Robert Murphy, M.D.

Professor of MedicineDirector, Center for Global Health

Feinberg School of MedicineNorthwestern University

Chicagoand

Professeur Associé de RechercheUniversité Pierre et Marie Curie

Paris

Current Treatment Practice and Future Treatment Options

Current Treatment Practice: Should there be two levels of guidelines?

The big questions remain:

– When to start? When is too early?

– What to use first? Does it really matter?

– What alternatives do we have with the currently available drugs? New strategies?

– Should we have 2 levels (rich and poor) of recommendations? No.

When to Start HIV Therapy?Why Are Trials Hard?

Outcome of therapy started late is still “good” Small expected differences require very large, very long period of study Most potential subjects either:

– Already in care

– Don’t want care

– Are not ideal trial participant

– May have non-B clades (so what?)

– May not be representative of “typical” chronic infection Treatment paradigm may well change during trial (integrase as first line?)

making results suspect Treatment guidelines may anticipate “answer” and make trial

impossible/unethical

IAS-USA Guidelines 21 July 2010: When To Start

IAS Guidelines Revised 21 July 2010, JAMA

Clinical Condition and/or CD4 Count Recommendations

Symptomatic HIV infectionand

Asymptomatic CD4 before CD4 <500

Start ART

CD4 > 500

Considerations: -VL > 100,000 -CD4 decline >100 cells/year -Age >60 years -HCV and/or HBV infection -Cardiovascular disease -HIV-associated nephropathy

-Pregnant women -Serodiscordant relationships

EACS Guidelines 2009: When to Start Therapy

Asymptomatic – CD4 350-500• Treatment recommended: HCV coinfection, HBV coinfection requiring therapy,

HIVAN or other specific organ deficiency• Treatment should be considered if VL>100,000 and/or CD4 decline >50-100 cells/yr

or age >50 or, pregnancy, high cardiovascular risk, malignancy

Asymptomatic – CD4 > 500

• Treatment generally deferred: regardless of VL (closer follow-up if VL >100,00)• Treatment can be offered with ≥ 1 of the above co-morbid conditions

EACS Guidelines for the Clinical Management and Treatment of HIV Infected Adults in Europe, Version 5, Nov 2009.

DHHS Guidelines 12/2009: When To Start

US DHHS Guidelines; Revised January 29, 2008. http://.aidsinfo.nih.gov/contentfiles/adultandadolescnetGL.pdf

Clinical Condition and/or CD4 Count Recommendations

• History of AIDS-defining illness• CD4 ≤ 350

Start ART (AI)

• Pregnancy (AI)• HIV-associated nephropathy (AII)• HBV coinfection when HBV therapy

indicated (AIII)

Start ART

• CD4 350-500 Start ART (55% AII, 45% BII)

• CD4 >500 50%: Start ART (BIII)50%: ART optional (CIII)

What to Start: It all works in First Line…

Regimen Recommend Potency Toxicity Resistance Ease of administration

EFV TDF FTC

Preferred except childbearing potential

LPV/r TDF FTC

Alternate FL except lipid problems

ATA/r TDF FTC

Alternate FL except proton pump inhibitor use

DAR/r TDF FTC

Alternate FL

When to Start Therapy: then…..

• Drug toxicity• Lipodystrophy• Neuropathy• Gastrointestinal

Delayed ART

• Resistance

• Limited Second Line Options

• Cost

When to Start Therapy: now…..

Higher success rates

Early ARTDelayed ART

Less resistance

Better tolerability

More treatment options

CVD, neuro, renal, disease and age benefit

Decrease HIV transmission

Short term costs

Patient reluctance

Preserve immune status

Better Regimens: Proportion of patients experiencing failure of >2 distinct regimens has declined dramatically

aRR=1.46

aRR=0.82

aRR=0.51 aRR=0.54

REF

NA-ACCORD, Clin Infect Dis 2009

N ~ 30,000

Prevalence of Specific Mutations Over a 7-Year Period: CNICS

0

10

20

30

40

50

60

2002 2004 2006 2008

M184V

≥1 TAMs

K103N

≥1 ETR

K65R

58[53,63]

45[40,50]

29[24,33]

16[12,19]

3[1,5]

52[47,56]

38[33,42]

37[32,41]

15[12,18]

9[6,11]

45[41,49]

27[23,30]

30[26,34]

14[11,16]

7[5,9]

37[30,44]

16[11,22]

26[20,32]

12[7,16]

5[2,8]

Mea

n P

rev

ale

nce

, %

[95

%

CI]

M184V

≥1 TAMs

K103N

≥1 ETR

K65R

Aldous J, CROI 2010; 585.

HIV Transmission Risk Serodiscordant Couples Initiating ARV

HIV transmission risk 92% lower in African serodiscordant couples with HIV+ partner on ART vs couples with untreated partner

– 102 of 103 transmission occurred in couples with HIV+ partner not receiving ART

– Adjusted RR: 0.08 (95% CI: 0.002-0.57; P = .004)

– Adjusted for visit and CD4 count at initiation

Donnell D, et al. CROI 2010. Abstract 136.

Outcome No ART ART

HIV infections,* n 102 1

Person-yrs 4558 273

Rate (95% CI) 2.24 (1.84-2.72) 0.37 (0.09-2.04)

*Genetically linked HIV transmissions.

Lower CD4 Count and Detectable Viral Load Associated With Increased Risk of Death in D:A:D

Smith C and D:A:D Study Group. 16th CROI; 2009; Montreal. Abstract 145.

VL (log c/mL) and ART Status

Ad

just

ed R

ate

Rat

io (

95%

Cl)

CD4

CD4 and HIV RNA StatusOverall AIDS Liver CVD Non-AIDS Malignancies

Per 100 <2.6 on >2.6 on <4 off 4-5 off >5 off0.1

0.5

1

5

10

Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start

• Magnitude of increase in CD4 count greatest if ART started at low CD4 counts, but greater likelihood of CD4 count normalization with earlier therapy

1Moore R, et al. Clin Infect Dis. 2007;44(3):441-446. 2Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.

Years on ART

Johns Hopkins HIV Clinical Cohort1

Mea

n C

D4

Co

un

t

1000

800

600

400

200

0

0 48 96 144 192 240 288 336

ATHENA National Cohort2

Weeks from Starting ART

0 1 2 3 4 5

200

400

600

800

0

1000

<200

201-350

>350

<5050-200200-350350-500≥500

Slower Immunologic Response and Greater Clinical Progression with Age > 50

Grabar S, et al. AIDS. 2004;18:2029-2038.

Mean CD4 Count Increase/Mo

Within First 6 Mos of ART* After 6 Mos of ART*

Age < 50 Yrs Age ≥ 50 Yrs Age < 50 Yrs Age ≥ 50 Yrs

BL VL < 5 log 17.3 14.1 11.1 9.8

BL VL ≥ 5 log 42.9 36.9 17.9 15.6*P < .0001 for younger than 50 years of age vs 50 years of age or older in all subgroups.

Outcome Adjusted HR P Value

Progression to ADE or death 1.52 .0035

Progression to new ADE 1.50 .0087

VL< 500 1.23 < .05

Non-AIDS events more common in HIV disease, even after adjustment for age, ART exposure and traditional risk factors

Lifestyle

NormalAging

ARTToxicity

ImmuneDysfunction

PrematureAging

Slide #16

Non-AIDS Events in Patients with Treated HIV Disease vs. Age-Matched HIV-Negative Controls

• Cardiovascular disease[1-4]

• Cancer (non-AIDS)• Bone fractures/osteopenia [5,6]

• Left ventricular dysfunction• Liver failure[7] • Kidney failure• Cognitive decline (?)[8]

• Frailty[9]

1. Klein D, et al. J Acquir Immune Defic Syndr. 2002;30:471-477. 2. Hsue P, et al. Circulation. 2004;109:316-319. 3. Mary-Kraus M, et al. AIDS. 2003;17:2479-2486. 4. Grinspoon SK, et al. Circulation. 2008;118:198-210. 5. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504. 6. Arnsten JH, et al. AIDS. 2007 ;21:617-623. 7. Odden MC, et al. Arch Intern Med. 2007;167:2213-2219. 8. McCutchan JA, et a. AIDS. 2007 ;21:1109-1117. 9. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007;62:1279-1286

Immune Activation, HIV Infection and ART

Hunt PW, et al. J Infect Dis. 2003;187:1534-1543.

Association Between Current CD4 Cell Count and Non-AIDS Complications

StudyNon-AIDS

MalignanciesRenal

Disease/DeathCVD

Events/DeathLiver Disease/

Death

FIRST Yes Yes Trend No

D:A:D Yes Yes Trend Yes

CASCADE Yes NA Yes Yes

SMART Trend Trend Trend Yes

Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.

CD4 Count and Malignancy: French Hospital Database

"Immunodeficiency increased the risk of all the cancers that we investigated… cART would be most beneficial if it restores or maintains CD4 count above 500 cells/μL, thereby indicating an earlier diagnosis of HIV infection and an earlier treatment initiation."

Malignancy RR: CD4 350-499 RR: CD4 <50

Kaposi’s sarcoma* 1.9 25.2

NHL* 1.3 (NS) 14.8

Hodgkin’s lymphoma 1.2 (NS) 5.4

Lung cancer 2.2 8.5

Liver cancer 2.0 (NS) 7.6

52,278 pts (255,353 pt-yrs of follow-up)

Guiguet M, et al. Lancet Oncology 2009;

*Risk also increased with VL >100,000 vs. <100,000

CHARTER Study: Predictors of HIV-Associated Neurocognitive Disorders (HAND)

Prospective observational study (N = 1525) Comprehensive neuropsychological and neuromedical testing conducted Risk of HAND associated with lower CD4 nadir, but not current CD4 count

– Remained significant after adjusting for other predictors: VL, age, sex, ethnicity, duration of infection

Ellis R, et al. CROI 2010. Abstract 429.

Od

ds

Rat

io f

or

Co

gn

itiv

e Im

pai

rmen

t

1.11

0.90.80.70.60.50.40.3

< 50 50-199 200-349 ≥ 350CD4 Nadir

Cardiovascular Risk

Brachial Artery Reactivity Testing

5.3 mm, NTGMD=18%5.0 mm, FMD=11%4.5 mm

Baseline

60 sec after

cuff release

3 min after

nitroglycerin

ACTG 5152s: Median Change in FMD Over Time

*p≤0.01; #0.01<p≤0.05 compared to baseline, within group; **comparison between arms

0.0

1.0

2.0

3.0

4.0

Week 0 Week 4 (p=0.61**) Week 24 (p=0.94**)

EFV/NRTI LPV/NRTI LPV/EFV All

∆ F

MD

(%

) #

***

*

Baseline FMD = 3.7% (2.0 – 5.5%)

Cardiovascular Risk and CD4 Nadir

CV risk strongly associated with arterial stiffness, as measured by: – carotid-femoral pulse wave velocity

(PWV)– augmentation index (Aix@75)

Nadir CD4 < 350 associated with 0.58 m/s increase in PWV (p=0.008) and 7.2% increase in Aix@75 (p=0.002).

Adjusted for CV risk factors and HIV-related covariates (age, BP, HTN, DM, hypercholesterolemia, FMH, smoking, IDU, eGFR)

No association with duration of ART or PI exposure

Ho JE, et al. CROI 2010, San Francisco, Abstract 707

Correlation between arterial stiffness and CD4 nadir

Aix@75 r=-0.37

p=0.0009

PWV r=-0.25 p=0.03

NA-ACCORD: Early vs. Deferred ART

– Study controlled for factors that could affect decision to defer ART– Adjustment for sex, age, and CD4 counts at baseline

– VL response similar in early vs. deferred arms– Results similar when IDUs excluded Limitations: observational study with potential for unmeasured confounding

CD4 CountRelative Risk

(95% CI) P Value

351-500 1.69 (1.26-2.26) <0.001

>500 1.94 (1.37-2.79) <0.001

aWithout inclusion of VL data.

Risk of Death With Deferral of ARTa

Adapted from Kitahata MM, et al. N Engl J Med. 2009;360:1815-1826.

ART-CC: Prognosis based on CD4 count at initiation of ART ART Cohort Collaboration:15 cohorts from US and Europe (N = 24,444)

Sterne J, et al. CROI 2009. Abstract 72LB. Graphic reproduced with permission for educational use only.

CD4 Threshold

Comparison HR* (95% CI)

1-100 vs 101-200 3.35 (2.99-3.75)

101-200 vs 201-300 2.21 (1.91-2.56)

201-300 vs 301-400 1.34 (1.12-1.61)

251-350 vs 351-450 1.28 (1.04-1.57)

351-450 vs 451-550 0.99 (0.76-1.29)

*Adjusted for lead-time and unobserved events.0.5

1.0

2.0

4.0

500 400 300 100

HR

for

AID

S o

r D

eath

*

200 0

Prospective Study in HaitiSevere et al. NEJM 15 July 2010

Starting ART when CD4 <200 cells/uL vs 200-350 cells/uL

N = 810

Deaths: 23 v 6 (CI 1.6,9.8; p=0.001)

New Tuberculosis: 36 v 18 (CI 1.2,3.6; p=0.01)

Life Expectancy in HIV-infected Patients

< 100 100-200 >200

Life expectancy (at age 20) 32 42 50

ART-CC1: Depending on when ART is started, life expectancy is 10-30 years less than that in uninfected patients

CD4 Nadir

1. ART-Cohort Collaboration. Lancet.;2. Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-7.3. Van Sighem A, et al. CROI 2010. Abstract 526

AQUITAINE cohort2: Mortality same as that of general population in patients with CD4 >500 after 6th year of ART

ATHENA cohort3: Modeled life expectancy for asymptomatic pts who remained naive and without AIDS at Wk 24 after Dx similar to age- and sex-matched uninfected controls: 52.7 vs 53.1 years

Future Treatment Options with Existing Drugs

Monotherapy following suppression– MONOI: effective, increase in body fat, future options preserved

PI/r plus raltegravir– As effective

– Fewer adverse effects

– Less lipoatrophy

What will it take to change the paradigm?

Current Treatment Practice and Future Options:

Recommendation for ART

Predicted non-adherenceReluctance to start

Low CD4High VL

Rapid CD4 declineAge

Opportunistic diseasesPregnancy

Cardiovascular riskHIVAN

HBV/HCV coinfectionSeronegative partner

High-risk behaviorWillingness to start

Thank you!

Joel Gallant Paul Volberding Christine Katlama