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!
[Default][MC Any][MC All]
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