robert murphy, m.d. professor of medicine director, center for global health
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Current Treatment Practice and Future Treatment Options. Robert Murphy, M.D. Professor of Medicine Director, Center for Global Health Feinberg School of Medicine Northwestern University Chicago and Professeur Associé de Recherche Université Pierre et Marie Curie Paris. - PowerPoint PPT PresentationTRANSCRIPT
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
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