 2006. Poster P196.
47
T20-401 Once-Daily vs Twice-Daily ENF

• Prospective, phase II, open-label pilot study

48 Weeks
ENF 180 mg SQ QD OBR (n 30)
ENF-naive patients VL 5000 copies/mL
Triple-class experienced Unchanged regimen for
28 days prior to study (N 61)
ENF 90 mg SQ BID OBR (n 31)
Given as 2 injections in different sites as
close in time as possible.
Walmsley S, et al. Glasgow 2006. Abstract P30.
48
T20-401 VL Week 48
100 90 80 70 60 50 40 30 20 10 0
64
QD OT
Patients ()
BID OT
47
QD ITT
23
BID ITT
23
P .97
0 4 8 12 16 20 24 28 32 36 40
44 48
Weeks

• Similar rates of virologic failure in QD vs BID
  arms VF by Week 48 (40 vs 36)
• Most virologic failures occurred before Week 24
• Greater proportion of patients in BID arm
  achieved VL

Walmsley S, et al. Glasgow 2006. Abstract P30.
49
T20-401 Adherence and Adverse Events With QD vs
BID ENF

• 93 in QD arm vs 81 in BID arm 85 adherent to
  ENF
• Of patients with 85 adherence, 21 in QD arm
  vs 28 in BID arm had VL
  Week 48 (P .58)
• 80 of patients in QD arm vs 58 in BID arm
  95 adherent to ENF at Week 48
• Of patients with 95 adherence, 25 in QD arm
  vs 28 in BID arm had VL
  Week 48 (P .84)

• 80 in QD arm vs 90 in BID arm reported 1 AE
• Ecchymosis, induration, erythema at injection
  site moderately less severe with BID dosing
• 1 patient in QD arm discontinued due to ISRs
• Diarrhea, URIs, headache, and depression more
  common in BID arm vs QD arm
• Nausea, vomiting, arthralgia, and bronchitis more
  common in QD arm vs BID arm

Walmsley S, et al. Glasgow 2006. Abstract P30.
50
RESIST Studies An Analysis of Combined Data
from Two Randomized Open-label Trials

• Background Treatment options for HIV-1 infected
  individuals who have received extensive previous
  antiretroviral therapy are limited
• Compared efficacy and safety of
• the novel non-peptidic protease inhibitor
  tipranavir co-administered with ritonavir plus an
  optimized background regimen
• An investigator-selected ritonavir-boosted
  comparator protease inhibitor (CPI-ritonavir in
  such patients.)

Hicks, Charles B., et al. Lancet 2006 368466-75
51
RESIST 1 2 Comparison Results

• January 2003 April 2004
• 1483 patients included in the pool
• Demographics were similar between both groups
• Results confirmed and extend the findings of
  RESIST-1 and RESIST-2 showing that
  Tipranavir-ritonavir (500mg/200mg twice daily)
  provides better viral suppression and
  immunological responses than an alternative
  comparator protease inhibitor (both in
  combination with an optimized background regimen)
  in this population with advanced disease and poor
  prognosis

52
RESIST 1 and 2 Week 96 Data From Phase III
Studies of TPV/RTV
Patients failing PI-containing HAART VL
1000any CD4
HIV resistance expert panel
TPV/RTV arm
Best PI choice
Preselection of regimen byinvestigator CPI
OBR ( ENF)
Baseline genotypic resistance testing
Computerizedrandomization to OBR plus
CPI arm LPV/RTV, IDV/RTV, SQV/RTV, APV/RTV
Failures in CPI arm after Week 8eligible for
TPV/RTV in rollover study
Entry criteria 3-class experienced 1 primary
PI mutation 30N, 46I/L, 48V, 50V, 82A/F/L/T,
84V, or 90M 2 mutations 33, 82, 84, or 90.
Gazzard B, et al. Glasgow 2006. Abstract P23.
Hicks CB, et al. Lancet. 2006368466-475.
53
RESIST 1 and 2 Week 96 Results With TPV/RTV
TPV/RTV
Control
100
100
80
80
P
P
60
60
P
44.4
Patients With VL
Patients With VL
P
34.7
40
40
26.9
20.4
14.4
14.4
10.9
9.1
20
20
n 746
n 746
0
0
All Patients
First-Time ENF Use
All Patients
First-Time ENF Use

• TPV/RTV similar toxicity profile to comparator
  PIs at Week 48, with 2 exceptions
• Grade 3/4 ALT (10.1 vs 3.3), AST (6.3 vs 2.9)
  
• Grade 3/4 TGs (30.8 vs 23.1), TC (4.3 vs 0.7)
  (P

Gazzard B, et al. Glasgow 2006. Abstract P23.
Hicks CB, et al. Lancet. 2006368466-475.
54
Discontinuing 3TC in Virologically Suppressed
Patients With M184V

• Randomized pilot study of continued vs
  discontinued 3TC in patients with viral
  suppression and M184V/I
• HIV-positive, HBV-negative adults (N 21)
• VL 3 other drugs, 2 of which were active
• Previous detection of M184V/I
• VL, CD4 count, safety, and quality of life
  assessed through 48 weeks

• No virologic failures occurred by Week 48
• Discontinuing 3TC may be safe in presence of 2
  active drugs when VL

Harris M, et al. Glasgow 2006. Abstract P22.
55
Abstract THLB215 Safety and efficacy of
maraviroc (MVC)

• A novel CCR5 antagonist when used in combination
  with optimized background therapy (OBT) for the
  treatment of antiretroviral-experienced subjects
  infected with dual/mixed-tropic HIV-1 24-week
  results of a phase 2b exploratory trial

56
Study 1029 Pilot Study Evaluating the Safety of
Maraviroc in Patients with Non-R5 HIV-1
57
Study Population
58
CD4 Count and Viral Load at Baseline
59
Efficacy Results
60
Changes in CD4 Cell CountPatients with
D/M-tropic HIV-1 at Screening
61
Abstract THLB215 Safety and efficacy of
miraviroc (MVC)

• Conclusions
• Maraviroc was safe and well tolerated in this
  advanced population with documented D/M HIV-1
  infection
• While superiority of either MVC dose added to
  OBT, versus OBT alone, was not achieved, there
  was no evidence of virological or immunological
  decline
• A greater CD4 increase occurred in both MVC
  groups versus the placebo group this requires
  further investigation

62
A5142 Grade 3 / 4 Laboratory Abnormalities
96-week Results
63
Potent Antiretroviral Effect of MK-0518, a Novel
HIV-1 Integrase Inhibitor, as part of Combination
ART in Treatment -Naïve HIV-1 infected Patients

• M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F.
  Mendo4, W. Ratanasuwan5, C. Kovacs6, J. Zhao2, L.
  Gilde2, R. Isaacs2, H. Teppler2, and the Protocol
  004 Part II Study Team
• 1Aaron Diamond AIDS Res. Ctr. New York, USA
  2Merck Res. Labs, West Point, USA 3Hosp. Nac.
  Cayetano Heredia, Lima, Peru 4Hosp. Nac. Edgardo
  Rebagliati, Lima, Peru 6Maple Leaf Med. Ctr,
  Toronto, Canada 5Siriraj Hosp., Bangkok,
  Thailand

64
MK-0518 Strand Transfer Inhibitor of HIV
Integrase

• HIV integrase inhibition a new mechanism of
  action
• MK-0518 potent in vitro activity
• IC95 33 nM ? 23 nM in 50 human serum
• Preclinical evaluation favorable
• Metabolism primarily via glucuronidation (UGT1A1)
• Not a potent inhibitor or inducer of CYP3A4
• Does not require ritonavir boosting
• Phase I and drug interaction data support
• Dosing 100 - 800 mg po bid without regard to food
• At 100mg b.i.d, mean C12hr IC95
• No dose adjustment when used with other ARTs

65
Protocol 004 Study Design
Interim analysis of Part I before initiating
Part II
Part I Integrase Monotherapy for 10 days
Part II Combination Therapy
Total
8pts
30 pts
MK-0518 600mg bid
MK-0518 600mg bid TFV/3TC
30 pts
MK-0518 400mg bid
MK-0518 400mg bid TFV /3TC
8pts
38 pts
30 pts
8pts
MK-0518 200mg bid
MK-0518 200mg bid TFV/ 3TC
38 pts
30 pts
8pts
MK-0518 100mg bid
MK-0518 100mg bid TFV/3TC
38 pts
30 pts
8pts
MK-0518 placebo bid
Efavirenz 600mg TFV/3TC
38 pts
Part I cohort Rx-naïve ptsstratified and
randomized to Integrase monotherapy or placebo
for 10 days
Part II cohort Rx-naïve ptsstratified and
randomized to combination therapy for 48 weeks
38 pts
TFV tenofovir
HIV RNA ? of 1.7 2.2 log10 copies/mL
Morales-Ramirez et al, EACS 2005
IAC 2006 Abs THLB0214
66
Protocol 004 Part II Design

• Part I patients continued at same dose in Part II
  (pbo?efv)
• 150 additional patients randomized for Part II
• Key inclusion criteria
• Susceptible to EFV, 3TC , TFV (by genotype)
• No prior ART (
• HIV RNA 5000 copies/mL
• baseline stratification for HIV RNA or 50,000
  copies/mL
• CD4 100 cells/mm3
• Endpoints
• HIV RNA and CD4 counts, Adverse experiences
• Hypotheses MK-0518 TFV/3TC
• will be generally safe and well tolerated
• will have similar antiretroviral activity vs
  efavirenz TFV/3TC

67
Protocol 004 Baseline Characteristics
With TFV/3TC geometric mean
68
Protocol 004 Patient Status at Week 24 Analysis
TFV/3TC n Number of patients in each
category N Total number of pts enrolled in
each group n/N for each category in each group
69
Protocol 004 Safety

• MK-0518 safety profile was similar to efavirenz
  (both with TFV/3TC)
• Most clinical adverse experiences (AE) were mild
  to moderate
• 8 serious adverse experiences overall (7/160 or
  4 in the 4 MK groups, 1/38 or 3 in EFV group)
  none considered drug related
• One discontinuation for increased AST/ALT
• Grade 3 / 4 lab abnormalities uncommon

70
Conclusion

• MK-0518 is a promising new strand transfer
  inhibitor of HIV integrase with potent and
  durable antiretroviral effect.
• In treatment naïve patients with HIV RNA 5000
  copies/ml and CD4 100/mm3, MK-0518 at all doses
  studied for 24 weeks
• had potent antiretroviral activity
• 85-95 with HIV RNA
• achieved viral suppression faster than EFV
• was generally well tolerated

71
Clinical Complications and Coinfections
72
MOPE0219 Potential Health Risks of
complimentary alternative therapy (CAM) in
HIV-positive patients taking antiretroviral (ARV)
drugs

• Cross-sectional survey of 253 patients
• 154 were taking herbal remedies or supplements
• 88 using physical treatments
• 67 used a combination of both
• 10 of patients were potentially compromising
  their ARV treatment by taking CAMs.

• Medical professionals need to be able to identify
  CAM use in patients and identify potential risks
• Patients should be encouraged to disclose CAM use
  to their clinicians

• Source. IAPAC Monthly, Sept. 2006. XVI
  International AIDS Conference, Aug. 2006

73
MOAB0304 Increasing rates of community-acquired
MRSA infections among HIV-infected persons

• Community-acquired MRSA infections are rapidly
  increasing among HIV-infected patients
• HIV patients have an 18-fold higher risk for
  CA-MRSA then the general populations

• Source. IAPAC Monthly, Sept. 2006. XVI
  International AIDS Conference, Aug. 2006

74
COOL Study

• 143 patients
• Randomized to TDF/EFV/3TC or TDF/EFV
• Similar characteristics of the two groups with
  the following overall average values
• 69kg
• CD4 473
• 3.7 years on ART
• 43.5 NNRTI-based
• 45.5 PI-based
• 71 including ZDV/3TC

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

75
COOL Study

• Conclusions
• TDF/3TC/EFV demonstrates an optimal success rate
  of 97 as a maintencance regimen when compared to
  TDF/EFV at 82.
• Switching to a TDF based regimen can
  significantly improve lipid profile even when the
  lipid levels are within the median normal range
• Other improvements were noted when switched from
  BID HAART to TDF-based HAART

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

76
ATV/EFV NRTI-sparing regimen effective, raises
lipid levels

• Regimens that spare NRTIs and consist of
  ritonavir (RTV)-boosted atazanavir (ATV) plus
  efavirenz (EFV) demonstrate potent antiviral
  activity in treatment-naïve patients, but raise
  levels of triglycerides and both LDL and
  high-density lipoprotein (HDL) cholesterol

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

77
ATV/EFV NRTI-sparing regimen effective, raises
lipid levels

• However
• Because both potentially dangerous triglycerides
  and LDL and protective HDL increased
  simultaneously, the researchers acknowledged that
  the long-term implications for cardiovascular
  health could not be determined

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

78
SHARE Lipid Effects of ATV/RTV ABC/3TC at Week
24

• Open-label, 48-week pilot study of safety and
  tolerability of ATV/RTV ABC/3TC QD in ART-naive
  subjects (N 112)
• Endpoints
• drug-related discontinuations
• 24-week analysis (ITT, M F)
• 85 with VL

Median Percent Changes in Lipids
Baseline
Week 24
250
17
200
30
150
7
Lipid Levels (mg/dL)
100
34
50
0
TC
LDL-C
HDL-C
TG
Dotted lines indicate NCEP III cutoffs
Elion R, et al. Glasgow 2006. Abstract P10.
79
Incidence of Diabetes Mellitusin DAD Cohort
10

• New-onset DM defined as
• Fasting plasma glucose 126 mg/dL ( 6.99
  mmol/L) measured on 2 consecutive occasions
• Initiation of antidiabetic therapy (diet or
  pharmacologic)
• Incidence of DM
• 952 (2.85) of the 33389 patients at entry
• 745 new diagnoses during follow-up
• Overall 5.72 per 1000 PY

8
6
Incidence of DM (/1000 PY)
4
2
0
0

1-2
2-3
3-4
4-5
5-6
6
Exposure to HAART (Years)

• Unadjusted RR/year of exposure to HAART 1.06
  (95 Cl 1.03-1.09 P .0001)

DeWit S, et al. Glasgow 2006. Abstract PL9.5.
80
Comparison of Lipid-Lowering Therapy vs ARV
Switch in DAD
12 months
Retrospective analysis
Start Lipid-Lowering Therapy (n 221)
Subset of DAD dataset PI exposure 6
months NNRTI naive TC 230 mg/dL (5.96 mmol/L)
on 2 occasions (N 1892)
Switch PI to NNRTI (n 208)
Control No Change to Therapy (n 1463)
Patients with other changes to ARV therapy or
additional interventions were excluded.
van der Valk M, et al. Glasgow 2006. Abstract
PL12.2.
81
Median Change in Lipids at Month 12 by Strategy
Total Cholesterol
LDL
Triglycerides
LL
P?N
C
LL
P?N
.C
LL
P?N
C
0
-0.2
-0.18
-0.4
? at Month 12 (mmol/L)
-0.40
-0.6
-0.45
-0.66
-0.8
-0.71
-0.82
-1.0
P .02
-0.92
P .03
-1.02
-1.1
-1.2
P .06
P
P .0001
P .27
P .007
P .0001
0.18
0.20
0.16
HDL
0.12
? at Month 12 (mmol/L)
0.08
Lipid lowering
0.08
PI?NNRTI
0.04
0.01
Control
0
LL
P?N
.C
82
No Frequent Neuropsychiatric Adverse Effects With
Etravirine at Week 24
Prevalence of Headache and Dizziness

• Subanalysis of TMC125-C203
• All patients treated at least 24 weeks with
• ETV 400 mg, 800 mg, or 1200 mg BID (n 174) or
• Placebo (n 66)
• Overall, no difference in frequency of
  neuropsychiatric events between ETV arms and
  placebo
• Majority of events of headache and dizziness
  occurred early during ETV treatment, were mild to
  moderate, and were transient
• In ACTG 5097s, neuropsychiatric AEs due to EFV
  not significantly different between EFV and
  non-EFV pts by Wk 4

20
Headache
15
10
Patients ()
5
0
0
4
8
12
16
20
24
Weeks
20
Dizziness
15
10
Patients ()
5
0
0
8
12
16
20
24
Weeks
400 mg BID (n 57) 800 mg BID (n 74) 1200 mg
BID (n 43) Placebo (n 66)
Woodfall B, et al. Glasgow 2006. Poster P146.
83
Bone Mineral Density in GS903E, Extension Study
of GS903
GS903 Participants
Week 144
Week 192
TDF 300 mg QD 3TC 150 mg BID EFV 600 mg QD (n
86)
TDF 300 mg QD 3TC 300 mg QD EFV 600 mg QD
d4T 40 mg BID 3TC 150 mg BID EFV 600 mg QD (n
85)

• GS903E open-label extension of randomized GS903
  study
• All patients had VL

Madruga JVR, et al. Glasgow 2006. Abstract
P120.Cassetti I, et al. Glasgow 2006. Abstract
P152.
84
GS903E Mean Change in BMD in Patients Initially
Assigned to d4T Arm
6
4
TDF 3TC EFV
d4T 3TC EFV
2
-0.6
Spine BMD
0
-1.1
Mean Percent Change in BMD (95 CI)
-2
-1.0
-3.3
-4
Hip BMD
P NS for change from time of switch.
-6
P
-8
2
3
4
5
0
1
Years
Madruga JVR, et al. Glasgow 2006. Abstract P120.
85
GS903E Mean Change in BMD in Patients Initially
Assigned to TDF Arm
6
4
TDF 3TC EFV
2
0
Spine BMD
Mean Percent Change in BMD (95 CI)
-1.5
-2
-2.7
-4
Hip BMD
P .003 for change from baseline.
-6
P
-8
2
3
4
5
0
1
Years
Cassetti I, et al. Glasgow 2006. Abstract P152.
86
Plasma Drug Levels in Cirrhotic Chronic
HCV-Infected Patients
Noncirrhotics Cirrhotics
12

• HIV/HCV-coinfected patients (N 279) (Child-Pugh
  C patients excluded)
• Treatment with PIs or NNRTIs 6 months at
  standard doses
• 103 (37) identified as cirrhotic by FibroScan
• Plasma drug levels by HPLC
• In compensated cirrhotics, plasma levels of EFV
  were ?
• May benefit from TDM to avoid drug overexposure

10
Therapeutic range for NNRTIs
P
8
Plasma Drug Levels (µg/mL)
6
4
2
0
NVP
EFV
LPV/RTV
ATV 400
ATV/RTV
Barreiro P, et al. Glasgow 2006. Abstract PL6.2.
87
NVP Hepatotoxicity After Switch No More Likely at
Higher CD4 Counts

• Patients with undetectable viral load who switch
  from current treatment to nevirapine (NVP) when
  they have a CD4 count above the recommended
  threshold for starting the NNRTI are no more
  likely to develop hepatotoxicity than women with
  CD4 counts below 250 cells/mm3 or men with CD4
  counts below 400 cells/mm3

• Source. IAPAC Monthly, October 2006. ICAAC,
  9/27-30/2006

88
Characteristics of Patients DevelopingRenal
Toxicity on TDF

• Case series from 2 large HIV clinics in London
• N 1406 patients treated with TDF n 20
  (1.4) developed renal toxicity
• 19/20 presented with proteinuria GFR mL/min/1.73m²
• Proteinuria 2º to proximal tubule dysfunction
• 95 had hypophosphatemia 7 had osteomalacia
• Prior to starting TDF, 17/17 with data had
  creatinine WNR
• At median of 237 days after d/c TDF, creatinine
  decreased in 95 of patients and returned to
  normal in 60

Davies C, et al. Glasgow 2006. Abstract P149
89
Oral Drugs for Hepatitis B
90
Telbivudine (Tyzeka)

• For Chronic Hepatitis B treatment of patients 16
  years and older
• At least as effective as lamivudine in
  treatment-naïve patients with HBV
• Treatment experience patients will be limited by
  cross-resistance with lamivudine
• Appears to suppress HBV DNA more than adefovir
  during the first year of treatment
• but the emergence of resistance is more frequent
  with telbivudine
• Comparative effectiveness with entecavir remains
  yet to be established

91
3 Million Years of Life Saved
At least 3 million years of life have been saved
in the United States as a direct result of care
of patients with AIDS, highlighting the
significant advances made in HIV disease treatment
Survival Benefits of AIDS Treatment, JID 2006194
(July 1)
92
Challenges for the Future

• Although antiviral treatment regimens have
  dramatically reduced the mortality rates there
  remain many obstacles to successful management of
  an HIV patient
• Lack of adherence
• Drug absorption
• Drug metabolism
• Drug toxicity
• Narrow therapeutic ranges
• Resistance

93
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