new treatment paradigms for therapeutically-naïve and treatment-experienced hiv patients a...

New Treatment Paradigmsfor Therapeutically-Naïve and Treatment-Experienced

HIV Patients

A Customized CME Learning Experience

Learning Needs Assessment Survey Among Treatment Providers for HIV

Experienced and Naïve Patients in the US

Summary of Results

Disclosures

Linda Raichle, PhD, FACME

President of Spectrum Medical Education, an instructional design company specializing in CME

Nothing to disclose

Vasant Kumar, MA, MBA

President of Scriplogix, an international healthcare information services company

Nothing to disclose

Survey

Rationale

Conduct a national needs analysis to identify learning gaps, guideline awareness, learning preferences, etc., among HIV treaters

Design learner-centric, customized educational programs specific to the needs of the learner

Method & Sample Demographics

A combination of 22 in-depth interviews and 150 web-based surveys among treaters of HIV across the USA form the basis of this study

The qualitative component informed the design of the study

The quantitative component provided the detailed analysis of the study

91% MDs and 9% DOs

58% practice in an urban setting, 32% semi-urban

9% NY, 8% NJ, 8% PA 13% CA, 7% each from FL, TX, MI

Number of patients see a month

– 66% < 100

– 24% < 200

– 9% > 200 per month

Awareness of Treatment Guidelines for HIV (N=150)

Organization Awareness Adherence First Choice

Infectious Disease Society of America (IDSA)

87% 84% 39%

U.S. DHHS 79% 75% 37%

International AIDS Society -USA

78% 65% 17%

US –CDC 65% 61% 3%

WHO 49% 34% 1%

American Medical Association

32% 28% 0%

(N=150) (N=150) (N=150)

Does a Gap Exist Between Treatment Guidelines and Practice? (N=150)

Response % RespondingStrongly Agree 3%

46%Agree 43%

Neither Agree nor Disagree 27% 27%

Disagree 26%

27%Strongly Disagree 1%

Total 100% 100%

CME Programs “Bridging” the Gap Between Guidelines and Practice? (N=150)

Response % Responding

Strongly Agree 8% 70%

Agree 62%

Neither Agree nor Disagree 25%

Disagree 1%

Strongly Disagree 3%

Total 100%

Priority of Information Sources (N=150)

Source 1st 2nd 3rd Top Three

Journals 53% 30% 12% 95%

CME Conferences

25% 22% 42% 89%

Professional Society Resources

17% 41% 30% 86%

Other 4% 3% 8% 15%

Pharma Reps

1% 4% 7% 11%

Total 100% 100% 100%*

* Column does not total to 100% due to rounding

Percentage of Respondents Having Experience Using Selected HIV Treatments (N=150)

Category # % Using

Boosted Protease Inhibitors (PIs)

143 95%

Entry Inhibitors 90 60%

Integrase Inhibitors (raltegravir – RAL)

89 59%

Newer NNRTI’s (etravirine – ETV)

69 46%

Coreceptor Inhibitors (CCR5) (maraviroc – MVC)

68 45%

Comfort Level with HIV Treatments

Category Comfort Level in Percentages Sample

High Medium LowBoosted Protease Inhibitors

86% 13% 1% 143

Entry Inhibitors *

43% 52% 4% 90

Integrase Inhibitors

45% 52% 3% 89

Newer NNRTI’s

41% 52% 7% 69

Coreceptor Inhibitors

26% 66% 7% 68

*Rows don’t total to 100% due to rounding

Ranking of Preferences of Topics for HIV/AIDS Learning Events (Aided Responses) (N-150)

Topic 1st 2nd 3rd Top 3

Newer treatment options/guidelines (ie, ART naive/experienced patients)

54% 23% 11% 88%

Salvage therapy, ART resistance issues and interpretation of resistance profiles – intelligent use of emerging ART drug classes and agents

31% 39% 12% 82%

ART drug toxicity, drug interactions, adherence and compliance with HIV medications

2% 14% 37% 53%

Coinfections (TB, HCV, HBV, MRSA) 2% 3% 17% 22%

Prevention of HIV infections 5% 6% 5% 16%

Recent advances in diagnosis and monitoring 1% 6% 7% 14%

Clinical manifestations 2% 3% 7% 12%

HIV in special populations (pregnancy, migrants, inmates, etc.)

1% 2% 5% 8%

Ranking of Preferences of Learning Formats (N=150)

Format 1st 2nd 3rd Top Three

Live – Didactic Event

43% 23% 15% 81%

Case-Based Discussions

32% 39% 15% 86%

Web-Based Blogs - Webinars

9% 7% 17% 33%

Text Manuals 5% 11% 18% 34%

Peer Consults 7% 9% 21% 37%

Illustrative Guides, Monographs

5% 11% 14% 30%

Total 100%* 100% 100%

*Column does not total to 100% due to rounding

Thank you!


HIV Patients


Salvage Therapy and Resistance Issues

Alexander A. McMeeking, MDAssociate Professor of Medicine

New York University Medical CenterNew York, New York

Strategies for Treatment-Experienced Patients

Current challenges in experienced patients

Approved drugs

Investigational drugs

Advantages and concerns about NRTI combos

Change or wait if virus not suppressed?

Strategies for Treatment-Experienced Patients

Treatment failure results in emergence of drug-resistant viruses

Drug class experience diminishes the future response to drugs in the same class

The challenge is in finding active drugs

– there are new drugs that may have activity despite resistance to other drugs in the same class

– advantage to have drugs in new classes

– best approach is to have at least 2 active drugs

Goals of Therapy With Multidrug Resistant (MDR) HIV

Patients with access to ≥2 active agents

– complete viral suppression

Patients with access to <2 active agents

– reduce viral load by 1 log10 copies/mL

– stabilize CD4+ cell counts

– minimize drug toxicity

– minimize mortality

– minimize accumulation of additional mutations that could cause resistance to drugs in development

Goals of Therapy for Treatment- Experienced Patients

1. DHHS Guidelines. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed June 3, 2008.

2. Hammer SM, et al. JAMA. 2006;296:827-843.

“The goal of treatment for patients with prior drug exposure and drug resistance is to re-establish maximal virologic suppression, HIV RNA <50 copies/mL”

— US DHHS Guidelines, January 29, 20081

“Trials with newer antiretroviral agents have shown that it is possible to achieve plasma HIV-1 RNA levels below 50 copies/mL even in highly treatment–experienced patients”

—IAS-USA Guidelines, August 20062

Assessing Active Agents

Genotypic and/or phenotypic resistance testing

– assess susceptibility to approved agents

• genotypic scores

• phenotypic cutoffs

– review previous tests to identify archived resistance

Integrase inhibitors and enfuvirtide presumed fully active in previously unexposed patients

Tropism testing to assess activity of CCR5 antagonists

– active in patients with detectable R5 virus only

Is Viral Load <50 Achievable in Treatment-Experienced Patients

With MDR HIV? Consider emerging treatment options and need

for immediate enhancement of current regimen (ie, risk of clinical progression)

Assess abilityto adhere to futuretreatment options

Availableactive agents

Except in extraordinary circumstances, adding

only 1 drug shouldbe avoided

Preferably ≥2 fully active agents

needed

Thorough assessmentof current and

past resistance

Treatmenthistory

Assessment of tropism

In Combination Therapy, Only the Active Drugs Count

Early “HAART” in NRTI-experienced patients often amounted to “serial monotherapy”

– new drugs (eg, PIs) added to a failing NRTI-based regimen

– fewer sustained responses with only 1 active drug

TORO results demonstrated applicability of this principle to the use of enfuvirtide (ENF)

Several recent studies demonstrate that, in triple-class-experienced patients, combining ENF + an active boosted PI improves response rate

TORO 1 and TORO 2 Study Design

*VF, criteria for virologic failure based on 2 consecutive values:

<0.5 log10 decrease from baseline starting at Weeks 6 and 8

<1.0 log10 decrease from baseline starting at Weeks 14 and 16

2 log10 response and > 1 log10 rebound at any time

Switch permittedVF* or at Week 48

Enfuvirtide (90 mg SC BID) + OB regimen

-6

Stable regimen

Screening period

OB alone

-4

GT/PT

Randomized 2:1

BL 8 16 24 48Weeks 96

TORO: Impact of Number of Active Agents on Response

Henry K, et al. International AIDS Society (IAS) Meeting. Dec 6, 2002. St Paul, MN. Abstract # LbOr19B.

Number of Active Antiretrovirals in OB Regimen(Genotypic Sensitivity Score)

ENF + OBOB

0 1-2 3-4 5

-2.0

-1.0

0

-3.0

Mea

n c

han

ge

in H

IV-1

RN

A

at W

eek

24 (

ITT

)(l

og

10 c

op

ies/

mL

)

CPI armLPV/r, IDV/r, SQV/r, APV/r

TPV/r arm

RESIST: Phase 3 Study of TPV/r

*Entry criteria: ≥1 primary PI mutation: 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V, or 90M; ≤2 mutations: 33, 82, 84, or 90.†CPI=comparator PI; OBR=optimized background.

Computerizedrandomization to OBR plus:

Best PIchoice Wk 48

Interim analysis,Wk 24

Failures in CPI arm after Wk 8 eligible for TPV/r in rollover study

Baseline genotypic

resistance testing*

Patients failing PI-containing

HAARTVL >1000Any CD4+

HIV-resistance

expert panel

Preselection of regimen

by investigator:CPI + OBR†

(± enfuvirtide)

1. Hicks C, et al.44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Oct 30 –Nov 2, 2004. Washington, DC. Abstract # 1137a.

2. Cahn P, et al. International Congress on Drug Therapy (ICDT). Jan 2004. Buenos Aires, Argentina. Abstract # PL14.3.

RESIST-1: Baseline Phenotypic Susceptibility and Agents Prescribed

Baseline median VL:4.8 log10 copies/mL

Baseline CD4+ cell count:123 cells/mm3

30% uptake of expert advice

Preselected comparator PIs:

– LPV/RTV: 61.0%

– IDV/RTV: 4.4%

– SQV/RTV: 20.6%

– APV/RTV: 14.0%

Enfuvirtide included in regimen: 36.1%

1.9

77.8

39

27.2

12.2

0

20

40

60

80

TPV LPV IDV SQV APV229 231 227 229 228n =

Med

ian

bas

elin

e F

C in

IC5

0

Hicks C, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Oct 30 –Nov 2, 2004. Washington, DC. Abstract # 1137a.

RESIST-1: Response to TPV/r vs CPI/r

Patients With HIV- 1 RNA <400 copies/mL

Patients With HIV- 1 RNA <50 copies/mL

0 4 8 12 16 20 24

0

100

40

60

80

20

0 4 8 12 16 20 24

Pat

ien

ts (

%)

16.5%

34.7%

TPV/r (n = 311)CPI/r (n = 309)

Week

ITT: NC=F

25.1%

10.0%

P<.001

Week

P<.0010

100

40

60

80

20P

atie

nts

(%

)

Hicks C, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Oct 30 –Nov 2, 2004. Washington, DC. Abstract # 1137a.

RESIST: Impact of Enfuvirtideon Virologic Response

ENF use comparable in both arms

– 27.1% TPV/r

– 22.2% CPI/r

ENF use improved treatment response in both arms

However, TPV/r superior to CPI/r with or without ENF

Deeks S, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract # WeFo0201.

No ENFENF

13.4

21.3

CPI/r0

20

40

60

80

100

Pat

ien

ts w

ith

HIV

-1 R

NA

<40

0

cop

ies/

mL

at

Wee

k 24

(%

)

30.2

53.9

TPV/r

Relationship of TPV Score to TPV Phenotype Results and Response

*24-week data from patients in RESIST-1 and -2 given TPV/r.Valdez H, et al. 14th International HIV Drug Resistance Workshop. June 7-11, 2005, Quebec City, Quebec, Canada. Abstract # 27.

-2

-1

0

-3

Med

ian

ch

ang

e in

VL

at

Wk

24*

(lo

g10

co

pie

s/m

L)

0-1 2-3 4-5 6-7 8-9

-2.10(n=144)

-0.89(n=242)

-0.45(n=260)

-0.49(n=68)

-0.08(n=4)

TPV Score

Median FC: 0.7-0.9 1.1-1.4 2.0-3.1 3.3-3.9 14.7-52.5

POWER 1: Efficacy and Safety of TMC114/r in PI-Experienced Patients

Ongoing 96 week randomized trial of 3-class-exp patients*

1 primary PI mutation

– BL HIV-1 RNA: TMC114/r 4.5 vs Control 4.4

– BL CD4+: TMC114/r 204 vs Control 233

Pooled interim results for POWER 1 and POWER 2 trials presented at CROI 2005

Current presentation shows data from the POWER 1 trial

TMC114 400 mg QDRitonavir 100 mg QD

(n=64)

TMC114 800 mg QDRitonavir 100 mg QD

(n=63)

TMC114 400 mg BIDRitonavir 100 mg BID

(n=63)

TMC114 600 mg BIDRitonavir 100 mg BID

(n=65)

Investigator-selected PI + OBR

(n=63)

Treatment Arms

*Katlama C, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract # WeOaLB0102.

POWER 1:Virologic Response to TMC114/r

0

80

60

20

40

100

Time (weeks)

Pat

ien

ts w

ith

HIV

-1 R

NA

<50

co

pie

s/m

L (

%)

1 2 4 8 12 16 20 24

TMC114/r 400 QD (n = 64)TMC114/r 800 QD (n = 63)TMC114/r 400 BID (n = 63)TMC114/r 600 BID (n = 65)Comparator PIs (n = 63)

P<.001 for all dosesvs control

43%48%49%53%

18%

Katlama C, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract # WeOaLB0102.

POWER 1: Subgroup Analyses of Response to TMC114/r 600/100 BID

% with HIV-1 RNA < 50 at Week 24 (ITT NC=F)

63% (n=19)22% (n = 18)

56% (n=34)19% (n = 36)

59% (n=29)

9% (n=35)

46% (n=28)16% (n=25)

17% (n=12)

0% (n=9)

ENF used (naïve)

ENF not used

3 Primary PI Mut

TMC114 FC >4

No sensitive ARV in OBR

0 20 40 60 80

TMC114/r 600/100 BIDControl

53% (n=60)18% (n=60)

Overall

100

*Katlama C, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract # WeOaLB0102.

Next-Generation NNRTI: Etravirine Unique Molecular Flexibility

Member of a new family of diaryl pyrimidine (DAPY) compounds

Etravirine binds to a narrow pocket close to the active site of RT

Flexible and compact molecule

Can bind in different conformations

Binding can accommodate common NNRTI-selected mutations

Flexibility may account for unique resistance profile

De Kerpel, et al. 224th American Chemical Society (ACS) National Meeting. Aug. 18-22, 2002. Boston, MA. Abstract # 560279.Das K, et al. J Med Chem. 2004;47:2550-2560.

DUET-1 and -2: Baseline ETR Mutations and Virologic Response at Week 24

13 mutations associated with ETR resistance

– V90I – A98G

– L100I – K101E/P

– V106I – V179D/F

– Y181C/I/V – G190A/S

Presence of ≥3 ETR mutations associated with response similar to overall placebo + OBR response

– 70% of patients had 0 or 1 ETR resistance mutations at BL

– 14% of patients had ≥3 ETR resistance mutations at BL

Kahn P, et al. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2007. Chicago, Ill. Abstract # H-717 .

1725

0 1 2 3

Pat

ien

ts W

ith

HIV

-1 R

NA

<

50 c

op

ies/

mL

(%

)0

20

40

60

80

100

≥4No. of BL ETR Mutations

Patients (%) 40 30 16 8 6

75

60 58

41

25

DUET-1 and -2 Pooled Analysis

ETR + OBRPlacebo + OBR

4438

25

K103N at Baseline Did Not Affect Virologic Response to Etravirine + BR at Week 24

K103N―the most prevalent NNRTI mutation at baseline in the DUET studies―K103N―the most prevalent NNRTI mutation at baseline in the DUET studies―

AT-TLOVR = as-treated time to loss of virologic response; BR = background regimen

Etravirine + BR(n=565)

Absent(n=379)

62.5% 59.9%67.7%

0

20

40

60

80

100

Pat

ien

ts (

%)

wit

h H

IV-1

RN

A

<50

co

pie

s/m

L a

t W

eek

24

(AT

-TL

OV

R)

Present(n=186)

Overall K103N at baseline

Vingerhoets J, et al. 11th European AIDS Conference (EAC). October 24-27, 2007. Madrid, Spain. Abstract # P7.3/05.

AT-TLOVR: as-treated time to loss of virologic response.*Based on the IAS-USA list of NNRTI mutations (2007): V90I, A98G, L100I, K101E/P, K103N, V106A/I/M, V108I, V179D/F, Y181C/I/V, Y188C/H/L,G190A/S,P225H.

Pat

ien

ts (

%)

wit

h H

IV-1

RN

A

<50

co

pie

s/m

L a

t W

eek

24

(AT

-TL

OV

R)

Overall

Y181C + ≥3(n=53)

Placebo+ BR

(n=593)

IAS-USA NNRTI Mutations at Baseline*

20

60

40

100

80

0Y181C + 0

(n=18)Y181C + 1

(n=48)Y181C + 2

(n=53) Etravirine

+ BR(n=565)

62.5%55.6%

60.4%

39.6% 39.6%41.8%

Decrease in Virologic ResponseY181C Conferred a Decreased Virologic Response Comparable

to Placebo Only in Combination With 2 or More AdditionalNNRTI Mutations* at Baseline

Vingerhoets J, et al. 11th European AIDS Conference (EAC). October 24-27, 2007. Madrid, Spain. Abstract # P7.3/05.

Randomization 1:2:2

MOTIVATE 1 (n=601)MOTIVATE 2 (n=475)

OBT + maraviroc (150 mg† BID)

OBT + maraviroc (150 mg† QD)

OBT + placebo

MOTIVATE 1 and 2: Maraviroc for Salvage Therapy (24-week Results)

R5 HIV infection; HIV RNA ≥5000 c/mL; stable pre-study ARV regimen, or no ARVs for ≥4 weeks

Resistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)

– 44% screened out as D/M or X4

Baseline CharacteristicsBaseline Characteristics

PBOM1 / M2

MVC QDM1–M2

MVC BIDM1–M2

n 118 / 91 232 / 182 235 / 191

CD4+ (cells/mm3)

163 / 174 168 / 174 150 / 182

HIV RNA(log10 c/mL) 4.84 / 4.89 4.85 / 4.87 4.86 / 4.84

OBT 2active drugs

66 / 66% 69 / 63 76 / 62

ENF in OBT 42 / 45% 43 / 37 46 / 39

†Patients receiving a PI (except TPV) and/or DLV in their OBT received 150 mg dose of MVC; all other patients received 300 mg dose of MVC.

1. Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 104aLB. 2. Lalezari J, et al. Ibid. Abstract # 104bLB.

MOTIVATE 1 and 2: Maraviroc in ARV-Experienced Patients (24-Week Results)

Mean Change from Baseline

PBOM1 / M2

MVC QDM1 / M2

MVC BIDM1 / M2

HIV RNA (log10 copies/mL)

-1.03/0.93

-1.82/1.95

-1.95/1.97

CD4+ (cells/mm3) 52/64 107/112 111/102

*P=.0006; **P<.0001; †P<.0001; ††P=.0005 vs control.

% HIV RNA <50 copies/mLat 24 weeks

24.6

42.2

48.5

20.9

45.640.8

0

10

20

30

40

50

60

PBO MVC QD MVC BID

M1M2 *

**†

††


HIV RNA <50 c/mL by No. of Active Drugs in OBT

MOTIVATE 1 and 2: Maraviroc in ARV-experienced Patients (Combined 24-week Results)

No clinically relevant difference in safety profile between MVC and PBO– no significant increase in liver toxicity/malignancies in MVC groups

Caution with interpretation of >3 active drug subset– subset off ART at entry not separated to assess impact on BL

resistance OBT = zero group showed difference favoring MVC BID

0

20

40

60

80

100

35 51 56 44 130 134 59 88 104 64 132 121

3

1829

9

43 43

19

52 53 5561 58

0 1 2 ≥3

Pat

ien

ts (

%)

N=

PBO + OBTMVC QD + OBTMVC BID + OBT


Viral Tropism Testing The tropism of a strain of HIV refers to the coreceptor,

CCR5 or CXCR4, which that strain requires to enter and infect a CD4 cell

Tropism testing helps determine the usefulness of therapy with a CCR5 inhibitor

One test is FDA approved to determine the tropism of HIV

– the FDA approved Monogram Bioscience’s Trofile Assay in August, 2007

– viral load must be >1000 copies/mL for testing

– to detect X4 virus 100% of the time, 10% or more of the sample tested would need to be X4 tropic

Prevalence of R5 Use by BaselineCD4 and HIV RNA Levels

71

92 89

60

8584

67

80 81

58

8278

Pre

vale

nce

of

R5

use

(%

)

Baseline CD4 (cells/mm3)Baselin

e HIV R

NA

(copies/mL)

>5-50K

>100K

<5K

100

80

60

40

20

0

>50-100K

N=563Moyle G, et al. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC. October 30-November 2, 2004. Abstract # H-1135.

≤100 101-300

≥300

*Gulick R, et al. 16th International AIDS Conference (IAC). Aug. 13-18, 2006. Toronto, Canada. Abstract # THLB0217.

Tropism Testing Proven negative predictive value

– identifies patients not likely to benefit from CCR5 antagonist

Detects X4 virus with 100% accuracy when X4 comprises ≥10% of viral population

– 83% accuracy when ≥5% of population

Success rate of amplification drops when VL <1000 copies/mL

Tropism evolves over time

– in one trial, 10% of samples rated as D/M-tropic at study entry, after rating them all R5-tropic at screening a few weeks before*

R5

Virus uses CCR5 coreceptors

to enter the CD4+ cell

D/M X4

Activity of CCR5 antagonist anticipated

BENCHMRK 1 and 2: Study Design – Raltegravir

2 identical ongoing Phase III randomized, double-blind, placebo controlled studies (in different countries) of integrase inhibitor

RAL 400 mg BID vs placebo (randomized 2:1)

– all in combination with optimized background therapy (OBT)

– selected investigational ART permitted as OBT; DRV allowed Key inclusion criteria:

– documented genotypic/phenotypic resistance to 1 drug in each of 3 classes (NNRTI + NRTI + PI)

– HIV RNA >1000 copies/mL Endpoints at Week 16:

– HIV RNA and CD4+ counts

– primary endpoint (%<400 copies/mL, noncompleter = failure)

– adverse experiences DSMB monitored study Patients virologically failing after 16 weeks of therapy could enter an open-label

raltegravir arm1. Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788. 2. Steigbigel R, et al. Ibid, #105bLB.

HIV RNA and CD4+ Response(BENCHMRK 1)1†

Effect of Background Regimen(BENCHMRK 1 & 22)

0 20 40 60 80 100

% patients <400 c/mL

43

87

63

55

29

79

98

90

90

74

447

44

42

80

191

230

23

24

47

90

n

RAL + OBTPBO + OBT

Overall

ENF* DRV*

+ +

+ -

- +

- -0 2 4 8 12 16 24

Weeks

-2

-1

0

Δ i

n H

IV R

NA

fro

m B

L

(lo

g1

0 c

op

ies/

mL

)

0

50

100

Δ i

n C

D4+

fro

m B

L

(cel

ls/m

m3)

CD4+RAL n= 231 228 150PBO n= 118 112 77

HIV RNARAL n= 232 225 155PBO n= 118 113 77

BENCHMRK 1 and 2: Secondary Analyses

*First use of ENF or DRV.†BENCHMRK 2 showed similar results.1. Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788. 2. Steigbigel R, et al. Ibid, #105bLB.

Raltegravir Resistance:In Vitro and Clinical Trials

Mutations observed in the HIV-1 integrase coding sequence that contributed to raltegravir resistance generally involved 1 of 2 genetic pathways

– an amino acid substitution at either Q148(changed to H, K, or R)

or

– an amino acid substitution at N155 (changed to H)

– plus one or more additional substitutions (ie, L74M/R, E92Q, T97A, E138A/K, G140A/S, V151I, G163R, H183P, Y226/D/F/H, S230R, and D232N)

– substitution at Y143C/H/R is another pathway to raltegravir resistance

BENCHMRK 1 and 2: Secondary Analyses% Patients with HIV RNA <400 copies/mL at Week 16 by PSS/GSS of OBT*

GSS=genotypic sensitivity score; PSS=phenotypic sensitivity score.*BENCHMRK 1 & 2 with virologic failures carried forward.

15970

17093

11163

222110

14168

6244

447230

n

≥2

1

0

GSS

≥2

1

0

PSS

Overall efficacy data

Subgroup

79

43

61

5

41

87

79

57

1057

85

89

71

43

% patients

RaltegravirPlacebo

0 20 40 60 80 100

1. Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788. 2. Steigbigel R, et al. Ibid, #105bLB.

BENCHMRK-1 and -2 Combined Efficacy*

*Virologic failures carried forward.The analysis by PSS score has been reanalyzed using the upper cutoff to better account for the impact of partial ART activity. Isolates with fold-change IC50 above the lower but below the upper cutoff are now reported as “partially sensitive.” The upper cutoff was developed because the lower cutoff may underestimate partial ART activity in a regimen. At the time the BENCHMRK studies were initiated, only the lower cutoff was reported. The efficacy by PSS has been reanalyzed using the upper cutoffs, where available, to better account for the impact of partial ART activity. At all levels of PSS, the results using the upper and lower cutoffs are similar, confirming the contribution of raltegravir in the treatment regimen.

Percent of Patients With HIV RNA <50 copies/mL at Week 48 by PSSBased on Upper and Lower Cutoffs

Percent of patients

NPSS

0 (based on lower cutoff )

0 20 40 60 80 100

51

52

61

48

71

70

2

8

29

13

48

43

65

33

137

71

221

313

44

12

69

54

108

153

Raltegravir + OBT Placebo + OBT

0 (based on upper cutoff )

1 (based on lower cutoff )

1 (based on upper cutoff )

≥2 (based on lower cutoff )

≥2 (based on upper cutoff )

Treatment Strategies in Experienced Patients: Role of NRTIs

Evidence for partial activity of NRTIs even with key resistance mutations present, eg, 3TC and d4T

M184V can confer improved phenotypic susceptibility to TDF and ZDV in viruses with TAMs and K65R

TDF and D-d4FC active against virus strains with TAMs

Both can select for K65R; ZDV shows hypersusceptibility

Strategic use of NRTI combinations possible

– TDF - FTC - ZDV

– TDF - ZDV - D-d4FC1. Walmsley S, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). Feb. 22-25,

2005. Boston, MA. Abstract # 580.2. Ruiz L, et al. Ibid. Abstract # 679.

Partial Treatment Interruption Demonstrates Residual NRTI Activity

Deeks SG, et al. 10th Conference on Retroviruses and Opportunistic Infections (CROI). Feb. 10-14, 2003. Boston, MA. Abstract # 640.Deeks SG, et al. J Infect. Dis. 2005;192:1537-1544.

Discontinue PIs, continue NRTIs (n=15)Discontinue NRTIs, continue PIs (n=5)

100

50

0

-50

-100

-150Wk 8 Wk 12 Wk 16

Ch

ang

e in

HIV

-1 R

NA

(l

og

10 c

op

ies/

mL

)

1.5

1.0

0.5

0

-0.5Wk 8 Wk 12 Wk 16

Ch

ang

e in

CD

4+ C

ell C

ou

nt

(cel

ls/m

m3 )

Castagna A, et al. 3rd IAS Conference on HIV Pathogenesis and Treatment. July 24-27, 2005. Rio de Janeiro, Brazil. Abstract # WeFo0204.

-300

-250

-200

-150

-100

-50

0

0

0.5

1.0

1.5

2.0

4 12 24 36 48

Mea

n c

han

ge

in H

IV-1

RN

A (

log

10 c

op

ies/

mL

)

Weeks

Mea

n c

han

ge

in C

D4+

ce

ll c

ou

nt

(ce

lls/

mm

3)

Weeks

4 12 24 36 48

P=NS

Mean CD4+ Decrease (ITT)Mean VL Increase (ITT)

P=.0015

3TC Alone vs Treatment Interruption in Patients Failing 3TC-Based HAART

In contrast to treatment interruption arm, 3TC alone resulted in:– smaller recovery in replication capacity– no further selection of resistance mutations

3TCTI

3TCTI

When To Use a New Drug, and When to Wait

Is there at least 1 new class available, and if so, will it be well “protected”?

What is the expected prognosis with continued nonsuppressive therapy?

– what are the resistance consequences of continued nonsuppressive therapy?

How can I maintain the “right” mutations without allowing the “wrong” ones to emerge?

When will new drugs be available, and will they be active against the patient’s virus?

Options If New Drugs Are Not Available

Multidrug Salvage Therapy (“mega-HAART”)

Difficult due to problems with tolerability and interactions

Dual-boosted PI Therapy

SQV (1000 mg BID) + LPV/r (400/100 mg BID): encouraging responses at Week 48(noncomparative studies)

Can have intolerable GI effects; ↑ risk of lipid abnormalities

Pharmacologic interactions not always predictable

Nonsuppressive Regimens

Risk of emergence of new resistance mutations

Potentially less response when new drugs approved in same class

Options If New Drugs Are Not Available (con’t)

Switch to a “Holding Regimen”

Maximal negative impact on viral fitness (ie, replication capacity)

Minimal risk of added resistance

Monotherapy with 3TC or FTC

Over 6 months, lower virologic rebound and less CD4+ loss

M184V linked to other mutations, reduce emergence of WT virus

Treatment Interruption (TI)

No clear evidence of improved response after TI

Risk of rapid CD4+ cell decline and increased risk of OIs

– potentially dangerous in advanced disease (CD4+ <200)

Continued Therapy in Patients With Virologic Failure: A Delicate Balance

Maintain mutations

Decrease fitness

Delay progression

Accumulate new mutations

Develop resistance to drugs in development


HIV Patients


New Therapeutic Agents and New Therapeutic Agents and Treatment GuidelinesTreatment Guidelines

Bruce Polsky, MDInterim Chairman, Department of Medicine

Chief, Division of Infectious DiseasesSt. Luke’s and Roosevelt Hospitals

New York, New York

Panel CD4 Count

US DHHS

June 1998 <500

February 2001 <350

April 2005 <200

International AIDS Society – USA Panel

July 1998 Any

January 2000 <500

July 2004 200

British HIV Association (BHIVA)

June 1998 >350

July 2003 201-350

July 2005 <200

Guidelines for Initiating Antiretroviral Therapy in Asymptomatic Patients:

1998–2005

The Rationale for Earlier Therapy

Easier, more effective, and less toxic therapy

Treatment Responses in First Year of HAART: Improving Over Time

4143 subjects from 5 clinic cohorts in Europe and Canada

Treatment-naïve; started HAART from 1996-2002

risk of virologic failure, med CD4 count increase in later years

– most “failure” now due to loss to follow-up or treatment discontinuation

Lampe F, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA. Abstract # 593.

24.8 23.017.3

12.4 10 8 8.4

1996 1997 1998 1999 2000 2001 2002

% with > 500 copies/mL

0

20

40

60

80

100

% w

ith

VL

>50

0 o

n A

RT

0

30

60

90

120

150

Med

ian

CD

4 in

crea

se

97

119 120 121127 125

150Median CD4 increase

Incidence of Second Virologic Failure Declining Over Time

30

90

0

60

120 RR*=1.46

RR*=0.54

Inci

den

ce p

er 1

00 P

Y

RR*=0.51

RR*=0.82

REF

1998-1999

2004-2005

1996-1997

2000-2001

2002-2003

*Adjusted for time from HAART initiation, sex, age, AIDS, CD4 count, VL at HAART initiation and switch, and type of HAARTDeeks S, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 41.

113.6

15.117.9

41.5

70.7

Decline in New Cases of Resistance British Columbia: 1996-2007

Decline in new cases of resistance in province-wide data from BC Centre for Excellence in HIV/AIDS Drug Treatment Program

– 21,300 resistance tests from 5216 subjects

Year2008200620042002200019981996

New

cas

es o

f d

etec

ted

re

sist

ance

(n

)

0

600

500

400

300

200

100

3TCNRTINNRTIPIAny

Lima VD, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 895.

Pro

po

rtio

n S

urv

ivin

g

MonthsAIDS Surveillance Report, 2004. http://www.cdc.gov/hiv/topics/surveillance/resources/slides/epidemiology/index.htm.

Proportion Surviving FollowingAIDS Diagnosis: 1996–2003

0 12 24 36 48 60 72 84 96 108

1.00

0.75

0.50

0.25

0.00

20032002

20012000

19991998

19971996


Easier, more potent, and less toxic therapy

Cohort studies showing benefit with earlier therapy

HAART and Survival Based on Initial CD4 Cell Count

Modeled data from ART Cohort Collaborative

10,855 patients included

934 progressed to AIDS or died

IDUs excluded from model

Sterne J, et al. 13th Conference on Retroviruses and Opportunistic Infections (CROI). February 5-8, 2006. Denver, CO. Abstract # 525.

<200 vs 201-350

<350 vs351-500

Hazard ratio for AIDS (95% CI)

3.68(3.01-4.51)

1.52 (1.10-2.10)

Hazard ratio for AIDS or death (95% CI)

2.93(2.41-3.57)

1.26(0.94-1.68)

Cumulative Probability of AIDS/Death According to CD4 Count at Initiation of HAART

Years since initiation of HAART0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Pro

ba

bil

ity

of

AID

S o

r d

ea

th

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3




Better response to therapy

Pre-HAART CD4 Predicts Progression to AIDS: Johns Hopkins Cohort

Johns Hopkins HIV Cohort

Patients with virologic suppression for up to 6 yrs (N=280)

Only patients with baseline CD4 >350 returned to near normal CD4 count levels

Rate of progression to AIDS or death significantly higher over time in patients with CD4 <200 and 201-350 vs >350

*percent developing AIDS over 6 years of study†P<.05 compared with CD4+ <200.Moore RD, et al. 16th International AID Council (IAC). August 13-18, 2006. Toronto, Canada. Abstract # THPE0109.

0

100

200

300

400

500

600

700

800

900

0 1 2 3 4 5 6

CD

4 ce

lls/m

m³

13%*

12%*

1.5%*†

Year

> 350 cells/mm3

201-350 cells/mm3

< 200 cells/mm3





Decreased transmission

Viral Load Affects Probabilityof HIV Transmission

GUD=genital ulcer diseaseGray R, et al. Lancet. 2001;357:1149-1153.

Log viral load (copies/mL)

GUDNo GUD

0

1.0

2.0

3.0

4.0

5.0

<1700 1700- 12500- 38500+

Pro

bab

ilit

y o

f tr

ansm

issi

on

/10

00 c

oit

al a

cts






Prevent specific complications of HIV infection

HIV-Associated Complications That Are Less CD4-Dependent

Neurocognitive impairment

Non-Hodgkin’s lymphoma

Neuropathy

HPV-associated dysplasia/cancer

Kaposi’s sarcoma






Prevent specific complications of HIV infection

Prevent non-opportunistic complications and death

D:A:D Study: CD4 Count Associated with Risk of Non-HIV Related Death

Cohort of >23,000 pts in Europe, Australia, USA

1248 (5.3%) deaths 2000–2004 (1.6/100 person-years)

– of these, 82% on ART

Weber R, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA. Abstract # 595.

RR of death according to immune function and specific cause

1.0

10

100

0.1

RR

>500<50 50-99

100-199

200-349

350-499

CD4 cells/mm3

OverallHIVMalignancyLiverHeart

Risk of Death in Naïve Patients with CD4 Counts >350

24 cohorts and collaborations

Mortality in naïve patients w/ CD4 >350 higher than in matched general population controls

487 deaths; 4.9/1000 patient-years– HIV-related deaths: 79 (16.2%)– non-HIV–related deaths: 235 (48.3%)– unknown cause of death: 173 (35.5%)

Despite high CD4 counts, ↑ CD4 still associated with ↓ risk of death– rate ratio: 0.95 per 100 cells higher (95% CI: 0.90-0.99; P=.0185)

SMR=sex-standardized mortality ratioLodwick R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 141.

HIV Risk Group Observed Deaths Expected Deaths SMR (95% CI)

MSM 117 97.08 1.21 (1.00-1.44)

Heterosexual 82 24.63 3.33 (2.65-4.13)

Injection drug user 227 22.22 10.21 (8.93-11.63)

When to Start Therapy:DHHS Guidelines 1/9/2008

AIDS or symptomatic HIV disease

Asymptomatic:

– CD4 <350

– Pregnancy

– HIV-associated nephropathy

– HBV coinfection when HB therapy required

When to Start Therapy:DHHS Guidelines 1/9/2008

CD4 >350

– Optimal time to start therapy unknown

– Considerations:

• Motivation and adherence

• Viral load

• Rate of CD4 decline

• Risk of sexual transmission(eg, discordant couples)

• Other comorbidities

Caveats!

Data guiding the initiation of therapy come from observational studies

Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts

We may never have data from controlled clinical trials

The Pros and Cons of a Randomized Trial

PROS

Could provide the definitive answer about when to start therapy

CONS

Previous attempts to enroll such trials have failed

Expensive

Observational data already compelling

Will the question or the chosen CD4 thresholds still be relevant by the time the results are available?

Caveats!

Data guiding the initiation of therapy come from observational studies

Patients who start therapy with advanced disease may do poorly for reasons unrelated to their CD4 counts

We may never have data from controlled clinical trials

Many patients present with advanced disease

When is ART Started?CD4 Count at Initiation, 2003-2005

42 countries, 176 sites; N=33,008

Since 2000, CD4 count at initiation in developed countries stable at ~150–200, increasing in Sub-Saharan Africa from 50 to 100

In US, CD4 at initiation lower than in many other resource-rich nationsEgger M, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 62.

ACTG A5164: Improved Outcomes with Immediate ART During Acute

Opportunistic Infections Immediate vs deferred ART during acute OI

No difference in composite primary endpoint (virologic response, clinical progression, and death; P=.215)

Immediate treatment:

– less clinical progression/death through Week 48 (P=.035)

– shorter time to clinical progression or death (P=.023)

Safety and incidence of IRIS similar between groups

– ~62% of patients presented with PCP; potential impact of steroids?

Zolopa A, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 142.

When to Start During Acute Opportunistic Infections

Treat immediately

Conditions for which ART is best or only therapy:

– Progressive multifocal leukoencephalopathy

– Dementia– HIV-associated nephropathy

Kaposis Sarcoma

– Cryptosporidiosis

– Microsporidiosis

Conditions for which higher CD4 count improves prognosis

– Primary CNS lymphoma

– Non-Hodgkin's lymphoma

Consider delaying treatment

Potential for immune reconstitution inflammatory syndrome (IRIS)

– Tuberculosis

– M avium complex

– Cryptococcal meningitis

Potential for overlapping drug toxicity or interactions

– Tuberculosis

The New Drugs

DHHS Treatment Guidelines: 1/29/20082 NRTIs + Either NNRTI or PI

www.aidsinfo.nih.gov

NRTIs NNRTIs PIs

Preferred

ABC/3TC EFV ATV/r

TDF/FTC FPV/r BID

LPV/r BID

Alternative

AZT/3TC NVP ATV

Ddl + 3TC FPV

FPV/r QD

LPV/r QD

SQV/r

Targets for Antiretroviral Therapy

Reverse Reverse Transcriptase Transcriptase

InhibitorsInhibitors

Protease Protease InhibitorsInhibitors

Integrase Integrase InhibitorsInhibitors

EntryEntryInhibitorsInhibitors

PIs

NRTIs,NNRTIs

CCR5 Antagonists

Fusion Inhibitors

Antiretroviral Agents Approved in the US

NRTIs NNRTIs PIs

Zidovudine (AZT)—Retrovir

Nevirapine (NVP)—Viramune

Saquinavir (SQV)—Invirase

Didanosine (ddI)—Videx, Videx EC

Delavirdine (DLV)—Rescriptor

Indinavir (IDV)—Crixivan

Stavudine (d4T)—Zerit

Efavirenz (EFV)—Sustiva

Ritonavir (RTV)—Norvir

lamivudine (3TC)—Epivir

Abacavir (ABC)—Ziagen Nucleotide RTIs Nelfinavir (NFV)—Viracept

Emtricitabine (FTC)—Emtriva

Tenofovir DF (TDF)—Viread

Lopinavir/RTV (LPV/r)—Kaletra

Fusion Inhibitors Atazanavir (ATV)—Reyataz

Enfuvirtide (ENF, T20)— Fuzeon

Fosamprenavir (FPV)—Lexiva

Tipranavir (TPV)—Aptivus

Darunavir (DRV)—Prezista


NRTIs NNRTIs PIs















CCR5 Inhibitors Fusion Inhibitors Atazanavir (ATV)—Reyataz

Maraviroc (MVC)— Selzentry





HIV-1 Entry Inhibitors

Virus-CellFusion

gp41

gp120

V3 loop

CD4Binding

CD4

CellMembrane

CoreceptorBinding

CCR5/CXCR4(R5/X4)

CCR5 antagonistsMaravirocVicrivirocPRO140

Enfuvirtide

TNX-355

CXCR4 antagonists

CCR5CCR5

CD4CD4

CXCR4CXCR4

R5 Viruses Utilize the CCR5 co-receptor Also known as M-tropic or

nonsyncytium inducing (NSI) Transmitted variants Prevalent in early disease

X4 Viruses Utilize the CXCR4 coreceptor Also known as T-tropic or

syncytium inducing (SI) Emerge in later disease Associated with accelerated

CD4 decline and disease progression

Dual VirusesCan utilize either

co-receptor

Berger EA, et al. Nature. 1998;391:240.

T-Cell Surface

40

20

0

100

80

60

MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48P

atie

nts

(%

)

Time (wks)

16.7%

43.2%*

45.5%*

0 4 20 288 12 16 24 32 36 40 44 48

PBO + OBT (n=209)MVC QD + OBT (n=414)MVC BID + OBT (n=426)

*P<.0001 vs placeboHardy D et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 792.


NRTIs NNRTIs PIs






















NRTIs NNRTIs PIs



















Integrase Inhibitors Tipranavir (TPV)—Aptivus

Raltegravir (RAL)—Isentress


HIV Integrase Mechanism

X

Strand Transfer Inhibitors

BENCHMRK-1: Patients with Viral Load <50 copies/mL at Week 48

Pat

ien

ts (

%)

Weeks

RAL n =PBO n =

60

40

0

100

80

20

0 2 8 12 16 24 32 40 484

118 118 118 118 117 118 118232 231 231 230 229 232 229

118230

118231

33%

P<0.001

62%

31%

P<0.001

65%

Cooper DA , et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788.

Raltegravir (RAL) vs Efavirenz (EFV) in ART-Naïve Patients

Pts randomized to TDF/3TC + EFV or RAL at 100, 200, 400 or 600 mg BID

– mean VL 4.6–4.8 log c/mL

– mean CD4 271–338

Adverse events similar

– more CNS AEs with EFV

– lower TC, LCL, TG with RAL

Markowitz M, et al. 4th International AIDS Society (IAS) Conference. July 22 – 25, 2007. Sydney, Australia. Abstract #TUAB104.

100

80

60

40

20

002 4 8 12 16 24 32 40 48

Week

RAL100 mg BID (n=39)RAL 200 mg BID (n=40)EFV 600 mg QD (n=38)

RAL 400 mg BID (n=41)RAL 600 mg BID (n=40)

Pts

wit

h V

L <

50 c

/mL

(%

)

VL <50 c/mL (95% CI) [NC=F]


NRTIs NNRTIs PIs










Lamivudine (3TC)—Epivir













NRTIs NNRTIs PIs










Lamivudine (3TC)—EpivirEtravirine (ETR)— Intelence












(February, 2008)

DUET-1 and -2: VL <50 at Wk 48 Mean CD4 change at Week 48 significantly greater in

ETR arm: +98 vs +73 1,2

1. Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 790.

2. Johnson M et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 791.

Time (wks)

VL

< 5

0 c/

mL

at

Wk

48(%

± 9

5% C

I)

ETR (n=599)

PBO (n=604)

0 20 484032242 4 8 12 16

20

0

60

80

40

61%

40%

P<.0001

ITT-TLOVR

MOTIVATE 1 and 2: VL <50 at Wk 24 byNo. of Active Drugs in OBR

No. of active drugs in OBR

0

20

40

60

80

100

35

51

56

44

130

134

59

88

104

64

132 121

3

18

29

9

43 43

19

52 53 5561 58

0 1 2 ≥3

Pat

ien

ts (

%)

N =

Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 104aLB.Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Feb 25-28, 2007.Los Angeles, CA. Abstract # 104bLB.

PBO + OBRMVC QD + OBRMVC BID + OBR

0 20 40 60 80 100

BENCHMRK-1 and -2: Undetectable VL at Week 48, Overall, and by Genotypic

Sensitivity Score RALPBO

By GSS:

65

166

68

443

112

158

0

1

≥2

n

Patients (%)

228

92

6434

453

3767

5975

Overall

Cooper DA, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 788.

DUET-1 and -2: Viral Load <50 at Wk 48,by Active Agents in OBR

1. Haubrich R, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 790.

2. Johnson M, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 791.

3. Winters B, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI). February 3-6, 2008. Boston, MA. Abstract # 873.

VL

< 5

0 c/

mL

at

Wk

48 (

%)

20

0

40

60

80

100

33

60

26

76

61

12/36

121/203

51/196

229/300

187/305

0/35

0 1 2Number of active agents in OBR by PSS

(DRV active if FC <40)

ETR (n=599)Placebo (n=604)

The Goal of Therapy

The goal of therapy is virologic

suppression to <50 copies/mL in

all patients.

DHHS & IAS-USA Guidelines

The goal of therapy is virologic

suppression to <50 copies/mL in

all patients.

DHHS & IAS-USA Guidelines

1. US Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/guidelines. Accessed May 7, 2007.

2. Hammer S, et al. JAMA. 2006;296:827-843.


HIV Patients


Treatment of HCV in HIV Disease:Treatment of HCV in HIV Disease:New Challenges, New PromiseNew Challenges, New Promise

Douglas T. Dieterich, MDProfessor of Medicine

Division of Liver Diseases,Gastroenterology, and Infectious Diseases

Department of MedicineMount Sinai School of Medicine

New York, New York

Worldwide Prevalence: Percent of HIV Patients Who Are Coinfected With HCV

1Soriano V, et al. AIDS. 2002;16:813-826.2Chanbancherd P, et al. Southeast Asian J Trop Med Public Health. 2003;34:580-582.

United States30%1 Spain

50%1

Western Europe33%1

Thailand~50%2

Disease Burden in the United StatesDisease Burden in the United States

1CDC: Acute Hepatitis C/NANB Hepatitis, 2004. Available at: www.cdc.gov/ncidod/diseases/hepatitis/resource/PDFs/hep_surveillance_61.pdf. Accessed Dec. 10, 2007.

2CDC: Hepatitis C Fact Sheet. Available at: www.cdc.gov/hepatitis. Accessed Dec. 10, 2007.3CDC. HIV/AIDS fact sheet. Available at: www.cdc.gov/hiv/topics/surveillance/basic.htm. Accessed Dec. 10, 2007.4CDC: Disease Burden from Hepatitis A, B, and C in the United States. Available at: www.cdc.gov/ncidod/diseases/hepatitis/resource/dz_burden.htm. Accessed Dec. 10, 2007.

5Edlin B, et al. American Association for the Study of Liver Diseases 2005, Nov 11-15, San Francisco, CA. Oral Presentation.

HCV HIV

Incidence/yr1-4 ~30,000 40,000

Prevalence1-4 4.0 million 1.0 million

Deaths/yr1-4 8000-10,000 15,000

Overall Prevalence of HCV Among HIV-Infected Persons in the US

Sulkowski M, et al. Ann Intern Med. 2003;138:197-207.Thomas D. Hepatology. 2002;36:S201-S209.

HIV MonoinfectedHIV Monoinfected

HCV/HIV CoinfectedHCV/HIV Coinfected

Prevalence of HCV in HIV-Infected Persons by Risk Factors

Sulkowski M, et al. Ann Intern Med. 2003;138:197-207.

In certain subpopulations (ICDU), prevalence may be as high as 90%,

as demonstrated in this self-reported survey from Johns Hopkins

Pre

vale

nce

(%

)

N=1955

85.1

14.39.8

45.1

0

20

40

60

80

100

IVDU Heterosexualcontact

Malehomosexual

contact

Entire cohort

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

Deaths in a Cohort of 23,441 Patients

Koziel M and Peters M. N Engl J Med. 2007;356:1445-1454.

Patients Treated withAnti-HIV Drugs

Patients WithLiver Disease

>500

350-499

200-349

100-199

50-99

<50C

D4

cell

co

un

t p

er m

m3

Death from liver disease (no./1000 people)

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

>500

350-499

200-349

100-199

50-99

<50

Death from liver disease (no./1000 people)

Dea

ths

(%)

0

5

10

15

20

25

30

35

AIDS

30

Liverdisease

14

Cardio-vasculardisease

9

Non-AIDS

cancers

8

Hospital Admissions for Liver Complications Increased 5-Fold

(1995–2000)

Gebo KA, et al. JAIDS. 2003;34:165-173.

Ho

spit

aliz

atio

ns

per

pat

ien

t-ye

ars

foll

ow

-up

Opportunistic infectionsOpportunistic infections

IDU-related complicationsIDU-related complications

Liver-related complicationsLiver-related complications

1995 1995 19961996 19971997 19981998 19991999 200020000

10

20

30

40

Liver Disease Is a Major Cause of Deathin the ART Era

Bica et al. Clin Infect Dis. 2001;32:492-497; Puoti et al. JAIDS. 2000;24:211-217;Soriano V, et al. Eur J Epidemiol. 1999;15:1-4; Soriano V, et al. PRN Notebook. 2002;7:10-15;Martin-Carbonero et al. AIDS Res Human Retrovirus. 2001;17:1467-1471.

Death from end-stage liver disease (ESLD) as a percentof all deaths among HIV patients

0

10

20

30

40

50

60

Mo

rtal

ity

(%)

Italy (Brescia) Spain (Madrid) USA (Boston)

13%

35%

5%

12%

45%50%Pre-HAART era

HAART era

HCV

Causes of Liver Disease in HIV Infection

Opportunistic infections

EtOH/IVDU

HCV treatment

NNRTI

Diabetes

Dyslipidemia

Protease inhibitors

Nucleosideanalogues

Immunereconstitution

HAV

HBV

P-114

Liver Biopsy

Gold standard for grading and staging disease

Invasive, expensive

Needle liver biopsy samples <1/50,000th of the liver

Incorrect staging of 1 stage in 10% to 20% of cases

– Dependent on:

• length of biopsy—25 mm optimal (16%)

• number of biopsies performed

• type of biopsy needle used

• etiology of liver disease

Ishak Fibrosis Stage on Second Biopsy Among Persons With Little or No Fibrosis

on First Biopsy

Sulkowski MS, et al. 12th Conference on Retroviruses and Opportunistic Infections (CROI). February 22-25, 2005. Boston, MA. Abstract # P-172.

Median (IQR) time between biopsies, 2.84 yrs (2.05–3.41) 28% with more than 2 stage progression N=51

45%

23%

10%14%

8%

0

20

40

60

0 1 2 3 or 4 5 or 6Fibrosis stage at second biopsy

Pat

ien

ts (

%)

Baseline Fibrosis Stage According to Age in HCV/HIV Coinfection

Soriano V. J Hep. 2006;44:S44-S48.

31-40<30 ≥41

Age (yrs)

Pat

ien

ts (

%)

F0-F2F3-F462

44

32

15

36

46

0

10

20

30

40

50

60

70

The Importance of Liver Biopsy

Conflicting Data on the Effects of HCV Upon HIV Disease

Meta-analysis involving 6216 patients from 8 trials

– mean increase in CD4 cell count among HIV/HCV coinfected patients was 33.4 cells/mm3 less than that observed in HIV-monoinfected patients

EuroSIDA

– after adjusting for baseline factors, investigators concluded that HIV/HCV-coinfected patients do not have a greater risk of progressing to AIDS

Miller M, et al. Clin Inf Dis. 2005;41:713-720. Rockstroh J, et al. J Inf Dis. 2005;192:992-1002.

Sexual Transmission of HCV

895 monogamous heterosexual discordant couples, Italy

– yearly HCV antibody testing

– follow-up: 10 years (8060 persons-yrs)

– average exposure: 1.8 per week, no condoms

Three spouses with acquired HCV infection

– 1 discordant genotype, other 2 (sequence analysis) not from the partner

– intraspousal transmission: no cases

Vandelli C, et al. Am J Gastroenterol. 2004; 99:855-859.

Significant Increase in New Acute HCV Infections in 2003

Inci

den

ce o

f ac

ute

HC

V i

nfe

ctio

n/1

000

pt-

yrs

0

5

10

15

20

25

30

1997 1998 1999 2000 2001 2002 2003

Test for trend P-value using Poisson regression P<.001. Error bars = 95% CI.Browne RE, et al. 2nd International AIDS Society (IAS) Meeting. July 13-17, 2003; Paris. France. Abstract # 972.

HCV: A New Epidemic Among MSM?

Newly infected male, MSM, HCV+ patients at a London clinic, January 1997–May 2003; n=44

Reasons for testing: ALT (35), sexual contact with HCV+ person (3), jaundice (3), HIV screening (2), H/O IVDU (1)

Risk factors identified: IVDU (1), sexual contact (39), none (4)

Browne RE, et al. 2nd International AIDS Society (IAS) Meeting. July 13-17, 2003. Paris, France. Abstract # 972.

HCV Infection of HIV+ MSM2004 Acute HCV in HIV-infected men-who-have-sex-with-men

(MSM). 1 (Paris)2005 A cluster of acute HCV infection among MSM–results from

contact tracing and public health implications.2 (Holland) Unsafe sex and increased incidence of HCV infection among

HIV-infected MSM: the Swiss cohort study.3

Transmission of HCV among HIV-positive homosexual men and response to a 24-week course of pegylated interferon and ribavirin.4 (London)

2006 Clinical presentation and course of acute HCV in HIV-infected

patients.5 (San Francisco)1. Ghosn J, et al. HIV Med. 2004;5:303-306. 2. Götz HM, et al. AIDS. 2005; 19: 969-974. 3. Rauch A, et al. Clin Infect Dis. 2005; 41:395–402. 4. Gilleece Yc, et al. JAIDS. 2005;40:41-46. 5. Luetkemeyer A, et al. JAIDS. 2006;41:31-36.

HCV Infection of HIV+ MSM: Europe

Incidence ~0.1 to 0.25 cases/100 person-yrs in Bristol (UK) and France

– comparable incidence to 1980s in US (~0.08 to 0.13 cases/100 person-yrs) before decline in IDU

Phylogenetic trees show clustering by country

Conference on Retroviruses and Opportunistic Infections 2006, 2007, 2008.

Possible Transmission Risk Factors:Results of Anonymous Questionnaire (N=11)

Unprotected anal sex with casual partner within six months prior to hepatitis

(N=11)

Met sex partner at gay venue or via internet

(n=11)

STI reported (n=10):- syphilis (n=6)- gonorrhea (n=3)- genital herpes (n=3)- chlamydia (n=3)- warts (n=3)- anal/genital infection (n=3)

“Hard sex” (n=8):- fisting (n=5) - bleeding (n=6)

Inhaled poppers during sex (n=11) Used psychoactive drugs during

sex (n=5)

Tattoos or piercing within 6 months prior to hepatitis C (n=3)

Gambotti L. Eurosurveillance. 2005;10:115-117.

Acute HCV Infection: Treatment Response in HIV Seronegatives

Acute period–twice as good in half as long 6 month treatment course

Response independent of genotype:

– Jaeckel E. NEJM. 2001: 43/44 (98%)

– Nomura H. Hepatol. 2004: 13/15 (87%)

– Santantonio T. J Hepatol. 2005: 15/16 (94%)

Chronic period 12 month treatment course

Response dependent on genotype:

– geno 1: 42% to 46%

– geno 2 and 3: 76% to 82% (may be 6-mo course)

Hep-Net Acute HCV Study HCV-IIHep-Net Acute HCV Study HCV-II

0

20

40

60

80

100P

atie

nts

(%

)

ETR SVR

71%

82%

ITT (n=89)ETR SVR

94%89%

Pts. adherent to therapy(n=65)

Adherent to therapy = 80% of pegylated interferon dose, 80% of treatment duration.ETR= end of treatment response, SVR=sustained virologic response. Wiegand J, et al. 2008 (Submitted).

Hôpital Pitié-Salpêtrière, Paris, France (N=14)

Week 12 Week 24 Week 48 (SVR)

HC

V R

NA

<50

IU

/mL

(%

pat

ien

ts)

Peg-IFN alfa-2a (40KD) 180 μg/wk plus ribavirin 800 mg/d for 24 weeks

86%79%

71%

0

20

40

60

80

100

Dominguez S, et al. 10th European AIDS Clinical Society (EACS) Conference. November 17–20, 2005. Dublin, Ireland. Oral presentation # PS7/6.

Acute HCV in HIV+ MSM: Study Schema

HCV Sequence(9 cases) 30 cases

Risk factor assessment(19 cases)

Liverhistopathology

(11 cases)

5000 MSM cared for in the Active

Case-Finding and Referral Network

Fierer DS, et al. J Infect. Dis. 2008; (in press).

†Fisher’s exact.

Activity withinprior 12 months

Casesn=19 (%)

Controls n=34 (%)

OR(95% CI)

P-value (chi-square)

Insertive oral sex+ ejaculation

13 (68) 10 (31) 4.77 (1.21, 19.64) .01

Receptive oral sex+ ejaculation

14 (74) 7 (22) 10.00 (2.28, 46.85) <.001†

Insertive anal intercourse+ ejaculation

11 (58) 7 (22) 4.91 (1.21, 20.32) .009

Receptive anal intercourse + ejaculation

13 (68) 11 (34) 4.14 (1.07, 16.86) .02

Sex toys 12 (63) 8 (24) 5.36 (1.35, 21.87) .006

Group sex (≥ two men) 15 (79) 13 (39) 5.77 (1.37, 28.34) .009†

Sex with >10 men 13 (68) 9 (27) 5.78 (1.45, 24.07) .004

>10 one-night stands 12 (63) 4 (12) 12.43 (2.59, 66.08) <.001†

Ever told had STI 16 (84) 18 (53) 4.74 (1.04, 29.21) .04†

Sexual Practices


HCV Genotype Distribution

26 genotype 1

– 23 genotype 1a

– 3 genotype 1b

1 genotype 3A (HIV-negative patient)

3 genotype unknown


**

********

Bootstrap value 71.2%

K2P distances, neighbor joining, bootstrapping (n=1000)

Arielle Arielle KlepperKlepper

Phylogenetic Analysis

Nine genotype 1a isolates sequenced†

Five were part of cluster

Bootstrap value 71.2%(at branch point of 22 sequences)

Cases 8+10 andCases 11+12 formed pairs

†Region sequences: 5’ UTR – E1 (868 bp).

Clinical Course: Treatment Response

14 patients initiated therapy during acute phase:

– 6 completed therapy and had sustained virologic response (SVR) (VL <5)

– 3 completed therapy, with end-of-treatment response (VL <5), SVR analysis pending

– 3 still receiving therapy, all with early virologic response (VL <5 @ 12 weeks)

– 1 each, treatment failure and lost to follow-up


Histopathology:9 (88%) of 11 patients had stage 2 of 4 fibrosis within 14 months of diagnosis

Fibrosis During Acute HCV Infection in HIV+ Men

Patient

Time tobiopsy(weeks)

Fibrosis Stage(0 to 4)

1 22 2

2 7 2

3 13 0

4 16 2

5 3 2

6 8 2

7 62 2

8 21 2

9 17 2

10 3 1

11 68 2


Fibrosis During Acute HCV Infection in HIV+ Men

No common risk factors for pre-existing fibrosis:

– normal ALT within one year (most)

– not all on ARVs; rare “d-drug” use

– alcohol intake low (<30 g/d)

– normal BMI/fasting glucose

– most without prior hepatitis B infection


Liver Fibrosis Is Not Highly Prevalent in HIV+ Patients

Liver biopsy of 30 HIV-infected patients with persistently elevated LFTs (HCV-negative)

24 (80%) of 30 had stage 0 or 1 fibrosis

3 (10%) had stage 2-3 fibrosis

3 (10%) had stage 4 fibrosis (cirrhosis)

– advanced fibrosis was associated with findings of non-alcoholic steatohepatitis (NASH)

Valantin M-A, et al. 15th Conference on Retroviruses and Opportunistic Infections. Feb. 3-5, 2008. Boston, MA. abstract # 961.

No Fibrosis During Acute HCV Infection Without HIV

Acute HCV does not cause significant fibrosis:

Multiple biopsy studies from ’80s during acute NANB hepatitis

0 of 87 patients in Egypt after acute HCV1

– 48/85 with schistosomiasis (rapid progressors)

4 of 9 patients in Italy had stage 1 fibrosis after acute HCV2

1Kamal SM and Nasser IA. Hepatology. 2008;47:1371-1383.2Larghi A, et al. Hepatology. 2002;36:993-1000.

Fibrosis Progression Rates in HCV Infection: Comparison of Various Settings

Fib

rosi

s p

rog

ress

ion

rat

e (

U/y

r)

0.11 0.11 0.14 0.150.61

0.91.2

4.35

4

3

2

1

0Chronic

HCVChronic

HCVESRD

ChronicHCV/ESRD

+kidney

transplant

ChronicHCV

+HIV

Schisto-somiasis

+acuteHCV

AcuteHCV

HCVpost-liver

trans-plantation

HIV+

acuteHCV

(case-patients)

Fat in the Wrong Placesand Insulin Resistance

Liver (Sutinen J, et al. AIDS. 2002;16:2183-2193

• Significantly higher % liver fat in HIV+ LD vs HIV+ no LD and HIV-

• Severity of insulin resistance related to liver fat but not VAT

% intramuscularfat in HIV+ men

(Sakkas D, unpubl, 2003)

HO

MA

-IR

r=0.7938P<.01

0

2

4

6

8

0 2 4 6 8 10S

eru

m f

asti

ng

insu

lin (

mU

/l)

r=0.65, P<.0012.5

5

10

40

60

20

0.5 1.0 2.5 5 10 6020 40

r=0.47, P=.017

Insulin Resistance and HCV: Effect on Response to PegIFN/RBV Therapy

% S

VR

in

Gen

oty

pe

HOMA: Homeostasis Model of Assessment – HOMA of insulin resistance; SVR=sustained virologic response.Romero-Gomez M, et al. Gastroenterology. 2005;128:636-641.

60.5

40

20

0.0

20.0

40.0

60.0

80.0

100.0

HOMA <2 HOMA 2-4 HOMA >4

Does Steatosis Affect Responseto Treatment?

Poynard T, et al. Hepatology. 2003;38:75-85.

Geno 2F0-1

Per

cen

t S

VR

High viral load

Geno 1,4.5.6

Geno 1,4.5.6

high viral load

Geno 1,4.5.6

high viral loadF2,3,4

No steatosisSteatosis

F2,3,4

98

59 59 5751

39

89

41 4035

24 21

0

20

40

60

80

100

Insulin Resistance and NAFLD inCoinfection

Baseline Insulin Resistance by EVR

Bas

elin

e IR

0

10

20

30

40

50

60

No YesEarly Virologic ResponseEarly Virologic Response

r=-0.282P=.031

NAFLD=Nonalcoholic Fatty Liver Disease

RIBAVIC-ANRS HC02:Mitochondrial Toxicity Event

6 acute pancreatitis (one with hyperlactatemia)

7 hyperlactatemia (hospitalization)

4 suspicions of hyperlactatemia

Association with didanosine treatment*

*Odds-ratio for ddi = 23 [95% CI : 5-105].

ddl D4t % with MTE

Yes Yes 24 (12/50)

Yes No 7 (3/30)

No Yes 0 (0/114)

No No 2 (2/98)

APRICOT: Occurrence of Hepatic Decompensation

1.6

10.5

00

2

4

6

8

10

12

All patients(N=868)

Cirrhotic patients(non-decompensated)

(n=133)

Non-cirrhotic patients (n=735)

Pat

ien

ts (

%)

n=14 n=14

Mauss S, et al. AIDS. 2004; 18:21-25.

Risk Factors

Total bilirubin (OR 1.12, P<.001)

Alkaline phosphatase (OR 1.02, P<.001)

Albumin (OR 0.83, P<.002)

Platelets (OR 0.96, P<.001)

Hemoglobin (OR 0.53, P=.001)

Didanosine treatment (OR 4.06, P=.03)

Lamivudine treatment (OR 0.30, P=.04)

PT INR, efavirenz, saquinavir and non-nucleoside inhibitor treatments (P<.20)

Mauss S, et al. AIDS. 2004; 18:21-25.

Ribavirin and Ribavirin and ddIddI = “ = “ddon’t on’t ddo o iit”t”

ddI

ddI-MP

ddA-MP

ddA-DP

ddA-TP

RT -Pol

(-) (-)

Inositol IMP XMP GTPIMP dehydrogenase

Ribavirin-MP

Ribavirin

(-)

Adenosine kinase

Ribavirin increases IMP• Increases ddATP• Increases inhibition of HIV RT• Increases inhibition of host -pol

Higher Rate of Failure of PEG/RBV in HIV Patients Receiving Abacavir

Retrospective analysis of 426 HIV/HCV patients was performed in Spain

72% failed to reach SVR on treatment

Factors associated with failure:

– higher HCV RNA RR 1.82*

– lower RBV levels RR 2.27

– use of ZDV RR 1.72

– use of abacavir (only no if RBV >2) RR 2.08*

• F3 or greater RR 1.63

• lower HIV RNA RR 1.69

*Also on MLR.Vispo E, et al. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2007. Chicago, IL. Abstract # H-1731.

Tenofovir is Associated With Improved Response to Peg/RBV in HIV HCV+

GeSIDA trial 35 sites 238 on TDF/FTC or 3TC vs 481 who took AZT, d4T or abacavir with 3TC.(excluding ddI or TDF+AZT,d4T or ABC

Multivariate analysis adjusting for HCV genotype, HCV and HIV viral load, AST/ALT ratio and alcohol history:

– TDF raised SVR by 70% OR 1.70 (P=.03)

– AZT lowered SVR by 40% OR 0.60 (P=.05)

– No EtOH raised SVR OR 4.65 (P=.012)

– HIV <50c/ml OR 2.68 (P=.034)

Gonzalez-Garcia J, et al. 15th Conference on Retroviruses and Opportunistic Infections (CROI); Feb 3-4 2008. Boston, MA. Abstract # 783.

Summary of Results From Coinfection Trials

SVR (%)

Study N Treatment All GT 1 GT non-1

RIBAVIC 412PEG IFN α-2b + RBV 800IFN α-2b + RBV 800

2720

17*6

4443

ACTG 133PEG IFN α 2a + RBV 600IFN α -2a + RBV 600

2712

146

73 33

APRICOT 860PEG IFN α 2a + RBV 800IFN α -2a + RBV 800

4012

297

6220

LAGUNO 93PEG IFN α-2b + W/B RBVIFN α-2b + W/B RBV

4421

387

5347

PRESCO 389PEG IFN α-2a + W/B RBVG1 48 w 31 72w 52G1 48 w 31 72w 52G2 24 w 67 48w 82G2 24 w 67 48w 82

5050 3636 7272

Apricot: Sustained Virologic Response*

12%12%

n=285

20%20%

n=286

40%40%

n=289

PP =.0084=.0084

PP .0001.0001

PP.0001.0001

*Defined as <50 IU/mL HCV RNA at week 72; ITT.*Defined as <50 IU/mL HCV RNA at week 72; ITT.Torriani FJ, et al. Torriani FJ, et al. N Eng J Med.N Eng J Med. 2004;351:438-450. 2004;351:438-450.

% R

esp

on

se%

Res

po

nse

00

1010

2020

3030

4040

5050

6060

IFN alfa-2a + RBVIFN alfa-2a + RBV PEG-IFN alfa-2aPEG-IFN alfa-2a(40 kDa) + Placebo(40 kDa) + Placebo

PEG-IFN alfa-2aPEG-IFN alfa-2a(40 kDa) + RBV(40 kDa) + RBV

SVR Rates: Genotype 1SVR Rates: Genotype 1

RVR=rapid virologic response; EVR-early virologic response; SVR=sustained virologic response.RVR=rapid virologic response; EVR-early virologic response; SVR=sustained virologic response.Rodrigues-Torres M, et al. American Association for the Study of Liver DiseasesRodrigues-Torres M, et al. American Association for the Study of Liver Diseases (AASLD). Nov 2-4, 2007. AASLD). Nov 2-4, 2007. Boston, MA. Abstract # 1300.Boston, MA. Abstract # 1300.

HCV RNA<400,000 IU/mL

HCV RNA≥400,000 IU/mL

No bridgingfibrosis/cirrhosis

Bridgingfibrosis/cirrhosis

SV

R r

ates

(%

)

RVRcEVRpEVR

1214

811

22

68

1627

644

1720

2133

841

12

35

86

75

85

50

73

5964

60

100

1420

00

20

40

60

80

100

120

SVR Rates: Genotype 2 or 3SVR Rates: Genotype 2 or 3

HCV RNA<400,000 IU/mL

HCV RNA≥400,000 IU/mL

No bridgingfibrosis/cirrhosis

Bridgingfibrosis/cirrhosis

SV

R r

ates

(%

)

RVRcEVRpEVR

1012

33

2323

2030

211

3132

2029

15

23

34

16

RVR=rapid virologic response; EVR-early virologic response; SVR=sustained virologic response.RVR=rapid virologic response; EVR-early virologic response; SVR=sustained virologic response.Rodrigues-Torres M, et al. American Association for the Study of Liver DiseasesRodrigues-Torres M, et al. American Association for the Study of Liver Diseases (AASLD). Nov 2-4, 2007. AASLD). Nov 2-4, 2007. Boston, MA. Abstract # 1300.Boston, MA. Abstract # 1300.

83

100 97

67

100

67 6975

18 20 17

0

20

40

60

80

100

120

Results: Treatment Factors Predictiveof an SVR

The relationship between various treatment factors and SVR rates were examined

Cumulative peginterferon-alfa-2a (40KD) dose was strongly correlated with cumulative ribavirin dose (r=0.87)

Ribavirin dose also correlated with ribavirin treatment duration (r=0.98)

0

20

40

60

100

80

0 20 40 60 80 100

Cumulative ribavirin dose

Cu

mu

lati

ve p

egin

terf

ero

n-

alfa

-2a

(40K

D)

do

se

SVR No SVR

MLR analysis: Impact on SVR RatesMLR analysis: Impact on SVR Rates

Receipt of ≥80/80/80(vs <80/80/80)

Body mass index(per 1 unit increase)

Baseline HCV RNA(per 1-log increase)

0.1 1.0 10.0

0.85 (0.75–0.95) (P=.0062)

0.32 (0.19–0.54) (P<.0001)

6.55 (2.43–17.7) (P=.0002)

Odds ratio (95% CI)

Less likely to have an SVR More likely to have an SVR

Only factors with a significant (P<.05) effect are shown.

PRESCO Trial in HCV/HIV Coinfection:Study Design

CH

C, n

aïve

, H

IV-H

CV

co

-in

fect

ion

, N =

389

Study WeeksOnly patients with EVR (≥2 log drop of HCV RNA at week 12) continue treatment; duration at the discretion of the investigator .

Follow-up

Follow-up

G2/

3G

1/4

PEG-IFN alfa-2a 180 µg + Ribavirin

1000-1200 mg

PEG-IFN alfa-2a 180 µg + Ribavirin

1000-1200 mg

Follow-upPEG-IFN alfa-2a 180 µg + Ribavirin 1000-1200 mg

Follow-upPEG-IFN alfa-2a 180 µg

* Ribavirin 1000-1200 mg

0 4824 9612 7212

PE

G-I

FN

alf

a-2

a 1

80

µg

plu

s

Rib

av

irin

10

00

-12

00

mg

n=192

n=45

n=96

n=56

Nuñez M, et al. American Association for the Study of Liver Diseases (AASLD). Oct. 27-31, 2006. Boston, MA. Abstract # 365.

PRESCO Trial in HCV/HIV Coinfection:Virologic Response by Genotype and Duration

30%

53%

67%

82%

0%

20%

40%

60%

80%

100%

48 weeks 72 weeks 24 weeks 48 weeks

SV

R (

%)

PRESCO: RBV 1000-1200 mgAPRICOT: RBV 800 mg

69/192 24/45 64/96 46/56

Genotypes 1 and 4 Genotypes 2 and 3

Nuñez M, et al. American Association for the Study of Liver Diseases (AASLD). Oct. 27-31, 2006. Boston, MA. Abstract # 365.

US Study in HIV–HCV Coinfected NR toIFN ± RBV (Dieterich, Sulkowski)

Study weeks

Follow-up

NR

to

IFN

or

IFN

/RB

V (

N=

100

)

24 1200 48 72 96

HCV RNA pos

HCV RNA n

eg

Follow-up

Peg-IFNα-2a 90 µg

Follow-up

Peg-IFNα-2a 180 µg + RBV 800–1200 mg

Peg-IFNα-2a 180 µg + RBV

1200 mg

No treatment

Randomization.

Untreated Follow-up

SLAM-C Trial in HIV–HCV CoinfectedNonresponders (Sherman)

Peg-IFNα-2a180 µg + RBV 800–1200 mg

HCV RNA 2 log dropNR and

naïve

n=200

HCV RNA

<2 log drop12 weeks

Peg-IFNα-2a 180 µg + RBV 800–1200 mg

Peg-IFNα-2a 180 µg

Stop treatment,observation period

60 weeks

72 weeks

24 weeks

Randomization

Orthotopic Liver Transplantation

23 HIV + compared to UNOS (11,453 HIV-)

– HCV, 14 and HBV, 9

– CD4, 200 (range 76–506)

– MELD 16

HCV worse than HBV

Drug-drug interaction (tacrolimus)

Outcome not associated with HIV RNA or CD4

Ragni M, et al. 10th Conference on Retroviruses and Opportunistic Infections (CROI). February 10-14, 2003. Boston, MA. Abstract #155.

HIV negativeHIV positive

Survival After OLT

70

80

90

100

12 24 36Months

%

Based on OPTN data as of February 4, 2005. One year survival is based on 1999 - 2001 transplants, and 3-year survival is based on 1996 - 1999 transplants.

1-Year Patient Survival 3-Year Patient Survival

Liver Kidney Liver Kidney

All OPTN87.6

(87.0, 88.2)95.6

(95.4, 95.8)79.9

(79.3, 80.5)90.8

(09.5, 91.1)

65 yrs + OPTN80.5

(77.9, 83.0)90.4

(89.4, 91.3)69.6

(66.9, 72.2)78.0

(76.6, 79.4)

HIV-infected study subjects

90.9(73.9, 100)

93.8(81.9, 100)

80.8(56.8, 100)

93.8(81.9, 100)

Patient Survival Compared With OPTN

Survival and Recurrence of HCV After Transplant in HIV HCV+ Patients

79 patients in France 1999-2005, 35 HIV+

HIV HCV patients were younger, 43 vs 55

– had a higher MELD, 19 vs 15

– had a lower 2 year survival, 73% vs 91%

– had a lower 5 year survival, 51% vs 81%

– multivariate analysis survival related to MELD

– progression to F2 significantly faster

Results: satisfactory survival, but earlier referral, HCV treatment and avoiding ART toxicity

Duclos-Vallee J, et al. Hepatology. 2003;38:375A.

Participating CentersParticipating CentersVisit the study website for updated list of centers and contact informationVisit the study website for updated list of centers and contact information

Atlanta Emory University (K)

Baltimore University of Maryland (K)

Boston Beth Israel Deaconess Medical Center (K, L)

Charlottesville University of Virginia (K, L)

Chicago University of Chicago (K, L, Peds K, Peds L)

Cincinnati University of Cincinnati (K, L)

Cleveland Cleveland Clinic (K, L)

Los Angeles Cedars-Sinai (L)

Miami University of Miami (K)

New Orleans Tulane (K, L)

New York Mount Sinai School of Medicine (K, L, Peds K)

New York Columbia University (L, Peds L)

Philadelphia Drexel University (K)

Philadelphia University of Pennsylvania (K, L)

Pittsburgh University of Pittsburgh (K, L)

San Francisco University of California (K, L, Peds K, Peds L)

Washington, D.C. Washington Hospital Center (K)

Washington, D.C. Georgetown Medical Center (K, L)

Chicago Rush University (K, L)

Conclusions

HCV is a major, if not the major cause of morbidity and mortality in HIV+ patients today

Successful treatment of HCV (cure) in HIV+ patients is possible and even likely with pegylated interferon and ribavirin

Side effects can be effectively managed to ensure treatment success

Liver (and kidney) transplant is possible and is being investigated in HIV+ patients

44thth International Coinfection Workshop International Coinfection WorkshopMadrid, 19-21 June 2008Madrid, 19-21 June 2008

Chairmen: Vincent Soriano & Douglas DieterichChairmen: Vincent Soriano & Douglas Dieterich

HIVHBVHCV

www.virology-education.comwww.virology-education.com

What I did on my summer vacation!What I did on my summer vacation!


HIV Patients


Michael L. Tapper, MDMichael L. Tapper, MDChairmanChairman

Hospital EpidemiologistDirector, Division of Infectious Diseases

Lenox Hill Hospital New York, New York

Program Joint Sponsors

Postgraduate Institute for Medicine (PIM)

Global Education Exchange (GLOBEX)

Spectrum Medical Education

Scriplogix

Educational Grant Merck & Co., Inc.

CME Information

Refer to your workbook for the following important information

– Designation (2.5 AMA PRA Category 1 Credit(s)™

– Faculty disclosures

– Disclaimers

– Evaluation form: last page of workbook

You must complete and return your evaluation form to receive credit for this

evening’s educational activity

Program Flow

Case Vignettes and Assessment

– Audience Response System

Didactic Presentations

Case Vignettes and Assessment

– Audience Response System

Question and Answer


HIV Patients


Case 1 Question 1

What is the percentage of patients from the RESIST studies who initially were susceptible to darunavir and remained fully susceptible to darunavir after failing tipranavir?

25%

42%

21%

13% A. <10%

B. 10%-20%

C. 30%-50%

D. 80%

Case 1 Question 2

At this stage, which of the following would you do ?

11%

29%

37%

6%

11%

6% A. Repeat resistance test

B. Run a tropism assay ( ie, Trofile)

C. Recheck her labs in 3 months

D. A and B

E. A and C

F. B and C

Case 1 Question 3 Her PhenoSense GT assay was unchanged from the last one obtained. She had R5 tropic virus. What would you do next?

19%

28%

13%

16%

3%

22% A. Intensify her prescription with maraviroc

B. Substitute her darunavir with maraviroc

C. Continue to watch her on the same regimen

D. Reiterate the importance of drug adherence

E. A and D

F. B and D

Case 2 May of 2003: Hepatitis Profile

HAV Ab Negative

HBV sAg Negative

HBV core Ab, sAb Positive

HCV Ab Negative

Case 2 Question 1

Is a Hepatitis A vaccine needed at this time?

21%

79% A. Yes

B. No

Case 2: October of 2005: Laboratory Values

ALT 1620 U/L

AST 1006 U/L

Bili 1.84 mg/dl

Alk P 216 U/L

HIV RNA 151,049 cps/ml

CD4 303 (27%)

Case 2 Question 2

What would you order next?

26%

58%

6%

3%

0%

6% A. IgM HAV

B. IgM HBV Core Ab

C. HCV Abs

D. HCV viral load

E. C and D

F. B and C

His HCV RNA is 123,000 IU/mL (genotype 1a) Case 2 Question 3 Based on this patient’s history which of the following is a reasonable diagnosis?

17%

83% A. Acute HCV

B. Chronic HCV

Case 2 Question 4

At this stage, is it reasonable to expect a spontaneous clearance?

79%

50% A. Yes

B. No

Case2His laboratory results for the next three months are as follows:

September 05 October 05 December 05

ALT, U/l 1142 179 101

AST, U/l 568 113 67

T Bili, mg/dl 0.64 0.5 0.7

HCV RNA, IU/ml

525,000 10,300,000 35,900,000

CD4, (cells/µl) 257 (19%) 195 (19%)

HIV RNA, cps/ml

110,673 86,217

Case 2A liver biopsy in January of 2006 revealed mononuclear portal inflammatory infiltrate Moderate piecemeal necrosis Mild lobular NI activity Bile duct damage NI grade 3-4

Case 2Portal fibrosis with occasional septum formation, Stage 2/4

Case 2 Question 5

Based on this patient’s history and histopathology, this case is compatible with:

72%

28% A. Acute hepatitis C

B. Chronic hepatitis C

Case 2:In February of 2006, the patient starts Peg IFN α2a 180 mcg/wk, ribavirin 1200 mg daily

Week 6: HCV RNA 15,600 IU/ml (3.0 log ↓)

Week 12: HCV RNA < 600 IU/mlALT/ AST 83/66HIV RNA 76,963 cps/mlCD4 167 (16%)

Case 2 Question 6

Which of the following is appropriate at this time?

13%

5%

48%

10%

20%

5% A. Sulfamethocazole and trimethoprim

B. Combination antiretrovirals

C. Watchful waiting

D. A and B

E. A and C

F. B and C

Case 2 Question 7

How long should HCV therapy be continued?

16%

16%

53%

16% A. 24 weeks

B. 48 weeks

C. 52 weeks

D. 1.5 years

Case 3 Question 1

All of the following are appropriate at this time, except:

18%

7%

14%

39%

21% A. Confirm with Orasure Western Blot

B. There are no potential barriers to adhere to HIV treatment

C. Refer the couple for marriage counseling if Western Blot positive

D. Offer HIV antibody testing for the wife now, and if negative, in 3 and 9 months

E. If Western Blot positive, check CD4 and viral load

Case 3 Question 2

Which of the following strategies would you recommend at this time?

72%

3%

9%

3%

13% A. Check baseline resistance testing

B. Discuss possible antiretroviral regimens

C. Delay antiretroviral therapy until his CD4+ cell count is < 350 cells/mm3

D. Initiate antiretroviral therapy at this visit

E. A and B

Case 3 Question 3Which of the following would be most appropriate for this patient if he tests negative for any drug resistance mutations and is asking for the lowest amount of pills, once a day and a regimen that doesn’t increase his chances for IDU to relapse or causes any depression?

3%

3%

19%

29%

45% A. Emtricitabine/tenofovir/efavirenz

B. Tenofovir/emtricitabine/nevirapine once a day

C. Ritonavir/atazanavir/emtricitabine/ tenofovir

D. Fosamprenavir/ritonavir/emtricitabine/tenofovir

E. Darunavir/ritonavir/abacavir/lamivudine


HIV Patients


Case Vignettes


Case 4 Question 1

Based on his history, what is the 10-year CHD risk in this patient?

74%

22%

4%

0% A. <5%

B. 5 to 10%

C. 10 –20%

D. >20%

Case 4 Question 2

What would you do at this stage?

93%

7%

0%

0%

0% A. Aggressive smoking cessation

B. Treat his dyslipidemia

C. Change his HIV therapy

D. Diet and exercise

E. All of the above

Case 4 Question 3 First time use of enfuvirtide has been shown to enhance antiviral activity in the TORO (1&2), RESIST (1 & 2), POWER (1 & 2) BENCHMRK (1 & 2), DUET (1 & 2) and MOTIVATE (1 & 2) studies.

0%

100% A. True

B. False

Case 4 Question 4

Based on these data and his treatment history, which of the following is a reasonable option in his new combination regimen?

77%

5%

18%

0%

0% A. Darunavir/ritonavir

B. Etravirine

C. Raltegravir

D. Lamivudine

E. All of the above

Case 4 Question 5

Which of the following agents should NOT be coadministered with etravirine?

A. Darunavir/ritonavir

B. Tipranavir/ritonavir

C. Raltegravir

D. Lamivudine

E. Maraviroc

Case 4 Question 6

According to the US Department of Health and Human Services guidelines regarding the use of antiretroviral therapy in HIV-infected adults, which of the following statements best describes the HIV treatment goal for highly antiretroviral–experienced patients with multidrug-resistant HIV?

A. Reduce HIV-1 RNA by ≥ 1 log10 copies/mL

B. Achieve HIV-1 RNA < 50 copies/mL

C. Achieve HIV-1 RNA < 400 copies/mL

D. Regain and maintain undetectable HIV-1 RNA

E. None of the above

Case 4 Question 7

Prior to initiating this salvage regimen, would you store blood for a tropism (Trofile) assay ?

A. Yes

B. No

Case 5 Question 1

K103N, G190a mutations confer resistance to all of the following except:

14%

4%

82%

0% A. Efavirenz

B. Etravirine

C. Viramune

D. Delarvidine

Case 5 Question 2

Is a phenotype indicated in the management of this patient?

8%

92% A. Yes

B. No

Case 5 Question 3

The M184V mutation can phenotypically resensitize a resistant virus to which of the following drugs?

23%

40%

20%

10%

7% A. TenofovirB. ZidovudineC. LamivudineD. A and BE. None of the above

Case 5 Question 4

A follow up PhenoSense assay confirmed the broad resistance to the NRTI, NNRTI and PI class with a fold change for darunavir of 18. A fold change of 18 to darunavir confers:

38%

41%

21% A. No resistance

B. Intermediate resistance

C. High level resistance

Case 5 Question 5

In the BENCHMRK study the percent of patients who achieved viral load reductions to less than 50 copies/ml at week 48 when using raltegravir added to regimens containing first-use of enfuvirtide or darunavir was

8%

25%

29%

29%

8% A. 30%-40%B. 50%-60%C. 70%-80%D. 80%-90%E. >95

Case 5 Question 6According to the DHHS guidelines, virologic failure on treatment can be defined as:

26%

9%

4%

4%

57% A. HIV RNA level >400 copies/mL after 24 weeks, >50 copies/mL after 48 weeks

B. HIV RNA level >500 copies/mL after 24 weeks, >60 copies/mL after 48 weeks

C. HIV RNA level >600 copies/mL after 24 weeks, >70 copies/mL after 48 weeks

D. HIV RNA level ,<500 copies/mL after 24 weeks, <60 copies/mL after 48 weeks

E. None of the above


HIV Patients


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