primary drug resistance and strategies for first-line hiv treatment this activity is supported by an...

Primary Drug Resistance and Strategies for First-Line HIV Treatment

This activity is supported by an educational grant from

Faculty: Ian Frank, M.D.Associate Professor of Medicine at theHospital of the University of Pennsylvania Ian Frank, M.D.

Copyright © 2008 Body Health Resources Corporation. All rights reserved.

The Body PRO Presents:

This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.

The Body PRO


2

Faculty for This ActivityFaculty for This Activity

Ian Frank, M.D.

Ian Frank, M.D., has worked for the past 10 years in the Infectious Diseases Division of the Hospital of the University of Pennsylvania where he serves as an Attending Physician; Director, Antiretroviral Clinical Research; and Associate Professor, Department of Medicine. Formerly he was Director, Immunodeficiency Program Clinic, and Director, Outpatient Infectious Diseases Program also at the Hospital of the University of Pennsylvania.

Dr. Frank is on numerous hospital and medical school committees, and national committees, such as the Undergraduate Medical Education Committee; the Institutional Review Board; the Medical Center AIDS Committee; and the Medical School HIV Curriculum Committee. He has also worked on the HIV Research Agenda Committee, Protease Inhibitor Focus Group, Adult AIDS Clinical Trials Group; and the Combination Therapy Working Group of Primary Therapy Committee, Adult AIDS Clinical Trials Group.

Dr. Frank received his M.D. from Dartmouth Medical School and is a member of many professional and scientific societies, including the American Association for the Advancement of Science, the Infectious Diseases Society of America, and the International AIDS Society.

The Body PRO


3

AgendaAgenda

• Review DHHS guidelines for the initiation of antiretroviral therapy

• Review DHHS guidelines with respect to the recommended agents and recent data influencing initial treatment decisions

• Discuss data on transmitted drug resistance and itsimpact on treatment response and the selection of an antiretroviral combination

• Discuss the selection of an initial antiretroviral combination based upon specific patterns of resistance and sequencing

• Discuss the selection of an initial combination when resistance testing isn’t available

The Body PRO


4

DHHS Guidelines: Recommendations for When to Initiate Antiretroviral TherapyDHHS Guidelines: Recommendations for When to Initiate Antiretroviral Therapy

Clinical Condition and/or CD4+ Cell Count Recommendations

History of AIDS-defining illness

Antiretroviral therapy should be initiated

CD4+ cell count < 350 cells/mm3

Other (regardless of CD4+ cell count)– Pregnant women– Persons with HIV-associated nephropathy– Patients coinfected with HBV when

treatment for HBV infection is indicated

CD4+ cell count > 350 cells/mm3 in the absence of any of the above conditions

Antiretroviral therapy should be considered, based on the benefits and risks, co-morbidities, patient readiness, and adherence

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. US Dept of Health and Human Services; 2008 Jan 29.

The Body PRO


5

DHHS Guidelines: Recommendations for Treatment-Naive PatientsDHHS Guidelines: Recommendations for Treatment-Naive Patients

Adapted from Panel on Antiretroviral Guidelines for Adults and Adolescents. US Dept of Health and Human Services; 2008 Jan 29.

Select One Component From Column A + One From Column B

Column A (NNRTI or PI—in alphabetical order)

Column B (Dual-NRTIs)

Preferred Components

NNRTI or PIEFV1 ATV/r FPV/r (BID) LPV/r2 (BID)

(in alphabetical order)ABC/3TC3 (coformulated) for HLA-B*5701 negative patients

orTDF/FTC3 (coformulated)

Alternative to Preferred Components

NNRTI or PINVP4 ATV5

FPV FPV/r (QD) LPV/r (QD) SQV/r

(in order of preference)AZT/3TC3 (coformulated)

orddI + (FTC or 3TC)

1EFV is not recommended for use in the first trimester of pregnancy or in sexually active women with childbearing potential who are not using effective contraception.2The pivotal study that led to the recommendation of LPV/r as a preferred PI component was based on twice-daily dosing [NEJM 2002]. A smaller study has shown similar efficacy with once-daily dosing but also showed a higher incidence of moderate to severe diarrhea with the once-daily regimen (16% vs. 5%) [JAIDS 2006]. In addition, once-daily dosing may be insufficient for those with VLs > 100,000 copies/mL [AIDS 2002]. 3FTC may be used in place of 3TC and vice versa.4NVP should not be initiated in women with CD4+ cell count > 250 cells/mm3 or in men with CD4+ cell count > 400 cells/mm3 because of increased risk of symptomatic hepatic events in these patients.5ATV must be boosted with RTV if used in combination with EFV or TDF.

The Body PRO


6

ACTG 5142: Study DesignACTG 5142: Study Design

Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.

Randomized, Multicenter, Open-Label TrialStudy Duration: 96 Weeks

N = 753

LPV/r given as soft gel capsules2 NRTIs included 3TC (150 mg twice daily or 300 mg once daily) + investigator selection of:

ZDV 300 mg twice daily or d4T XR† 100 mg‡ once daily or TDF 300 mg once daily

*Based on the presence of hepatitis C antibody or hepatitis B surface antigen, or both ‡75 mg if subject weighed < 60 kg†d4T XR was an investigational formulation of stavudine that is not commercially available

ARV-Naive≥ 13 Years of Age

HIV-1 RNA ≥ 2,000 Copies/mL

Stratified at randomization HIV-1 RNA < 100,000 vs. ≥ 100,000 Copies/mL

Chronic Hepatitis B/C Infection*NRTI Selection

EFV 600 mg at bedtime + 2 NRTIsN = 250

LPV/r 400/100 mg twice daily + 2 NRTIsN = 253

EFV 600 mg at bedtime + LPV/r 533/133 mg twice daily

N = 250

The Body PRO


7

ACTG 5142: Virologic Response Through 96 WeeksACTG 5142: Virologic Response Through 96 Weeks

Reprinted with permission from Ian Frank, M.D. Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.

100

90

80

70

60

50

40

30

20

10

0

Percent at 96 Weeks EFV + 2 NRTIs 89%LPV/r + 2 NRTIs 77%EFV + LPV/r 83%

0 16 32 48 64 80 964 8 24 40 56 72 88

ITT: Missing Values Ignored

EFV + 2 NRTIsLPV/r + 2 NRTIsEFV + LPV/rP

erce

nt

wit

h H

IV-1

RN

A<

50

cop

ies/

mL

EFV + 2 NRTIs

LPV/r + 2 NRTIs

EFV + LPV/r

250

253

250

236

235

242

224

226

228

212

217

217

201

201

206

178

177

180

Weeks After RandomizationNumber of Patients

The Body PRO


8

ACTG 5202: Study DesignACTG 5202: Study Design

96-Week, Phase 3B, Randomized, Partially Blinded Study

Comparing efficacy, safety and tolerability of regimens shown below as initial therapy for HIV-1 infection

HIV-1 RNA ≥ 1,000 Copies/mLAny CD4+ Cell Count

≥ 16 Years of Age

Stratified by HIV-1 RNA (< or ≥ 100,000 Copies/mL)

ART-naïve N=1858

Randomized 1:1:1:1

EFV

EFV QD

ATV/rQD

ATV/rQD

ART-NaiveN = 1,858

Randomized 1:1:1:1

QDTDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

TDF/FTC QD

ABC/3TC Placebo QD

ABC/3TC QD

TDF/FTC Placebo QD

Adapted from Paul Sax et al. AIDS 2008; abstract THAB0303.

The Body PRO


9

ACTG 5202: DSMB Efficacy FindingsACTG 5202: DSMB Efficacy Findings

Adapted from ACTG news and announcements page. A5202 study. Available at: http://aactg.org/news_results.asp. Accessed March 4, 2008.Adapted from NIAID press release. NIAID modifies HIV antiretroviral treatment study combination therapy that includes ABC/3TC found less effective in

subgroup of antiretroviral-naive individuals. Available at: http://www3.niaid.nih.gov/news/newsreleases/2008/actg5202bulletin.htm. Accessed February 28, 2008.

• Virologic failure rates were significantly higher among those randomized to ABC/3TC than to TDF/FTC within the high viral load stratum*

• No difference by use of EFV versus ATV + RTV

ComparisonLog-rank test

P-ValueEstimated

Hazard Ratio95% CI

ABC/3TC vs. TDF/FTC .0003 2.33 (1.46, 3.72)

Cumulative Virologic Failure Data, Screening HIV-1 RNA ≥ 100,000

*Subjects with HIV RNA > 100,000 copies/mL at screening.

The Body PRO


10

When to Use Resistance TestingWhen to Use Resistance Testing

1 US Dept of Health and Human Services. Antiretroviral Guidelines for Adults and Adolescents. 2008 Jan 29. 2Anne-Mieke Vandamme et al. Antivir Ther. 2004;9:829-848. 3Martin Hirsch et al. Clin Infect Dis. 2003;37:113-128.

DHHS1 European2 IAS-USA3

Primary/Acute Recommend‡ Recommend Recommend

Post-Exposure Prophylaxis — Recommend —

Chronic, Treatment Naive Recommend‡ Strongly Consider* Consider*

Failure Recommend Recommend Recommend

Pediatric — Recommend† —

Pregnancy Recommend Recommend† Recommend†

*Especially if exposure to someone receiving ARVs is likely or if prevalence of drug resistance in untreated patients ≥ 5% (European: ≥ 10%)†When viral load is detectable‡December 1, 2007: The Panel recommends performing genotypic drug resistance testing for all treatment-naive patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated

*Especially if exposure to someone receiving ARVs is likely or if prevalence of drug resistance in untreated patients ≥ 5% (European: ≥ 10%)†When viral load is detectable‡December 1, 2007: The Panel recommends performing genotypic drug resistance testing for all treatment-naive patients entering into clinical care, regardless of whether antiretroviral therapy is to be initiated. This recommendation is based on the fact that transmitted resistance mutation may be detected at a time point more proximal to the time of infection than later. Repeat testing may be considered at the time when therapy is to be initiated

The Body PRO


11

Ordering Resistance Testing Prior to Initiation of Antiretroviral TherapyOrdering Resistance Testing Prior to Initiation of Antiretroviral Therapy

• A genotypic resistance test is adequate to determine the pattern of resistance and select an initial combination

• Obtain a genotype as part of the initial evaluation of a patient

– Don’t delay ordering a resistance test in patients with high CD4+ cell counts

The Body PRO


12

Patterns of Resistance Among Newly Diagnosed Patients–CDC DataPatterns of Resistance Among Newly Diagnosed Patients–CDC Data

1Hillard Weinstock et al. J Infect Dis. 2004;189:2174-2180. 2William Wheeler et al. CROI 2007; abstract 648.

0

2

4

6

8

10

12

Pat

ien

ts W

ith

Tra

nsm

itte

d

Res

ista

nce

(%

)

1998 1999 2000 2003-2006

MDR NNRTI NRTI PI Any Resistance

1 1 1 2

N = 257 N = 239 N = 299 N = 3,130

0 00.4

5.15.5

7.1

8.8

2.1

1.30.8

1.31.7

3.0

7.7

10.7

1.92.4

3.6

6.9

10.4

The Body PRO


13

PREPARE Study: Transmitted Drug ResistancePREPARE Study: Transmitted Drug Resistance

Lisa Ross et al. ICAAC 2006; abstract H-993. Reprinted with permission.

Percentage of ART-Naïve Subjects With Resistance Mutations to Any Drug or by Drug Class From 2000-2005 Using the IAS-USA Defined Primary Resistance Mutations.

Bars Shown in Purple Use the Stanford Resistance Mutation Definitions.

Summary from Ian Frank, M.D.: Cohort (N = 2,035) from clinical trials (2000-2005) sponsored by one pharmaceutical company.Increase in primary resistance in 2005 primarily due to increased incidence of NNRTI mutations (10% to 11%).

The Body PRO


14

Transmission of Drug-Resistant HIV in New York CityTransmission of Drug-Resistant HIV in New York City

Adapted from Anita Shet et al. CROI 2005; abstract 289.

Acute or recent infection from primary infection cohort in

New York City

112 ART-naive individuals (January 2003 to December 2004)

> 25% with resistance

NNRTI resistance increased from

1995 thru 1998 (2.6%) to 2003 thru 2004 (13.4%); P = .04

11 (9.8%) with MDR: increase in MDR resistance from previous

dates; P =.03

0 4 8 12 16 20 24 28

Percentage of Newly Infected Individuals

2003-2004

2001-2002

1999-2000

1995-1998

Prevalence of Transmitted ART Resistance Mutations, 1995 - 2004

MDR NNRTI NRTI PI All Resistance

The Body PRO


15

Declines in Transmitted Drug Resistance In the UKDeclines in Transmitted Drug Resistance In the UK

Adapted from UK Collaborative Group on HIV Drug Resistance et al. AIDS. 2007;21:1035.

Analysis of results of genotypic resistance tests reported to the UK HIV Drug Resistance Database in patients who were antiretroviral treatment-naive at the time of sampling

Rate of Transmitted Drug Resistance by Chronicity of Infection

All Patients

Acutely Infected Patients

0

2

4

6

8

10

12

14

1997 1999 2001 2003 2005

Rat

e o

f T

DR

(%

)

Year of Sample

10

0

2

4

6

8

1997

Rate of Transmitted Drug Resistance by Drug Class

NRTI

NNRTI

PI

1999 2001 2003 2005

Year of Sample

The Body PRO


16Acquired Resistance Persists After Acute Infection in the Absence of Any Selective Pressure

Acquired Resistance Persists After Acute Infection in the Absence of Any Selective Pressure

1Susan Little et al. N Engl J Med. 2002;347(6):385-394. 2Phillippe Colson et al. AIDS. 2002;16(3):507-509.3Bluma Brenner et al. J Virology. 2002;766:1753. 4Keith Chan et al. AIDS. 2003;17:1256.

n=101

NNRTI(n=9)NRTI(n=3)PI(n=3)

Resistance

9-145 1 of 10

Reversions

n=1 MDR2 156 None

n=4 MDR3 36-260

None

n=2 MDR4 26-156

None

Follow-up (Weeks)

MDR = multiple drug resistanceMDR = multiple drug resistance

The Body PRO


17

Genotype Predicts Virologic FailureGenotype Predicts Virologic Failure

Adapted from Katyna Borroto-Esoda et al. AIDS Res Hum Retroviruses. 2007;23:988-995.

Prospective, international study of 571 ARV-naive patients (FTC 301).

95% (546/571) had baseline resistance testing.

16% (90/546) showed baseline NRTI and/or NNRTI resistance.

0

15

30

45

60

75

90

Vir

olo

gic

Fa

ilure

(%

)

d4T + ddI + EFV FTC + ddI + EFV

Genotype Results and Virologic Failure Rates

Any (N = 90)

K103N (N = 14)

NRTI (N = 34)

Other NNRTI (N = 34)

WT (N = 456)

The Body PRO


18

Resistance Testing Can ImproveOutcomes in ARV-Naive PatientsResistance Testing Can ImproveOutcomes in ARV-Naive Patients

Adapted from Mark Oette et al. JAIDS. 2006;41:573-581.

Prospective, multicenter studyN = 269

ARV-naive, chronically infected patients between January 2001 and

December 2003

All had baseline resistance testing to select initial HAART.

Primary drug resistance [mostly NRTI] in 11.2% of patients.

Week 48: No difference in virologic outcomes if HAART selected based

on resistance testing.

83

67

85

74

0

10

20

30

40

50

60

70

80

90

100

On Treatment Intent-to-Treat

< 5

0 co

pie

s/m

L (

%)

Baseline Resistance No Resistance

The Body PRO


19

Cost Effectiveness of Genotype Resistance TestingCost Effectiveness of Genotype Resistance Testing

Adapted from Paul Sax et al. Clin Infect Dis. 2005;41:1316-1323.

• Simulation model of HIV disease– Life expectancy, lifetime

costs, and cost-effectiveness projected

• Assumed baseline prevalence of drug resistance– All: 8.3%

• NRTI: 4.7%• PI: 1.9%• NNRTI: 1.7%

• Genotypic resistance testing– Improves clinical outcomes– Cost effective

Resistance TestingNewly Diagnosed

Cost ($)/Quality Adjusted Life-Year

$20,200

$25,900

$23,900

HAART

Resistance Testing Post-Treatment Failure

The Body PRO


20

ACTG 5095: AZT+3TC+EFV vs. AZT+3TC+ABC+EFV Impact of Minority Variants ACTG 5095: AZT+3TC+EFV vs. AZT+3TC+ABC+EFV Impact of Minority Variants

Adapted from Roger Paredes et al. CROI 2008; abstract 83.

N = 219 183 183 183

Preexisting minority Y181C mutants associated with > 3-fold increased risk of virologic failure of first-line EFV-based HAART, even among adherent patients.

The Body PRO


21

Mutations Associated WithResistance to NRTIsMutations Associated WithResistance to NRTIs

Reprinted with permission from Ian Frank, M.D. Adapted from Victoria Johnson et al. Top HIV Med. 2006;14:125-130.

The Body PRO


22

NRTI Mutations, NRTI Resistance and NRTI OptionsNRTI Mutations, NRTI Resistance and NRTI Options

Mutation(s) Resistant NRTIs NRTI Options

184V 3TC, FTC ABC, ddI, d4T, TDF, AZT

74V ABC, ddI 3TC, FTC, d4T, TDF, AZT

65R ABC, ddI, 3TC, FTC, TDF d4T, AZT (do not use together)

Single TAM: 41, 67, 70, 210, 215, 219

AZT, d4T 3TC, FTC, TDF, ddI, ABC

41L + 210WAZT, d4T, ABC (if 184V), TDF (if 215Y)

ddI (?), 3TC (?), FTC (?)

67N + 70R AZT, d4T, ABC (if 184V) ddI, 3TC, FTC, TDF

The Body PRO


23

ACTG 5142: Virologic Response Through 96 WeeksACTG 5142: Virologic Response Through 96 Weeks

Reprinted with permission from Ian Frank, M.D. Adapted from Sharon Riddler et al. N Engl J Med. 2008;358:2095-2106.

100

90

80

70

60

50

40

30

20

10

0

Percent at 96 Weeks EFV + 2 NRTIs 89LPV/r + 2 NRTIs 77%EFV + LPV/r 83%Nucleoside-Sparing Arm

0 16 32 48 64 80 964 8 24 40 56 72 88

ITT: Missing Values Ignored

EFV + 2 NRTIsLPV/r + 2 NRTIsEFV + LPV/rP

erce

nt

wit

h H

IV-1

RN

A<

50

cop

ies/

mL

EFV + 2 NRTIs

LPV/r + 2 NRTIs

EFV + LPV/r

250

253

250

236

235

242

224

226

228

212

217

217

201

201

206

178

177

180

Weeks After RandomizationNumber of Patients

The Body PRO


24

Mutations Associated WithResistance to NNRTIsMutations Associated WithResistance to NNRTIs


L

100

I

K

103

N

V

106

AM

V

108

I

G

190

A

Y

181

CI

Y

188

CLH

K

103

N

V

106

M

V

108

I

G

190

SA

P

225

H

Y

181

C

I

Y

188

L

K

103

N

V

106

M

Y

181

C

Y

188

L

P

236

L

L

100

I

V

106

I

G

190

S

A

Y

181

C

I

V

V

90

I

A

98

G

V

179

D

F

K

101

E

P

*No single mutation confers full resistance; efficacy decreases as number of mutations increases.

Delavirdine

Efavirenz

Nevirapine

Etravirine*

The Body PRO


25In Second-Line Therapy After NNRTI Resistance, the Boosted PI ContributesMost of the Activity

In Second-Line Therapy After NNRTI Resistance, the Boosted PI ContributesMost of the Activity

Adapted from Jean-Francois Delfraissy et al. AIDS 2006; abstract THLB0202.

MONARK Study: LPV/r Monotherapy vs. LPV/r + AZT/3TC in ARV-Naive Patients

P-value LPV/r AZT/3TC + LPV/r

Patients Randomized 83 53

Intent-to-Treat, M = FViral Load < 50 Copies/mL

at Week 480.69 58/82

(71%) 40/53(75%)

As Treated, available VLViral Load < 50 Copies/mL

at Week 480.03 56/67

(84%) 40/41(98%)

Good response rates to LPV/r alone, though outcomes better when used with NRTIs.

The Body PRO


26

Boosted PIs in ARV-Naive Patients: Virological SuppressionBoosted PIs in ARV-Naive Patients: Virological Suppression

1Edwin De Jesus et al. ICAAC 2007; abstract H-718b. 2Jean-Michel Molina et al. CROI 2008; abstract 37. 3Sharon Walmsley et al. EACS 2007; abstract PS1/4. 4Joseph Eron et al. Lancet. 2006;368:476-482.

KLEAN4

(ITT-E, TLOVR) 48 wk

CASTLE2

(ITT) 48 wk

GEMINI3

(ITT) 48 wk

ARTEMIS1

(ITT) 48 wk

NoninferiorityNoninferiorityNoninferiority Noninferiority

ATV/r 300/100

QD

LPV/r 400/100

BID

7678

0

10

20

30

40

50

60

70

80

90

100

65

FPV/r700/100

BID

LPV/r400/100

BID

66

LPV/r† 400/100

BID

LPV/r†

800/200 QD

DRV/r 800/100

QD

84*

71*

N=440 N=443 N=434 N=444N=346N=343

65

SQV/r1000/100

BID +TDF/FTC

LPV/r400/100 BID +

TDF/FTC

N=170 N=167

64

N=346

81

*P <.05 between LPV/r QD and DRV/r QD; no other significant differences in any of the comparisons above†Use of LPV/r BID or QD was not randomized and was dependent on site and patient preference

The Body PRO


27

PI Potency: The Impact of Baseline Viral LoadPI Potency: The Impact of Baseline Viral Load

1Donna Mildvan et al. CROI 2007; abstract 138. 2Nathan Clumeck et al. EACS 2007; abstract LBPS7/5.3Joseph Eron et al. Lancet. 2006;368:476-482.

*P < .05 comparing LPV/r BID and QD in ACTG 5073 and comparing DRV/r QD and LPV/r QD in ARTEMIS†Use of LPV/r BID or QD was not randomized and was dependent on site and patient preference

ACTG 50731

(ITT)

Pa

tie

nts

wit

h V

L <

20

0 c

op

ies

/mL

(%

)

< 100,000≥ 100,0000

10

20

30

40

50

60

70

80

90

100

8076*

72

89*N = 402

Baseline HIV RNA (copies/mL)

KLEAN3

(ITT-E, TLOVR)

0

10

20

30

40

50

60

70

80

90

100

< 100,000≥ 100,000

6764 65 66

Pa

tie

nts

wit

h V

L <

50

co

pie

s/m

L (

%)

ARTEMIS2

(ITT-E, TLOVR)

8679

8679*

56*

71

0

10

20

30

40

50

60

70

80

90

100

< 100,000 ≥ 100,000

Pa

tie

nts

wit

h V

L <

50

co

pie

s/m

L (

%)

LPV/r 800/200 mg QDLPV/r 400/100 mg BID

DRV/r 800/100 mg QD LPV/r† 800/200 mg QDLPV/r† 400/100 mg BID LPV/r 400/100 mg BID

FPV/r 700/100 mg BID

The Body PRO


28

DUET 1 and 2: Etravirine vs. Placebo Virologic Response by Baseline MutationsDUET 1 and 2: Etravirine vs. Placebo Virologic Response by Baseline Mutations

Adapted from Christine Katlama et al. IAS 2007; abstract WESS204-2.

0.940 30 16 8 5% =

HIV

RN

A <

50

Co

pie

s/m

L (

%)

Number of Etravirine RAMs

0 1 2 3 4 50

20

40

60

80

13 Baseline Resistance-Associated Mutations (RAMs) Associated With a Decreased Response to Etravirine:

A98G G190A/S K101E/P L100I V106I V179D/F V90I Y181C/I/V

If three or more mutations are present, response similar to placebo.

Note: 14% had > 3 etravirine RAMs.

The Body PRO


29

Etravirine + Two NRTIs After Viremia on First NNRTI-Based RegimenEtravirine + Two NRTIs After Viremia on First NNRTI-Based Regimen

Brian Woodfall et al. Glasgow 2006; abstract PL5.6. Reprinted with permission.

• Pilot study to evaluate activity of etravirine plus NRTIs in patients viremic on an NNRTI / NRTI first regimen– PI naive– Randomized to two

NRTIs plus either: • Etravirine• PI (95% boosted)

• Study stopped prematurely due to superiority of PI arm

• Predictors of response:– # NNRTI mutations– # NRTI mutations

The Body PRO


30

Activity of 2 NRTIs + Etravirine by Number of NRTI (TAMS / 184V) MutationsActivity of 2 NRTIs + Etravirine by Number of NRTI (TAMS / 184V) Mutations

Brian Woodfall et al. Glasgow 2006; abstract PL5.6. Reprinted with permission.

Summary From Ian Frank, M.D.

Use of etravirine with “compromised” NRTIs not as durable as

PI-based regimen

Activity of etravirine preserved with a

more active background regimen

The Body PRO


31

Mutations Associated With Resistance to PIsMutations Associated With Resistance to PIs


Atazanavir +/- Ritonavir

Fosamprenavir/r

Darunavir/r

Tipranavir/r

Saquinavir/r

Lopinavir/r

L G K L V L E M M G I F I D I I A G V I I N L I10 16 20 24 32 33 34 36 46 48 50 53 54 60 62 64 71 73 82 84 85 88 90 93I E R I I I Q I I V L L L E V L V C A V V S M

LF M F L L Y V M I S T

MV I V V M V T T FL T T L A IC V M I I I,A G V I L

10 32 46 47 50 54 73 82 84 90F I I V V L S A V M I L V FR M T V V V L I I I G L S I L

11 32 33 47 50 54 73 76 84 89 I I F V V M S V V V IL G K L L V L E M M M I G I F I D I I A G V V I I N L I

10 16 20 24 24 32 33 34 36 36 46 47 48 50 53 54 60 62 64 71 73 77 82 84 85 88 90 93F E R I I I I Q I I I V V L L L E V L V C I A V V S M

LL G K L L V L E M M M I G I F I D I I A G V V I I N L I

10 16 20 24 24 32 33 34 36 36 46 47 48 50 53 54 60 62 64 71 73 77 82 84 85 88 90 93F E R I I I I Q I I I V V L L L E V L V C I A V V S M

LL K L V L M I I F I L A G V I L

10 20 24 32 33 46 47 50 53 54 63 71 73 82 84 90

F M I I F I V V L V P V S A V MI R L L,A T FR M,T TV S S

The Body PRO


32

TITAN: LPV/r vs. DRV + RTV inPI-Experienced—Study DesignTITAN: LPV/r vs. DRV + RTV inPI-Experienced—Study Design

Adapted from Jose Valdez Madruga et al. Lancet. 2007;370:49-58.

aOBR = ≥ 2 ARVs from approved NRTI/NNRTIs, enfuvirtide and tipranavir use excludedbUse of tablet formulation of LPV/r allowed if approved within country

Treatment Phase (96 Weeks)

LPV/r-NaiveVL > 1,000 Copies/mL

Stable HAART for > 12 Weeks OR Treatment Interruption

for > 4 Weeks(N = 595)

DRV/r 600/100 mg BID + OBRa

LPV/rb 400/100 mg BID + OBR

Primary EndpointHIV RNA

< 400 Copies/mL at 48 Weeks

1:1

DRV/r (N = 298) LPV/r (N = 297) Median VL, log10 copies/mL Median CD4+ cell count, cells/mm3

4.35235

4.30230

Previous antiretroviral experience, % ≥ 4 NRTIs 0 PI 1 PI2-class experienced, % NRTI + NNRTI NRTI + PI3-class experienced, %

523236

292246

513139

292148

The Body PRO


33

TITAN: LPV/r vs. DRV + RTV in PI-Experienced— Impact of Baseline PI MutationsTITAN: LPV/r vs. DRV + RTV in PI-Experienced— Impact of Baseline PI Mutations

Adapted from Daniel Berger et al. EACS 2007; abstract P7.3/27.

aExcludes patients with missing LPV FC at baseline; †D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50V/L, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S or L90M. [Johnson VA, et al. Top HIV Med. 14:22-30.]

Number of IAS-USA Primary PI Mutations†

DRV/r (N = 263)

LPV/r (N = 261)

All Patients With LPV FC ≤ 10a

0

10

20

30

40

50

60

70

80

90

0 1 2 ≥ 3

HIV

RN

A <

50

Co

pie

s/m

L (

ITT

-TL

OV

R, %

)

66

59

5043

69

78

6865

DRV/r (N = 172)

LPV/r (N = 174)

Patients With Prior PI Experience and LPV FC ≤ 10a

69

77

6863

6155

4743

0

10

20

30

40

50

60

70

80

90

0 1 2 ≥ 3H

IV R

NA

< 5

0 C

op

ies/

mL

(IT

T-T

LO

VR

, %)

195 197 32 32 19 18 17 14N = 106 114 31 29 19 17 16 14

The Body PRO


34

Trial 004: Raltegravir vs. Efavirenz in ART-Naive PatientsTrial 004: Raltegravir vs. Efavirenz in ART-Naive Patients

Adapted from Martin Markowitz et al. IAS 2007; abstract TUAB104.

m518p4 r50 7 July 10, 2007

0 2 4 8 12 16 24 32 40 48Week

0

20

40

60

80

100

Per

cent

of P

atie

nts

With

HIV

RN

A <

50

Cop

ies/

mL

Raltegravir 100 mg BID (N = 39) Raltegravir 200 mg BID (N = 40) Raltegravir 400 mg BID (N = 41) Raltegravir 600 mg BID (N = 40) Efavirenz 600 mg QD (N = 38)

In ART-naive patients with viral load ≥ 5,000 copies/mL and CD4 ≥ 100 cells/mm3, RAL studied for 48 weeks at all doses

• Had potent antiretroviral activity: 83% - 88% with viral load < 50 copies/mL Achieved viral suppression faster than EFV

• Was well tolerated, with no effect on lipids

The Body PRO


35MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

MERIT: Percentage of Patients With Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

Michael Saag et al. IAS 2007; abstract WESS104. Reprinted with permission.

The Body PRO


36MERIT: Percentage of Patients With HIV-1 RNA < 50 Copies/mL at Week 48 by Tropism Result at Baseline

MERIT: Percentage of Patients With HIV-1 RNA < 50 Copies/mL at Week 48 by Tropism Result at Baseline

Jayvant Heera et al. CROI 2008; abstract 40LB. Reprinted with permission.

The Body PRO


37

Use of the Trofile AssayUse of the Trofile Assay

• Obtain a Trofile Assay to determine the tropism of virus before prescribing maraviroc

– R5 virus uses CCR5 for entry

– X4 virus uses CXCR4 for entry

– Dual-tropic virus uses CCR5 or CXCR4

• Maraviroc is not active against X4 or dual-tropic virus

• An enhanced sensitivity Trofile assay is available

– Able to detect the presence of dual-tropic or X4 viruses present in mixtures with a sensitivity of <1%

The Body PRO


38Choosing an Initial Combination in a Patient With Reverse Transcriptase Inhibitor Resistance

Choosing an Initial Combination in a Patient With Reverse Transcriptase Inhibitor Resistance

• If NRTI resistance is present alone

– Use an NNRTI + boosted PI

– Use a boosted PI with the best NRTI combination available

– Do not use an NNRTI and partially active NRTIs

• If NNRTI resistance is present alone

– Use a boosted PI with two active NRTIs

The Body PRO


39

Choosing an Initial Combination in a Patient With PI Resistance AloneChoosing an Initial Combination in a Patient With PI Resistance Alone

• Use two NRTIs + one NNRTI

• Virus with primary PI resistance does not usually contain multiple PI-associated mutations

– If there is a PI with full or partial activity that agent can be included in a regimen with two other fully active drugs

The Body PRO


40

Choosing an Initial Combination in a Patient With Multi-Drug ResistanceChoosing an Initial Combination in a Patient With Multi-Drug Resistance

• If the virus is fully susceptible to a protease inhibitor

– Use a boosted protease inhibitor and one or two new agents

• Etravirine is an option if K103N is present alone

• Maraviroc is an option if the virus is pure R5

• Raltegravir should be fully active

• If the virus is resistance to protease inhibitors

– Use the boosted PI with the most activity against the virus

– Add two fully active drugs among the newer agents

– Use enfuvirtide in the setting of broadly resistant virus

The Body PRO


41

ACTG A5164: Immediate vs. Delayed ARVs in Setting of Acute Opportunistic InfectionsACTG A5164: Immediate vs. Delayed ARVs in Setting of Acute Opportunistic Infections

Adapted from Andrew Zolopa et al. CROI 2008; abstract 142.

• 282 patients with treatable opportunistic infection or AIDS-associated bacterial infection within 14 days of study entry; no ARV within eight weeks

• Randomized to starting ARV within 48 hours (immediate) or after 42 days (deferred)• Baseline: Median CD4+ = 29 cells/mm3, with 70% CD4+ < 50; > 90% of patients ARV naive• All received 3TC or FTC; 80% received LPV/r• Primary endpoint was composite endpoint consisting of:

– Death/AIDS progression– No disease progression/HIV RNA ≥ 50 copies/mL – No disease progression/HIV RNA < 50 copies/mL

P-valueTime of ARV initiation

Immediate ARV Deferred ARV

Days to ARV N/A 0 35

Days from OI to ARV (95% CI)

< .001 12 (11–12) 45 (43–48)

The Body PRO


42

ACTG A5164: Immediate vs. Delayed ARVs in Setting of Acute Opportunistic Infections (2)ACTG A5164: Immediate vs. Delayed ARVs in Setting of Acute Opportunistic Infections (2)

Adapted from Andrew Zolopa et al. CROI 2008; abstract 142.

0

0.2

0.4

0.6

0.8

1

4 12 20 28 36 44

Immediate Deferred

Pro

bab

ilit

y o

f S

urv

ivin

g W

ith

ou

t D

eath

/New

AID

S-D

efin

ing

Ill

nes

s

Time to Death/New AIDS-Defining Illness (Weeks)

HR = 0.53 99% CI (0.25, 1.09) P = .023

116

94

• Immediate treatment group had reduced rate of AIDS progression or death (14.2%) versus deferred treatment group (24.1%).– Most common OIs: PCP

(63%), Cryptococcus (12%), bacterial infection (12%); TB excluded.

• More rapid increase in CD4+ cell counts to > 50 and > 100 cells/mm3 for immediate group versus deferred group.

• No differences in IRIS (10 immediate versus 13 deferred).– However, 70% of patients

with PCP received corticosteroids.

The Body PRO


43

Starting Therapy in the Absence of Resistance Test ResultsStarting Therapy in the Absence of Resistance Test Results

• Obtain a resistance test

• Begin a boosted PI-based regimen

– PI resistance is less common than NRTI and NNRTI resistance

– Consider a PI with a greater threshold for resistance

• Simplify therapy when the resistance test results are available

The Body PRO


44

ConclusionsConclusions

• Genotypic resistance testing should be obtained before prescribing an antiretroviral combination in a treatment-naive patient.

• In the presence of mutations, the antiviral combination prescribed should contain three fully active drugs, or a boosted protease inhibitor and one or two additional fully active drugs.

• If an antiretroviral combination must be prescribed in the absence of resistance test results, start with a boosted PI-based combination and modify therapy when results are available.

primary drug resistance and strategies for first-line hiv treatment this activity is supported by an...

Documents

line hiv treatment

antiretroviral guidelines

transmitted drug resistance

treatment response

antiretroviral therapyadapted

medical center aids

hiv research agenda

agendareview dhhs guidelines