The International AIDS Society–USA

Strategies forAntiretroviral Therapy:

When to Start, How to Finish

Michael S. Saag, MDProfessor of Medicine

The University of Alabama at Birmingham

M Saag, UAB

HIV Infected Cells

Uninfected Resting CD4+ Lymphocytes

Uninfected Activated CD4+ Lymphocytes

Antiretroviral Rx

Latently Infected CD4+ Lymphocytes

HIV virions

M Saag, UAB

Vir

al L

oad

101

102

1

0310

4

105

10

6

0 2 4 6 8 10 12

Weeks

T1/2 = 1.1 days

RNA+ cells in Lymph node vs RNA in Plasma

HIV RNA+ cells/106 LN cells0.1 1 10 100 1000 10000

Pla

sma

Vira

l Loa

d (c

opie

s/m

l)

10

100

1000

10000

100000

1000000

10000000

<50

At steady state, when an actively producing cell dies, it is replaced by how many newly infected cells?

A. OneB. Twenty-fiveC. One hundredD. One thousandE. It depends on the viral load

M Saag, UAB

VL = 100,000

VL < 50

Vir

al L

oad

101

102

1

0310

4

10

5

106

0 2 4 6 8 10 12

Weeks

T1/2 = 1.1 days

Goals of Antiretroviral Therapy

• Prevent Clinical Progression• Prevent Resistance

NEJM, 1993

Impact of Replication on Resistance

0

10

20

30

40

50

60

High

Like

lihoo

d of

Res

istan

ce

Degree of Suppression

Case 1

–30 yo white man–Diagnosed on routine insurance examination–PMHx remarkable for HTN, diet controlled–No medications–Understands treatment issues and wants to

begin therapy if you think it is appropriate

If his viral load is 30,000 c/ml, at which CD4 count would you recommend starting

therapy?A. 750 cells / ulB. 500 cells / ulC. 350 cells / ulD. 300 cells / ulE. 250 cells / ulF. ≤ 200 cells / ulG. Would observeH. Would treat at any CD4 count

[Default][MC Any][MC All]

When To Start Treatment? – Summary of Current Guidelines

Guidelines symptoms orCD4 <200

CD4 200-350

CD4 >350

IAS-USA:JAMA 2008<www.iasusa.org>

treat treat Therapy should be considered and decision individualized

DHHS:<www.aidsinfo.nih.gov>

treat treat treat*

* Split opinion > 500

symptoms

CD4 Count at Initiation of ARV 2003-2005

Egger M, 14th CROI; 2007; Abstract 62.

Which of the following convinces you MOST to start therapy earlier in course of

HIV infection?

A. Cohort Study Results (NA-ACCORD / ART-CCB. Consequences of unchecked viral replication

(Inflammation / Harm)C. Improved tolerability / convenience of newer ARV

regimensD. Treatment reduces transmission of HIV E. Cost SavingsF. I have my own personal reasons!

[Default][MC Any][MC All]

Inverse Probability Weighted Cox Regression Multivariate Analysis

*Stratified by Cohort and Year

Relative Hazard (RH)*

95% Confidence

IntervalP-value

Deferral of HAART at 351-500 1.7 1.4, 2.1 <0.001

Female Sex 1.1 0.9, 1.5 0.290

Older Age (per 10 years) 1.6 1.5, 1.8 <0.001

Baseline CD4 count (per 100 cells/mm3) 0.9 0.7, 1.0 0.083

• Results were similar when restricting the analysis to the 77% of participants with baseline HIV RNA data• Adjusted RH for deferral vs. immediate treatment was also 1.7 95% C.I. 1.4, 2.2; p <0.0001• HIV RNA was not an independent predictor of mortality

.51

24

Haz

ard

Rat

io f

or A

IDS

or

Dea

th

0 100 200 300 400 500CD4 threshold (cells/mm3)

Hazard ratios for AIDS or death, adjusted for lead times and unseen events

Comparison Hazard ratio (95% CI)276-375 vs 376-475 1.19 (0.96 to 1.47) 251-350 vs 351-450 1.28 (1.04 to 1.57) 226-325 vs 326-425 1.21 (1.01 to 1.46)

A Randomized Clinical Trial of Early Versus Standard Antiretroviral

Therapy for HIV-infected Patients with a CD4 T Cell Count of 200 – 350

cells/ml (CIPRAHT001)

Daniel Fitzgerald, MDThe GHESKIO Centers, Haiti

Weill Cornell Medical College, USA

Baseline CharacteristicsEarly

(n=408)Standard (n=408)

Median age (years) 40 40

Male – n (%) 167 (41%) 179 (44%)

Median CD4 T cells/ml 280 282

Body Mass Index, kg/m2 21.4 21.0

Clinical Endpoints

Early (n=408)

Standard (n=408)

Hazards Ratio

(p value)

Death 6 23 4.0(.0011 )

Incident Tuberculosis

18 36 2.0(.0125 )

Slide 31

Case 1

–30 yo white man–Diagnosed on routine insurance examination–PMHx remarkable for HTN, diet controlled–No medications–Understands treatment issues and wants to

begin therapy if you think it is appropriate– VL is 30,000 c/mL– CD4 is 650 cells/ul

If his viral load is 30,000 c/ml, and his CD4 count is 650 cells/ul, at what age would

you recommend starting therapy?

A. 20 yrsB. 30 yrsC. 40 yrsD. 50 yrsE. 60 yrsF. 70 yrsG. Would treat at any ageH. Would not treat

[Default][MC Any][MC All]

Relative Time on Treatment…

30 35 40 45 50 55 60 65 70AGE (years)

CD4 650/ul

CD4 500/ul

40 years on Rx

35 years on Rx

5 years

Cohort Study Results (NA-ACCORD / ART-CC)

Consequences of unchecked viral replication (Inflammation / Harm)

Improved tolerability / convenience of newer ARV regimens

Treatment reduces transmission of HIV

Cost Savings I have my own personal reasons!

Relative Time on Treatment…

30 35 40 45 50 55 60 65 70AGE (years)

CD4 650/ul

CD4 500/ul

40 years on Rx

35 years on Rx

5 years

HARM?

So ….what is the harm?(Pick the most compelling reason)

A. Destruction of lymphoid tissueB. InflammationC. Increased Cardiovascular eventsD. Increased incidence of certain

malignanciesE. Increased ‘aging’F. Accelerated cognitive declineG. Another reason[Default]

[MC Any][MC All]

Question 1 – Cognitive Differences Detected?

*

*

Lower scores reflect better function.Trails A - Sig. Dif. for Age and HIVTrails B – Sig. Dif. For HIV

Question 1 – Cognitive Differences Detected?

*

Higher scores reflect better function.Finger Tapping - Sig. Dif. for HIV

Question 2 – Differences in TIADLs in Older and Younger Adults with

and without HIV?

*

*

Lower scores reflects better function.Age, HIV, and AgeXHIV effects observed.

Question 2 – Differences in TIADLs in Older and Younger Adults with

and without HIV?

Lower scores reflects better function.Age, HIV, and AgeXHIV effects observed for Total Score.

*

*

Cohort Study Results (NA-ACCORD / ART-CC)

Consequences of unchecked viral replication (Inflammation / Harm)

Improved tolerability / convenience of newer ARV regimens

Treatment reduces transmission of HIV Cost Savings I have my own personal reasons!

Willig, et al, AIDS, 2008

1st Line ARV Therapy: 2003- 2007

McKinnell, et al, AIDS Pt Care & STDs, 2010

Does treating HIV lead to reduced transmission of HIV?

A. YesB. NoC. Depends on the sexual practices!

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Most New Infections Transmitted by Persons who Do Not Know Their Status

~25% Unaware

of Infection

~75% Aware

of Infection

account for…

~54% New

Infections

~46% of New

Infections

Source: G. Marks et al. AIDS 2006

TNT: Based on the association of viral load and HIV transmission risk

0

5

10

15

20

25

30

Viral load (HIV-1 RNA copies/mL) and HIV transmission

Tran

smis

sio

n r

ate

per

100

Per

son

-Yea

rs

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

Quinn TC, et al. NEJM 2000; also Fideli U, et al. AIDS Res Hum Retrovir 2001

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

<40

0

400

-349

9

350

0-99

99

10 0

00-4

9 99

9

>50

000

All subjectsMale-to-FemaleTransmission

Female-to-MaleTransmission

Cohort Study Results (NA-ACCORD / ART-CC)

Consequences of unchecked viral replication (Inflammation / Harm)

Improved tolerability / convenience of newer ARV regimens

Treatment reduces transmission of HIV

Cost Savings I have my own personal reasons!

Prevention of Transmission

• TEST and TREAT – Testing and Linkage to Care (TLC+)

National AIDS Strategy…

Cohort Study Results (NA-ACCORD / ART-CC)

Consequences of unchecked viral replication (Inflammation / Harm)

Improved tolerability / convenience of newer ARV regimens

Treatment reduces transmission of HIV Cost Savings I have my own personal reasons!

Cost-Effectiveness of Early vs. Deferred ART

“Starting ART earlier … rather than later … is a cost-effective strategy (by the generally accepted benchmark in the US).”

ART Initiation

Incremental Lifetime Costs

Incremental Discounted

QALY* Gained

Cost Per Life-Year Gained

Cost PerQALY* Gained

CD4 >350 vs 200-350 $19,074 0.75 (0.61) $25,567 $31,226

CD4 200-350 vs < 200 $28,066 1.27 (1.09) $22,064 $25,806

Mauskopf JA, et al. JAIDS 2005;39:562-569.

Case 1

–30 yo white man–Diagnosed on routine insurance examination–PMHx remarkable for HTN, diet controlled–No medications–Understands treatment issues and wants to

begin therapy if you think it is appropriate

If his viral load is 30,000 c/ml, at which CD4 count would you recommend

starting therapy?

A. 750 cells / ulB. 500 cells / ulC. 350 cells / ulD. 300 cells / ulE. 250 cells / ulF. ≤ 200 cells / ulG. Would observeH. Would treat at any CD4 count[Default]

[MC Any][MC All]

START (Strategic Timing of ART) Study• INSIGHT Network: multinational• Study population: adults with CD4 >500• Study treatment:

– Immediate ART– CD4 <350

• Study endpoints:– Serious AIDS-defining illness, non-AIDS illness, death

• Sample size:– N=900 (pilot for feasibility)– N=4000 (definitive)

• Duration: ~6 yrs.

http://insight.ccbr.umn.edu/official_documents/START/protocol_documents/START_ProtocolSynopsis.pdf

CD4 Count at Initiation of ARV 2003-2005

Egger M, 14th CROI; 2007; Abstract 62.

Which of the following convinces you MOST to start therapy earlier in course of HIV infection?

A. Cohort Study Results (NA-ACCORD / ART-CC)B. Consequences of unchecked viral replication

(inflammation / harm)C. Improved tolerability / convenience of newer ARV

regimensD. Treatment reduces transmission of HIVE. Cost savingsF. I have my own personal reasons![Default][MC Any][MC All]

Case 1

–30 yo White Male–Diagnosed on routine insurance examination–PMHx remarkable for HTN, diet controlled–No medications–Understands treatment issues and wants to

begin therapy if you think it is appropriate

If his viral load is 30,000 c/ml, at which CD4 count would you recommend starting therapy?

A. 750 cells / ulB. 500 cells / ulC. 350 cells / ulD. 300 cells / ulE. 250 cells / ulF. ≤200 cells / ulG. Would observeH. Would treat at any CD4 count[Default][MC Any][MC All]

END of SESSION 1