Supported by an unrestricted educational grant from

Supported by an unrestricted educational grant from

ANTIRETROVIRAL TREATMENT HIGHLIGHTS

Summarized by

Douglas J. Ward, MD, FACPDupont Circle Physicians Group, Washington, DC

An HIV/AIDS Overview from the

44th Annual Interscience Conference onAntimicrobial Agents and Chemotherapy

October 30 - November 2, 2004; Washington, DC

44th ICAAC

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

ANTIRETROVIRAL TREATMENT HIGHLIGHTS44thICAAC

Virologic Monitoring and Drug Resistance

44thICAAC

www.medscape.com/hiv-aidshome

Intermittent Low-Level HIV-1 Viremia (“Blips”) in Virologically Controlled Patients

10 patients with HIV-1 RNA < 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.

Viremic “blips” during antiretroviral therapy do not appear to result in evolution of resistant virus or virologic failure.

Nettles RE, et al. 44th ICAAC, 2004. Abstract H-1134.

44thICAAC


Frequency of NRTI-Associated Mutations in 2003 (ViroLogic Database)

% Genotypes (n > 16,000)

Frequency and Characteristics of the NRTI-Associated K65R and L74V/I RT Mutations

McColl DJ, et al. 44th ICAAC, 2004. Poster H-178.

0 5 10 15 20 25 30 35 40 45 50

T69 ins

Q151M

Y115F

K65R

L74V/I

L210W

K70R

K219Q/E/N/R

D67N

M41L

T215Y/F

M184V/I

1%

1%

2%

4%

12%

15%

16%

20%

20%

25%

31%

44%

44thICAAC


Phenotypic NRTI Resistance of HIV-1 Variants With K65R


% A

bo

ve C

ut-

off

ZDV(1.9)

d4T(1.7)

TDF(1.4)

ABC(4.5)

ddl(1.7)

3TC(3.5)

0

20

40

60

80

100

2 0 613

0

29

85

13

83

1

96

22

62

96

71

97100

99

NRTIs (PhenoSense cut-off)

K65R alone K65R + M184V K65R + NAMs


44thICAAC


Phenotypic NRTI Resistance of HIV-1 Variants With L74V/I


% A

bo

ve C

ut-

off

NRTIs (PhenoSense cut-off)

L74V/I + M184V L74V/I + NAMsL74V/I alone

100

ZDV(1.9)

d4T(1.7)

TDF(1.4)

ABC(4.5)

ddl(1.7)

3TC(3.5)

0

20

40

60

80

0 0

85

0 0

79

0 0

57

0

85

3629

92

55

3

100

63


44thICAAC

www.medscape.com/hiv-aidshomeStaszewski S, et al. 44th ICAAC, 2004. Poster H-177.

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

Predictors of K65R With Tenofovir in Antiretroviral Therapy (ART)-Experienced and -Naive PatientsIn patients taking tenofovir, emergence of the K65R drug resistance mutation was associated with the

absence or presence of other specific regimen components.

44thICAAC


Proportion of Patients With Reduced Susceptibility to > 1 Drug (N = 317)

Prevalence of Transmitted HIV Drug Resistance in ART-Naive Individuals in the United States in 2003

Ross LL, et al. 44th ICAAC, 2004. Poster H-173.

0 5 10 15 20 25

3 PI

2 PI

1 PI

> 1 PI

3 NNRTI

2 NNRTI

1 NNRTI

> 1 NNRTI

> 1 NRTI

Any ARV

% Subjects

23%

0.9%

18%

10%

3%

6%

6%

4%

0.9%

0.3%

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 > 1%

Nucleoside/Nucleotide Reverse Transcriptase InhibitorOptions and Regimens

for First- and Second-line Therapy

44thICAAC

www.medscape.com/hiv-aidshomeMoyle G, et al. 44th ICAAC, 2004. Abstract H-1131.

Median HIV RNA (log10 copies/mL) 5.26 5.13

Median CD4+ (cells/mcL) 194 153

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 (n=57)

ZDV/3TC/ABC 300/150/300 mg BID + TDF 300 mg QD

Triple (n=56)

ZDV/3TC 300/150 mg BID + Efavirenz 600 mg QD

Baseline characteristics were comparable, including:

or

A single-class, quadruple-NRTI regimen was shown to be equivalent to a standard, 2-class efavirenz-based regimen for first-line therapy.

44thICAAC

www.medscape.com/hiv-aidshomeMoyle G, et al. 44th ICAAC, 2004. Abstract H-1131.

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

1 virologic failure (Quad-NRTI)

ITT , intention-to-treat analysis; M=F, missing equals failure

0

20

40

60

80

100

0 4 8 12 24 36 48

EFV+ZDV/3TCQuad-NRTI

Treatment Time (Weeks)

% S

ub

ject

s 68 %67 %

Trizivir + Tenofovir vs Combivir + Efavirenz in ART-Naive Patients

Proportion of Subjects With HIV-1 RNA <50 Copies/mL Through Week 48 (ITT, M=F)

44thICAAC


Proportion of Subjects With HIV-1 RNA <50 Copies/mLat Week 24

No of Subjects Overall <100,000 >100,000

ITT M=F 123 52 71

AT 94 40 54

ITT M=F AT

5465

46

7185

61

0

20

40

60

80

100

Overall BL VL<100,000

BL VL> 100,000

% S

ub

ject

s

Trizivir + Tenofovir in ART-Naive Subjects: COL40263

DeJesus E, et al. 44th ICAAC, 2004. Poster H-564.

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• >1 TAMs only, 3

• >1 TAMs+M184V, 3

• Wild-type, 2

ITT, intention-to-treat analysis; M=F, missing equals failure; AT, as treated

44thICAAC


Trizivir + Tenofovir in Patients With Early Virologic Failure on Initial Regimen: ESS30005

Rodriguez AE, et al. 44th ICAAC, 2004. Poster H-563.

ESS30005: Open-label study

51 patients with early virologic failure (VL >400 but <10,000 copies/mL)

• Failing regimens: zidovudine (or stavudine)/lamivudine + PI or NNRTI

Baseline characteristics:

• Median HIV-1 RNA: 3.3 log10 copies/mL (68% <5000 copies/mL)

• Median CD4+ cell count: 436 cells/mcL (37% > 350 cells/mcL)

• < 2 NRTI mutations: M184V (82%), TAMs (24%), no K65R

43 patients (84%) completed > 24 weeks of follow-up

Zidovudine/lamivudine/abacavir (Trizivir) + tenofovir may be a viable rescue option for patients with early virologic failure on a standard initial regimen.

44thICAAC

www.medscape.com/hiv-aidshomeRodriguez AE, et al. 44th ICAAC, 2004. Poster H-563.

Proportion of Subjects With HIV-1 RNA <50 Copies/mL Through Week 24

93%

80%

75%65%

Trizivir + Tenofovir in Patients With Early Virologic Failure on Initial Regimen: ESS30005

0

20

40

60

80

100

0 4 8 12 16 20 24


% S

ub

ject

s

Obs <400 Obs <50 ITT M=F <400 ITT M=F <50

ITT, intention-to-treat analysis; M=F, missing equals failure; Obs, observed analysis

44thICAAC


Tenofovir/Emtricitabine + Efavirenz vs Combivir + Efavirenz in ART-Naive Patients

Gazzard B, et al. 44th ICAAC, 2004. Abstract H-1137c.

Study 934: Open-label, randomized, noninferiority study

Better overall responses were seen with tenofovir/emtricitabine than with zidovudine/lamivudine (Combivir) in the preliminary analysis of this head-to-head study.

Tenofovir/Emtricitabine (n=255)

TDF 300 mg + FTC 200 mg

+ EFV (all QD)

Combivir (n=254)

ZDV/3TC 300/150 mg (BID)

+ EFV (QD)

or

Planned 24-week analysis (96-week study)

ART-naive patients were randomized to receive:

Baseline characteristics were comparable, including:

Median HIV RNA (log10 copies/mL) 5.0 5.0

% HIV RNA > 100,000 52 50

Median CD4+ (cells/mcL) 233 241

% < 200 42 41

44thICAAC



Time to Loss of Virologic Response (TLOVR) <50 Copies/mL (ITT)

ITT, intention-to-treat analysis


0

20

40

60

80

100

0 4 8 16 24

TDF/FTC ZDV/3TC


% S

ub

ject

s 73%65%

P = .038

44thICAAC




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

Patient Disposition Through Week 24

* P = .003 † P = .008

Significantly better overall response with tenofovir/emtricitabine due

to fewer adverse events leading to fewer discontinuations in that arm

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

44thICAAC


Efficacy of Fixed-Dose Abacavir/Lamivudine + Efavirenz: ESS30009

Proportion of Subjects With HIV-1 RNA <50 Through Week 24 (ITT, M=F)

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%)


% S

ub

ject

s

0

20

40

60

80

100

0 4 8 12 16 20 24

69%

Terminated

ABC/3TC+EFV

ABC/3TC+TDF

ITT, intention-to-treat analysis; M=F, missing equals failure

Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.

44thICAAC


Virologic Response Following Switch to Second-line Regimens up to 12 Weeks

Gallant JE, et al. 44th ICAAC, 2004. Poster H-567.

Predictors of a 12-week post-switch viral load < 50 copies/mL:

• Baseline viral load: OR, 0.163; P = .001

• Abacavir use: OR, 7.731; P = .009

Efficacy of Subsequent Treatment of Tenofovir + Abacavir/Lamivudine Nonresponders: ESS30009

Treatment Time Post Switch (Weeks)

% S

ub

ject

s

0

20

40

60

80

100

2 4 8 12

ITT M=F <400 ITT M=F <50

Obs <400 Obs <50

• Efavirenz use: OR, 5.797; P = .015

• Zidovudine use: OR, 5.032; P = .022

ITT, intention-to-treat analysis; M=F, missing equals failure; Obs, observed

44thICAAC


Early Virologic Failure With Once-Daily Didanosine/Tenofovir/Efavirenz in ART-Naive Patients

In an open-label trial, ART-naive individuals were randomized to receive:

• QD didanosine/tenofovir/efavirenz (n=41)

• QD didanosine/lamivudine/efavirenz (n=36)

The study was terminated after an unplanned analysis at week 12

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.

ddI/TDF/EFV ddI/3TC/EFV

n (%) with VL <50 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%)*

Drug-resistant virus emerged rapidly in first 4 virologic failures

All 5 subjects with virologic failure had baseline VL >100,000 copies/mL and CD4+ cell count < 200 cells/mcL

*P < .05

Moyle G, et al. 44th ICAAC, 2004. Poster H-566.

44thICAAC


Tenofovir/Didanosine: Paradoxical CD4+ Cell Declines Despite Good Virologic Control

Barrios A, et al. 44th ICAAC, 2004. Abstract H-1132.

All subjects had HIV RNA <400 copies/mL for >1 year (N=570)

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

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

Simplification/Switch Strategies for Patients With Virologic Suppression

44thICAAC

www.medscape.com/hiv-aidshomeCohen C, et al. 44th ICAAC, 2004. Poster H-577.

• Efavirenz + didanosine/lamivudine (all QD)

• Efavirenz + current NRTIs (ZDV/3TC, 51%; d4T/3TC, 30%; other, 19%)

Virologic Response at Week 24 (ITT NC=F):

Switching From a PI- to a Once-Daily Efavirenz-Based Regimen: VEST-QDOnce-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 <50 copies/mL on PI regimens were randomized to:

ddI/3TC (n=92) Current NRTI (n=94)

HIV RNA <400 copies/mL (%) 89 90

HIV RNA <50 copies/mL (%) 85 87

1 virologic failure (current-NRTI arm)

HDL-C levels increased in both arms (P < .0001)

Adherence improved in both arms (P < .05)

• No difference between arms ITT, intention-to-treat analysis; NC=F, noncompletion equals failure

44thICAAC

www.medscape.com/hiv-aidshomeBonjoch A, et al. 44th ICAAC, 2004. Poster H-562.

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.

ZDV/3TC/ABC (n=68) ZDV/3TC/NVP (n=66)

% Undetectable VL (ITT NC=F) 71 73

% Undetectable VL (OT) 98.6 98.5

SimplifiHAART: 48-week randomized, open-label switch study

134 patients with undetectable VL (not defined) for > 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

ITT, intention-to-treat analysis; NC=F, noncompletion equals failure

44thICAAC


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 >5.2 mmol/L - Trizivir (%) 55.6 30.5 .019

LDL-C TC >3.36 mmol/L - Trizivir (%) 60.0 20.6 .003

TC >5.2 mmol/L - Combivir/nevirapine (%) 68.9 42.2 .019

LDL-C >3.36 mmol/L - Combivir/nevirapine (%) 59.3 41.7 NS

Bonjoch A, et al. 44th ICAAC, 2004. Poster H-562.

44thICAAC


Favorable Lipid Changes With Switch From Stavudine to Tenofovir: GS903E

Suleiman JMAH, et al. 44th ICAAC, 2004. Poster H-158.

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 (<50 copies/mL) through 24 weeks post-switch

No patient discontinued due to adverse events

*P < .001

Week 12(n=85)

Week 24(n=83)

Mea

n C

han

ge

(mg

/dL

)

-70

-60

-50

-40

-30

-20

-10

0

-23*-17*

-6* -4*-0.2 -0.2

-40*-38*

-62*

-44*

TC LDL-C HDL-C LDL-C/HDL-C TG

Current and Investigational Protease Inhibitors

44thICAAC


Favorable Increases in HDL-Cholesterol With Fosamprenavir in ART-Naive Patients: NEAT

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 (n=166)

• nelfinavir 1250 mg + abacavir 300 mg/lamivudine 150 mg (n=83)

Baseline lipids were similar, with relatively low HDL-C, in both arms

HDL-C and other lipid changes were observed through week 48:

In the NEAT study, treatment with unboosted fosamprenavir + abacavir/lamivudine was associated with increases in high-density lipoprotein cholesterol (HDL-C) levels.

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.

44thICAAC


Increases in HDL-C to Maximum Post Baseline by NCEP Lipid Category

Favorable Increases in HDL-Cholesterol With Fosamprenavir in ART-Naive Patients in the NEAT Study

<40 mg/dL

>40 to <60 mg/dL

>60 mg/dL69

24

76

47

27

49

21

43

2710

0%

20%

40%

60%

80%

100%

BL Max. post-BL

BL Max. post-BL

Fosamprenavir (n=148) Nelfinavir (n=72)

% S

ub

ject

s

Nadler JP, et al. 44th ICAAC, 2004. Poster H-156.

44thICAAC


Tipranavir/Ritonavir vs Other Boosted PIs in ART- Experienced Patients: RESIST-1

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:

Following 24 weeks of treatment, tipranavir/ritonavir appeared to be superior to other boosted PIs in patients with PI-resistant virus.

Tipranavir (n=311)

Tipranavir/ritonavir 500/200 mg + optimized background regimen

Comparator PI (n=309)

Comparator PI/ritonavir + optimized background regimen

36.1% of subjects received enfuvirtide

or

Hicks C, et al. 44th ICAAC, 2004. Abstract H-1137a.

44thICAAC


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

Tipranavir (n=311) Comparator PI (n=309)

On treatment 263 151

Discontinued• Virologic failure• Adverse events

481325

139

109

9

ALT elevation (%) 6.9 1.3 *

Cholesterol (%) 4.2 0*

Triglycerides (%) 21.7 12.5†

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

* P < .001 † P < .01


Discontinuations and Adverse Events


44thICAAC


Virologic Responses at 24 Weeks (ITT, LOCF)

< 400 copies/mL < 50 copies/mL

*P < .001

34.7

16.5

25.1

10

0

20

40

60

Tipranavir Comparator PI

*

*

**

% S

ub

ject

s

*P < .001



ITT, intention-to-treat analysis; LOCF, last observation carried forward

44thICAAC


Impact of Enfuvirtide (ENF) on Virologic Responses (ITT, LOCF)

% S

ub

ject

s

< 400 copies/mL < 50 copies/mL

Tipranavir/r Comparator PI

0

All +ENF All +ENF All +ENF All +ENF

20

40

60

34.7

47.1*

16.5

21.9* 25.1

32.8*

10.014.3*

*P < .001



ITT, intention-to-treat analysis; LOCF, last observation carried forward

CCR5 Antagonists and Viral Tropism

44thICAAC


873140, a Novel CCR5 Antagonist: 10-Day Responses to Monotherapy

Lalezari J, et al. 44th ICAAC, 2004. Abstract H-1137b.

Median Change in Viral Load at Day 10 by Dose Group

21 ART-experienced, 19 ART-naive subjects

HIV RNA >5000 copies/mL, CD4+ >200 cells/mcL, CCR5-tropic virus at baseline

No serious adverse events in any treatment group

HIV

-1 R

NA

(lo

g10

co

pie

s/m

L)

-0.12

-0.46

-1.23

-1.03

-1.66-1.8

-1.6

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Placebo(n=9)

200 QD(n=7)

200 BID(n=8)

400 QD(n=8)

600 BID(n=8)

44thICAAC


Distribution of Coreceptor Tropism According to Treatment Status

Demarest J, et al. 44th ICAAC, 2004. Abstract H-1136.

Tropism

% S

amp

les

Total

ART-Naive

ART-Experienced

n = 339 263 76 67 6 63136

82

16

2

88

12

0

67

28

5

0

20

40

60

80

100

R5 R5/X4 X4

Relative Distribution of HIV-1 Tropism Among ART-Naive and -Experienced Patients*

* Source = 442 stored samples from GlaxoSmithKline clinical trials; 412 were successfully typed

44thICAAC


Distribution of Coreceptor Tropism According to CD4+ Cell Count

Moyle G, et al. 44th ICAAC, 2004. Abstract H-1135.

% X

4 o

r R

5/X

4

16 16

41.9 40

14.8

0

20

40

60

80

> 300 (n=248)

> 201-300(n=104)

> 101-200(n=81)

> 51-100(n=31)

< 50(n=50)

CD4+ cell count (cells/mcL)

Prevalence of R4- or R5/X4-Tropic Isolates by Absolute CD4+ Cell Count*

* Source = 865 stored samples from Chelsea and Westminster Hospital, London; 616 were successfully typed

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