When to START Antiretroviral Therapy?

When to START Antiretroviral Therapy?

Dr. José R Arribas

HIV Unit

0 10 20 30 40 50

Age 20 y

Life Expectancy (years; adjusted)

Life expectancy of individuals on combination antiretroviral therapy in high-income countries

Non-IVDU

IVDU

Female

Male

Adapted from ARTC Collaboration. Lancet 2008; 372: 293–99

Survival from age 25 years (Non HCV)

Lohse N et al. Ann Intern Med. 2007;146:87-95.

Smoking?Lifestyle?Socioeconomic?HIV?

clinicaloptions.com/hiv

SMR in 2435 HIV-infected adults, ANRS CO8APROCO-COPILOTE, and ANRS CO3 AQUITAINE cohorts, 1997 to 2005.

Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77


SHOULD WE START HAART IN THIS PATIENT NOW?

32 year old male

HIV negative: Sept/2000. HIV positive Dec/2000

Nadir CD4 cell count: 453

Current CD4 cell count: 479

Current viral load: 16000

No hepatitis coinfection.

HIV negative couple


WAITING AHEAD (NO TREATMENT)

DEATH

AIDS

32 y/o maleCD4 cell count: 479Current viral load: 16000


101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

DEATH & AIDS. 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 censored from model

Sterne J, et al. CROI 2006. Abstract 525.

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

Years Since Initiation of HAART

0 1 2 3 4 50.00

0.02

0.04

0.06

0.08

0.10

0.12

Pro

ba

bil

ity

of

AID

S o

r D

ea

th

0.14

Progression and Death According to CD4+ Cell Count (cells/mm3)

< 200 vs 201-350

< 350 vs 351-500

Hazard ratio for AIDS or death (95% CI)

2.93 (2.41-3.57)

1.26(0.94-1.68)

Initiating Rather than Deferring Haart at a CD4+ Count Between 351-500 Cells/mm3 is Associated with Improved Survival

(74% Lower risk)Kitahata MM et al. ICAAC 2008. H-896b


AIDS. Hazard Ratio from initiation of HAART to AIDS by CD4 cell count

Jaen J, et al. JAIDS 2008;47:212–220

Similar data: ARTCSterne J, et al. CROI 2006. Abstract 525.

clinicaloptions.com/hivBHIVA Guidelines 2008

PREDICTED 6-month risk of AIDS


The NNT (Number Needed to Treat) is 203 This means that about one in every 203 patients will benefit from the treatment.

Panel CD4+ Cell Count, cells/mm3

US DHHS

June 1998 < 500

February 2001 < 350

April 2005 < 200

January 2008 < 350

International AIDS Society-USA Panel

July 1998 Any

January 2000 < 500

July 2004 <200

August 2008 < 350

British HIV Association (BHIVA)

June 1998 < 350

July 2003 201-350

July 2005 < 200

September 2008 < 350



DEATH

AIDS


Adapted from SMART Study Group. N Engl J Med 2006;355:2283-96.

NON-AIDS EVENTS. SMART STUDY

< 250 > 350

Of the 85 deaths that occurred in SMART, only 7 (8%) were due to

opportunistic disease



DEATH

AIDS

NON-AIDS EVENTS

– CARDIOVASCULAR DISEASE

– RENAL DISEASE

– LIVER DISEASE

– CANCER


200 – 350 – > 500 349 499

CD4 count (/mm3)

Rate

/ 100 personyears

95% CI

Non-AIDS causes All causes0.0

0.4

0.8

1.2

1.6

0.0

0.4

0.8

1.2

1.6

200 – 350 – > 500 349 499

DAD

CASCADE(ART-naïve)

Weber et al, Arch Intern Med 2006 Marin et al 4th IAS [WEPEB019]

NON-AIDS EVENTS. CD4+ Cell Count and risk of death



DEATH

AIDS

NON-AIDS EVENTS

– CANCER

– CARDIOVASCULAR

– OTHER

“IRREVERSIBLE” IMMUNODEFICIENCY

HIV TRANSMISSION

COST



“IRREVERSIBLE” IMMUNODEFICIENCY. CD4+ Count Response Based on Baseline CD4+ Count

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

Keruly J, et al. CROI 2006. Abstract 529. Gras L, et al. CROI 2006. Abstract 530.

Johns Hopkins HIV Clinical Cohort

Mea

n C

D4+

Co

un

t (c

ells

/mm

3 )

1000

800

600

400

200

00 48 96 144 192 240 288 336

ATHENA National Cohort

0 1 2 3 4 5

200

400

600

800

0

1000

Years on HAART Weeks From Starting HAART


“IRREVERSIBLE” IMMUNODEFICIENCY. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression

Mocroft A, et al. Lancet 2007; 370: 407–13.


HIV TRANSMISSION. HIV RNA level affects probability of HIV transmission

GUD = genital ulcer disease.

Gray R et al Lancet 2001;357:1149-1153

GUD No GUD

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

<1700 1700- 12500- 38500+

Log Viral Load (c/mL)

Pro

bab

ility

of

Tra

nsm

issi

on

/10

00 C

oit

al A

cts

GUD


WAITING AHEAD (TREATMENT)

TOXICITY RESISTANCE

– Transmitted resistance

COST QOL DEATH AIDS NON-AIDS EVENTS

– CANCER

– CARDIOVASCULAR

– OTHER

– HIV TRANSMISSION “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION


0

10

20

30

40

48 96Weeks on Study

% L

ipo

atro

ph

y (>

20%

Lo

ss) EFV LPV/r LPV/r + EFV

TOXICITY. A5142: Lipoatrophy (> 20% loss Extremity Fat)

P-values at Week 96 LPV/r+EFV vs LPV/r: 0.023LPV/r+EFV vs EFV: <0.001LPV/r vs EFV: 0.003

9%

17%

32%

7%10%

21%

EFV 188 171LPV/r 191 166LPV/r + EFV 197 173

Haubrich R et al., 14th CROI, Los Angeles 2007, #38 ACTG A5142


RR adjusted by year of PI: 1.15 [1.062–1.25]RR adjusted by year of NNRTI: 0.94 [0.74–1.19]

None <1 1-2 2-3 3-4 4-5 5-6 >60 -1 -

2 -

3 -

4 -

5 -

6 -

7 -

8 -M

Is p

er

10

00

PY

FU

(9

5%

CI)

Years of Exposure to PI or NNRTI Total

PIs MI 16 7 12 19 25 23 12 22 136

PYFU 11815 3108 3808 5144 6108 5199 3525 3306 42013

NNRTIs MI 16 6 3 3 3 2 33

PYFU 11815 2585 2294 1980 1525 1425 21623

Friis-Møller N et al 13th CROI; 2006, #144 D:A:D

TOXICITY. HAART effect on CV risk driven by PIs


TOXICITY. A5152s: VL Decrease Associated With Improved Endothelial Function

HIV infection itself affected endothelial function

– Baseline FMD: 3.7%

FMD improved during HAART

No consistent correlations between changes in FMD and changes in any lipids or glycemic parameter

Improvement in FMD significantly associated with decrease in HIV-1 RNA at Week 24

– No relationship with baseline HIV-1 RNA Med

ian

Ch

ang

e in

FM

D F

rom

Bas

elin

e (%

)LPV/NRTI

EFV/NRTI

EFV/LPV

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Overall

Week 4 Week 24

* * *

†

*P < .01 compared with baseline.†P < .01 compared with baseline and within group.

Torriani F, et al. Lipodystrophy Workshop 2007. Abstract O-18. Torriani F, et al. IAS 2007. Abstract WEAB302.


RESISTANCE. Unadjusted and adjusted risk ratios

of virological failure by year of starting cART

1999 is reference category. Unadjusted*=adjusted for cohort only; Adjusted 1#=adjusted for cohort, age, risk group, pre-HAART VL and CD4, previous AIDS; Adjusted 2$ =adjusted for all above factors plus starting regimen as defined by 3rd drug count and nucleoside combination.

Lampe et al, Arch Intern Med 2006;166:521-528

0.5

1.0

1.5

2.0

2.5

3.03.54.0

Ris

k ra

tio

Strategy A

1996 19981997 1999 2000 2001 2002Year of starting CART

UnadjustedAdjusted 1Adjusted 2


DEATH AIDS NON-AIDS EVENTS

– CANCER

– CARDIOVASCULAR

– OTHER “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION COST


TOXICITY RESISTANCE

– Transmitted resistance COST QOL DEATH AIDS NON-AIDS EVENTS

– CANCER

– CARDIOVASCULAR

– OTHER

– HIV TRANSMISSION “IRREVERSIBLE” IMMUNODEFICIENCY HIV TRANSMISSION

NO TREATMENT TREATMENT


PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular) & Toxicity & Transmission

32 y/o maleCD4 cell count: 479Current viral load: 16000Framingham risk: 8%Hepatitis Coinfection: No


PREDICTED 6-month risk of AIDS & Non-AIDS (Cancer, Cardiovascular, Other) & Toxicity & Transmission

32 y/o maleCD4 cell count: 479Current viral load: 16000Framingham risk: 8%Hepatitis Coinfection: No

?

NNT: ?

NNH: ?

NNT (Prevent Transmission): ?

NNH (Transmitted resistance): ?

SMART SUBSTUDY (NAÏVE/OFF-HAART, > 350)

Virologic Suppression StrategyContinuous therapy

(n = 249 not receiving ART at trial start)

Treatment Interruption StrategyDeferred therapy until CD4+ cell count < 250 cells/mm³; discontinue therapy when CD4+ cell count > 350 cells/mm³(n = 228 not receiving ART at trial start)

Patients with CD4+ cell count > 350 cells/mm³

who are antiretroviral naive (n = 249) or have not

received ART for ≥ 6 mos (n = 228)

(N = 477)

Mean follow-up: 16 months

Study halted early

SMART. The Journal of Infectious Diseases 2008; 197:1133– 44

No. at RiskNo. at Risk

Opportunistic disease and death

Months

Cum. Probability (X100)

Immediate ARTDeferred ART

Deferred ARTImmediate ART

Hazard Ratio = 4·38 (95%CI: 1·45-13·.2) p=0·009

Opportunistic disease (fatal and non-fatal)

Months


Hazard Ratio = 4·40 (95%CI: 1·23-15·8) p=0·02

Serious non-AIDS

Months


No. at Risk

Hazard Ratio = 7·05 (95% CI: 1·58-31·5) p=0·01

Composite endpoint

Months


No. at Risk

Hazard Ratio = 5·08 (95% CI: 1·91-13·5) p=0·001

Imm ARTDef ART

Imm ART

Def ART

Immediate ARTDeferred ART

CLINICAL OUTCOMES

START: Design

HIV-infected participants with CD4+ cell counts > 500 cells/mm3

Early ART Group

Immediately initiate ART

N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study

Deferred ART Group

Defer ART until CD4+ <350 cells/mm3 or symptoms develop

N=450 at 70 sites for pilot phaseN=2,000 (est.) for definitive study


Composite Primary Endpoint(Time to first event)

AIDS*

– Clinical events included in 1993 CDC case definition, plus additional conditions related to immunodeficiency (non-fatal esophageal candidiasis and herpes simplex are excluded)

Non-AIDS

– Cardiovascular disease: MI, angioplasty, CABG, stroke

– Chronic end-stage renal disease (ESRD): initiation of dialysis, renal transplantation

– Decompensated cirrhosis

– Non-AIDS defining cancers (basal and squamous cell skin cancers are not counted)

Death from any cause

Panel CD4+ Cell Count, cells/mm3

US DHHS

June 1998 < 500

February 2001 < 350

April 2005 < 200

January 2008 < 350 (> 350 Individualized)

International AIDS Society-USA Panel

July 1998 Any

January 2000 < 500

July 2004 <200

August 2008 < 350 (> 350 Individualized)

British HIV Association (BHIVA)

June 1998 < 350

July 2003 201-350

July 2005 < 200

September 2008 < 350 (> 350 Individualized)

INDIVIDUALIZING FACTORS> 55 y/o↑ Cardiovascular RiskHepatitis CoinfectionHigh Viral LoadRapid CD4 cell decline


When to start antiretroviral treatment?

Current global consensus: < 350. This represents a prudent decision given the available evidence.

> 350?:

– Precise estimates of the risk of Death/AIDS are available

– Precise estimates of the risk non-AIDS (on/off HAART) events are not available

– We do not know the exact individual risk/benefit ratio NNH/NNT.

– We do not know the exact population risk/benefit ratio NNH/NNT.

A RCT might be a very important instrument but there are still questions about feasibility (enrolment, duration, duration of benefit, impact of toxicity, other)


“The practice of medicine is an art, based on science. Medicine is a science of uncertainty and an art of probability”

Sir William Osler

Dealing with uncertainty

Documents

When to START Antiretroviral Therapy?