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

The Rationale for Earlier Therapy

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

The Rationale for Earlier Therapy

Easier, more potent, and less toxic therapy

Cohort studies showing benefit with earlier therapy

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

The Rationale for Earlier Therapy

Easier, more potent, and less toxic therapy

Cohort studies showing benefit with earlier therapy

Better response to therapy

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

The Rationale for Earlier Therapy

Easier, more potent, and less toxic therapy

Cohort studies showing benefit with earlier therapy

Better response to therapy

Decreased transmission

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

The Rationale for Earlier Therapy

Easier, more potent, and less toxic therapy

Cohort studies showing benefit with earlier therapy

Better response to therapy

Decreased transmission

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

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

CCR5 Inhibitors Fusion Inhibitors Atazanavir (ATV)—Reyataz

Maraviroc (MVC)— Selzentry

Enfuvirtide (ENF, T20)— Fuzeon

Fosamprenavir (FPV)—Lexiva

Tipranavir (TPV)—Aptivus

Darunavir (DRV)—Prezista

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.

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

CCR5 Inhibitors Fusion Inhibitors Atazanavir (ATV)—Reyataz

Maraviroc (MVC)— Selzentry

Enfuvirtide (ENF, T20)— Fuzeon

Fosamprenavir (FPV)—Lexiva

Integrase Inhibitors Tipranavir (TPV)—Aptivus

Raltegravir (RAL)—Isentress

Darunavir (DRV)—Prezista

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]

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.