ICAAC

1
44th ICAAC
ANTIRETROVIRAL TREATMENT HIGHLIGHTS
An HIV/AIDS Overview from the 44th Annual
Interscience Conference on Antimicrobial Agents
and Chemotherapy October 30 - November 2, 2004
Washington, DC
Summarized by Douglas J. Ward, MD, FACP Dupont
Circle Physicians Group, Washington, DC
Supported by an unrestricted educational grant
from
2
44thICAAC
ANTIRETROVIRAL TREATMENT HIGHLIGHTS

• New Findings on
• Virologic Monitoring and Drug Resistance
• Nucleoside/Nucleotide Reverse Transcriptase
  Inhibitor Options and Regimens for First- and
  Second-line Therapy
• Simplification/Switch Strategies for Patients
  With Virologic Suppression
• Current and Investigational Protease Inhibitors
  in First- and Second-line Therapy
• CCR5 Antagonists and Viral Tropism

3
Virologic Monitoring and Drug Resistance
4
Intermittent Low-Level HIV-1 Viremia (Blips) in
Virologically Controlled Patients
Viremic blips during antiretroviral therapy do
not appear to result in evolution of resistant
virus or virologic failure.

• 10 patients with HIV-1 RNA lt 50 copies/mL for
  11-79 months
• Viral loads measured 3 times weekly for 3-4
  months
• Each test read by 2 independent labs
• 18 blips detected in 9 patients
• Only 1 confirmed by both labs
• No significant genotypic changes detected
• No correlation found with any demographic,
  clinical, or treatment-related factor

Viremic blips are common, do not predict
treatment failure or development of resistance,
and likely represent laboratory variation in the
majority of cases.
Nettles RE, et al. 44th ICAAC, 2004. Abstract
H-1134.
5
Frequency and Characteristics of the
NRTI-Associated K65R and L74V/I RT Mutations
Frequency of NRTI-Associated Mutations in 2003
(ViroLogic Database)
44
31
25
20
20
16
15
12
4
2
1
1
0
5
10
15
20
25
30
35
40
45
50
Genotypes (n gt 16,000)
McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.
6
Frequency and Characteristics of the
NRTI-Associated K65R and L74V/I RT Mutations
Phenotypic NRTI Susceptibility of HIV-1 Variants
With K65R
100
100
99
98
100
94
87
87
78
80
71
60
Below Cut-off
38
40
29
17
20
15
4
4
3
1
0
0
ZDV (1.9)
d4T (1.7)
TDF (1.4)
ABC (4.5)
ddl (1.7)
3TC (3.5)
NRTIs (PhenoSense cut-off)
K65R M184V
K65R NAMs
K65R Alone
McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.
7
Frequency and Characteristics of the
NRTI-Associated K65R and L74V/I RT Mutations
Phenotypic NRTI Susceptibility of HIV-1 Variants
With L74V/I
100
100
100
100
100
100
100
97
100
80
71
64
60
Below Cut-off
45
43
37
40
21
15
15
20
8
0
0
ZDV (1.9)
d4T (1.7)
TDF (1.4)
ABC (4.5)
ddl (1.7)
3TC (3.5)
NRTIs (PhenoSense cut-off)
L74V/I M184V
L74V/I NAMs
L74V/I alone
McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.
8
Predictors of K65R With Tenofovir in
Antiretroviral Therapy (ART)-Experienced and
-Naive Patients
In patients taking tenofovir, emergence of the
K65R drug resistance mutation was associated with
the absence or presence of other specific regimen
components.

• 258 ART-experienced and 37 ART-naive patients
• median follow-up, 67 weeks
• K65R developed in 29 (11) ART-experienced
  persons
• 28 had virologic failure
• No K65R in ART-naive persons
• Taking triple-NRTI regimens including tenofovir
  increased risk of K65R
• Tenofovir/didanosine lamivudine or
  emtricitabine
• Tenofovir/abacavir lamivudine or emtricitabine
• Taking tenofovir with zidovudine or lamivudine
  reduced risk of K65R

Staszewski S, et al. 44th ICAAC, 2004. Poster
H-177.
9
Prevalence of Transmitted HIV Drug Resistance in
ART-Naive Individuals in the United States in 2003
Proportion of Patients With Reduced
Susceptibility to gt 1 Drug (N 317)
23
Any ARV
0.9
gt 1 NRTI
18
gt 1 NNRTI
10
1 NNRTI
3
2 NNRTI

• NRTI mutations 15
• V118I (4), D67N (1), M41L (or mix, 1)
• NNRTI mutations 6
• K103N (3), G190A (or mix, 1), V108I (or mix,
  1)
• Primary PI mutations 4
• None gt 1

6
3 NNRTI
6
gt 1 PI
4
1 PI
0.9
2 PI
0.3
3 PI
0
5
10
15
20
25
Subjects
Ross LL, et al. 44th ICAAC, 2004. Poster H-173.
10
Nucleoside/Nucleotide Reverse Transcriptase
Inhibitor Options and Regimens for First- and
Second-line Therapy
11
Trizivir Tenofovir vs Combivir Efavirenz in
ART-Naive Patients

• TIMS 48-week randomized, open-label trial
• 113 ART-naive subjects were randomized to
  receive

Quad-NRTI (n57)
ZDV/3TC/ABC 300/150/300 mg BID TDF 300 mg QD
Triple (n56)
ZDV/3TC 300/150 mg BID Efavirenz 600 mg QD
or

• Baseline characteristics were comparable,
  including

Median HIV RNA (log10 copies/mL) 5.26 5.13
Median CD4 (cells/mcL) 194 153
12
Trizivir Tenofovir vs Combivir Efavirenz in
ART-Naive Patients
Proportion of Subjects With HIV-1 RNA lt50
Copies/mL Through Week 48 (ITT, MF)
100
80
68
67
60
Subjects
40
EFVZDV/3TC
20
Quad-NRTI
0
0
4
8
12
24
36
48
Treatment Time (Weeks)

• Total cholesterol decreased significantly in
  Quad-NRTI arm -0.2 mmol/L vs 0.8 mmol/L (P
  lt.001)

• 1 virologic failure (Quad-NRTI)

ITT , intention-to-treat analysis MF, missing
equals failure
13
Trizivir Tenofovir in ART-Naive Subjects
COL40263
Proportion of Subjects With HIV-1 RNA lt50
Copies/mL at Week 24

• 27 subjects (22) discontinued study
• 12 (9.8) due to adverse events
• 9 (8) had grade 3/4 lab abnormalities
• 8 (7) had suspected ABC hypersensitivity
• Reductions in lipids were observed
• 8 virologic nonresponders
• gt1 TAMs only, 3
• gt1 TAMsM184V, 3
• Wild-type, 2

Subjects
No of Subjects Overall lt100,000 gt100,000
ITT MF 123 52 71
AT 94 40 54
ITT, intention-to-treat analysis MF, missing
equals failure AT, as treated
14
Trizivir Tenofovir in Patients With Early
Virologic Failure on Initial Regimen ESS30005
Zidovudine/lamivudine/abacavir (Trizivir)
tenofovir may be a viable rescue option for
patients with early virologic failure on a
standard initial regimen.

• ESS30005 Open-label study
• 51 patients with early virologic failure (VL gt400
  but lt10,000 copies/mL)
• Failing regimens zidovudine (or
  stavudine)/lamivudine PI or NNRTI
• Baseline characteristics
• Median HIV-1 RNA 3.3 log10 copies/mL (68
  lt5000 copies/mL)
• Median CD4 cell count 436 cells/mcL (37 gt
  350 cells/mcL)
• lt 2 NRTI mutations M184V (82), TAMs (24), no
  K65R
• 43 patients (84) completed gt 24 weeks of
  follow-up

15
Trizivir Tenofovir in Patients With Early
Virologic Failure on Initial Regimen ESS30005
Proportion of Subjects With HIV-1 RNA lt50
Copies/mL Through Week 24
100
80
60
Subjects
40
20
0
0
4
8
12
16
20
24
Treatment Time (Weeks)
ITT, intention-to-treat analysis MF, missing
equals failure Obs, observed analysis
16
Tenofovir/Emtricitabine Efavirenz vs Combivir
Efavirenz in ART-Naive Patients
Better overall responses were seen with
tenofovir/emtricitabine than with
zidovudine/lamivudine (Combivir) in the
preliminary analysis of this head-to-head study.

• Study 934 Open-label, randomized, noninferiority
  study

• Planned 24-week analysis (96-week study)
• ART-naive patients were randomized to receive

Tenofovir/Emtricitabine (n255)
TDF 300 mg FTC 200 mg EFV (all QD)
Combivir (n254)
ZDV/3TC 300/150 mg (BID) EFV (QD)
or

• Baseline characteristics were comparable,
  including

Median HIV RNA (log10 copies/mL) 5.0 5.0
HIV RNA gt 100,000 52 50
Median CD4 (cells/mcL) 233 241
lt 200 42 41
17
Tenofovir/Emtricitabine Efavirenz vs Combivir
Efavirenz in ART-Naive Patients
Time to Loss of Virologic Response (TLOVR) lt50
Copies/mL (ITT)
100
P .038
80
73
65
60
Subjects
40
20
0
0
4
8
16
24
Treatment Time (Weeks)
TDF/FTC
ZDV/3TC
ITT, intention-to-treat analysis
18
Tenofovir/Emtricitabine Efavirenz vs Combivir
Efavirenz in ART-Naive Patients
Patient Disposition Through Week 24
TDF/FTC ZDV/3TC
Permanent Study Regimen Discontinuation () 11 21
Adverse Event () 3 9
Noncompliance/Lost Follow-up () 4 6
Suboptimal Virologic Response () 2 1
Other () 3 5
P .003 P .008

• 5 (vs 0 ) discontinued due to anemia in the
  Combivir arm

Significantly better overall response with
tenofovir/emtricitabine due to fewer adverse
events leading to fewer discontinuations in that
arm
19
Efficacy of Fixed-Dose Abacavir/Lamivudine
Efavirenz ESS30009
Proportion of Subjects With HIV-1 RNA lt50 Through
Week 24 (ITT, MF)
Treatment Time (Weeks)

• Abacavir/lamivudine tenofovir stopped due to a
  49 failure rate
• Patients in that arm were assigned new regimens
  and followed
• ABC/3TC/EFV (35), ABC/3TC/TDF/ZDV (15),
  ZDV/3TC/EFV (11),
• ABC/3TC/ZDV/EFV (9), TDF/3TC/ZDV/EFV (5)

ITT, intention-to-treat analysis MF, missing
equals failure
Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.
20
Efficacy of Subsequent Treatment of Tenofovir
Abacavir/Lamivudine Nonresponders ESS30009
Virologic Response Following Switch to
Second-line Regimens up to 12 Weeks

• Predictors of a 12-week post-switch viral load lt
  50 copies/mL
• Baseline viral load OR, 0.163 P .001
• Abacavir use OR, 7.731 P .009

• Efavirenz use OR, 5.797 P .015
• Zidovudine use OR, 5.032 P .022

ITT, intention-to-treat analysis MF, missing
equals failure Obs, observed
Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.
21
Early Virologic Failure With Once-Daily
Didanosine/Tenofovir/Efavirenz in ART-Naive
Patients
Didanosine/tenofovir/efavirenz, but not
didanosine/lamivudine/efavirenz, was associated
with poor virologic responses in patients with
high viral loads and low CD4 cell counts.

• In an open-label trial, ART-naive individuals
  were randomized to receive
• QD didanosine/tenofovir/efavirenz (n41)
• QD didanosine/lamivudine/efavirenz (n36)
• The study was terminated after an unplanned
  analysis at week 12

ddI/TDF/EFV ddI/3TC/EFV
n () with VL lt50 copies/mL at week 12 22 of 36 (61) 24 of 34 (71)
n () with virologic failure through week 12 5 of 41 (12) 0 of 36 (0)
P lt .05

• Drug-resistant virus emerged rapidly in first 4
  virologic failures
• All 5 subjects with virologic failure had
  baseline VL gt100,000 copies/mL and CD4 cell
  count lt 200 cells/mcL

Moyle G, et al. 44th ICAAC, 2004. Poster H-566.
22
Tenofovir/Didanosine Paradoxical CD4 Cell
Declines Despite Good Virologic Control
The combined use of tenofovir didanosine can
cause CD4 cell counts to fall, even as viral
load goes down or remains undetectable.
Retrospective assessment 570 patients were
taking TDF/ddI, TDF, ddI, or neither agent

• All subjects had HIV RNA lt400 copies/mL for gt1
  year (N570)
• Paradoxical CD4 cell decreases seen only with
  TDF/ddI
• not observed with TDF or ddI individually or
  with other NRTI
• CD4 cell decreases were more common in patients
• who switched to TDF/ddI to simplify regimen
• on NRTI-only regimens that included TDF/ddI
• with longer exposure to higher doses of ddI
• Median CD4 cell decline of 385 cells/mcL among
  subjects who switched to a triple-NRTI regimen
  containing TDF/ddI
• CD4 cell decreases appeared after 6 months of
  TDF/ddI and then increased in magnitude

23
Simplification/Switch Strategies for Patients
With Virologic Suppression
24
Switching From a PI- to a Once-Daily
Efavirenz-Based Regimen VEST-QD
Once-daily efavirenz didanosine/lamivudine
appears to be a safe and effective option for
virologically suppressed patients switching from
a PI-based regimen.

• VEST-QD Interim results of an ongoing 48-week
  open-label trial
• Patients with VL lt50 copies/mL on PI regimens
  were randomized to

• Efavirenz didanosine/lamivudine (all QD)
• Efavirenz current NRTIs (ZDV/3TC, 51
  d4T/3TC, 30 other, 19)
• Virologic Response at Week 24 (ITT NCF)

ddI/3TC (n92) Current NRTI (n94)
HIV RNA lt400 copies/mL () 89 90
HIV RNA lt50 copies/mL () 85 87

• 1 virologic failure (current-NRTI arm)
• HDL-C levels increased in both arms (P lt .0001)
• Adherence improved in both arms (P lt .05)
• No difference between arms

ITT, intention-to-treat analysis NCF,
noncompletion equals failure
Cohen C, et al. 44th ICAAC, 2004. Poster H-577.
25
Trizivir vs Combivir Nevirapine in Patients
With Virologic Suppression SimplifiHAART
Two PI-sparing simplification strategies for
patients with virologic suppression appear to be
comparably safe and effective, and associated
with improvements in cholesterol levels.

• SimplifiHAART 48-week randomized, open-label
  switch study
• 134 patients with undetectable VL (not defined)
  for gt 24 months were randomized to
• zidovudine/lamivudine/abacavir
• zidovudine/lamivudine nevirapine
• 90 were taking a PI-based regimen at baseline

• Results through week 48
• 13 (19) and 14 (21) subjects discontinued due
  to side effects
• 1 virologic failure in each arm

ZDV/3TC/ABC (n68) ZDV/3TC/NVP (n66)
Undetectable VL (ITT NCF) 71 73
Undetectable VL (OT) 98.6 98.5
ITT, intention-to-treat analysis NCF,
noncompletion equals failure
Bonjoch A, et al. 44th ICAAC, 2004. Poster H-562.
26
Trizivir vs Combivir Nevirapine in Patients
With Virologic Suppression SimplifiHAART
Proportion of Patients with Elevated TC and LDL-C
Levels at Baseline and Week 48
Baseline Week 48 P
TC gt5.2 mmol/L - Trizivir () 55.6 30.5 .019
LDL-C TC gt3.36 mmol/L - Trizivir () 60.0 20.6 .003
TC gt5.2 mmol/L - Combivir/nevirapine () 68.9 42.2 .019
LDL-C gt3.36 mmol/L - Combivir/nevirapine () 59.3 41.7 NS
Bonjoch A, et al. 44th ICAAC, 2004. Poster H-562.
27
Favorable Lipid Changes With Switch From
Stavudine to Tenofovir GS903E
Mean Changes in Fasting Lipid Parameters After
d4T to TDF Switch

• 85 patients substituted tenofovir for stavudine
  in rollover phase of GS903
• No patient lost viral suppression (lt50
  copies/mL) through 24 weeks post-switch
• No patient discontinued due to adverse events

Suleiman JMAH, et al. 44th ICAAC, 2004. Poster
H-158.
28
Current and Investigational Protease Inhibitors
29
Favorable Increases in HDL-Cholesterol With
Fosamprenavir in ART-Naive Patients NEAT
In the NEAT study, treatment with unboosted
fosamprenavir abacavir/lamivudine was
associated with increases in high-density
lipoprotein cholesterol (HDL-C) levels.

• Secondary analysis of the 48-week NEAT study
• Randomized, open-label study in ART-naive
  patients, comparing
• fosamprenavir 1400 mg abacavir 300
  mg/lamivudine 150 mg (n166)
• nelfinavir 1250 mg abacavir 300 mg/lamivudine
  150 mg (n83)
• Baseline lipids were similar, with relatively low
  HDL-C, in both arms
• HDL-C and other lipid changes were observed
  through week 48

Mean Change From Baseline at Week 48 Fosamprenavir Nelfinavir
Total cholesterol (TC) () -1 12
HDL-C () 37 22
TC/HDL-C ratio () 31 29
Triglycerides (mg/dL) 2 46
Nadler JP, et al. 44th ICAAC, 2004. Poster H-156.
30
Favorable Increases in HDL-Cholesterol With
Fosamprenavir in ART-Naive Patients in the NEAT
Study
Increases in HDL-C to Maximum Post Baseline by
NCEP Lipid Category
Subjects
Nadler JP, et al. 44th ICAAC, 2004. Poster H-156.
31
Tipranavir/Ritonavir vs Other Boosted PIs in ART-
Experienced Patients RESIST-1
Following 24 weeks of treatment,
tipranavir/ritonavir appeared to be superior to
other boosted PIs in patients with PI-resistant
virus.

• RESIST-1 Randomized, controlled, open-label,
  phase 3 trial
• Study participants had multiple PI experience and
  PI-resistant virus
• failing a PI-containing regimen at entry
• ? 1 primary PI mutation
• ? 2 mutations at codon 33, 82, 84, or 90
• 620 patients were randomized to receive

Tipranavir (n311)
Tipranavir/ritonavir 500/200 mg optimized background regimen
Comparator PI (n309)
Comparator PI/ritonavir optimized background regimen
or

• 36.1 of subjects received enfuvirtide

Hicks C, et al. 44th ICAAC, 2004. Abstract
H-1137a.
32
Tipranavir/Ritonavir vs Other Boosted PIs in ART-
Experienced Patients RESIST-1
Discontinuations and Adverse Events

• More people discontinued a control PI than
  tipranavir, usually because of virologic failure

Tipranavir (n311) Comparator PI (n309)
On treatment 263 151
Discontinued Virologic failure Adverse events 48 13 25 139 109 9

• Rates of grade 3/4 side effects were similar
  overall (22.8 and 18.1) but differed
  significantly for certain parameters

ALT elevation () 6.9 1.3
Cholesterol () 4.2 0
Triglycerides () 21.7 12.5
P lt .001 P lt .01
Hicks C, et al. 44th ICAAC, 2004. Abstract
H-1137a.
33
Tipranavir/Ritonavir vs Other Boosted PIs in ART-
Experienced Patients RESIST-1
Virologic Responses at 24 Weeks (ITT, NF)
60
P lt .001
40
P lt .001

Subjects
34.7

25.1
20

16.5

10
0
Tipranavir
Comparator PI
ITT, intention-to-treat analysis NF,
noncompletion equals failure
Hicks C, et al. 44th ICAAC, 2004. Abstract
H-1137a.
34
Tipranavir/Ritonavir vs Other Boosted PIs in ART-
Experienced Patients RESIST-1
Impact of Enfuvirtide (ENF) on Virologic
Responses at 24 Weeks (ITT, NF)
60
47.1
40
32.8
Subjects
21.9
20
14.3
0
Tipranavir ENF
Comparator PI ENF
ITT, intention-to-treat analysis NF,
noncompletion equals failure
Hicks C, et al. 44th ICAAC, 2004. Abstract
H-1137a.
35
CCR5 Antagonists and Viral Tropism
36
873140, a Novel CCR5 Antagonist 10-Day Responses
to Monotherapy
Median Change in Viral Load at Day 10 by Dose
Group

• 21 ART-experienced, 19 ART-naive subjects
• HIV RNA gt5000 copies/mL, CD4 gt200 cells/mcL,
  CCR5-tropic virus at baseline
• No serious adverse events in any treatment group

Lalezari J, et al. 44th ICAAC, 2004. Abstract
H-1137b.
37
Distribution of Coreceptor Tropism According to
Treatment Status
Relative Distribution of HIV-1 Tropism Among
ART-Naive and -Experienced Patients
Source 442 stored samples from
GlaxoSmithKline clinical trials 412 successfully
typed
Demarest J, et al. 44th ICAAC, 2004. Abstract
H-1136.
38
Distribution of Coreceptor Tropism According to
CD4 Cell Count
Prevalence of R5- and X4/Dual-Tropic Isolates by
Absolute CD4 Cell Count
100
14.8
40
41.9
16
16
80
X4 or R5/X4
85.2
60
84
84
R5
Samples
60
58.1
40
20
0
gt 300 (n248)
gt 201-300(n104)
gt 101-200(n81)
gt 51-100 (n31)
lt 50 (n50)
CD4 cell count (cells/mcL)
Source 865 stored samples, Chelsea and
Westminster Hospital, London 616 successfully
typed