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Current Clinical Controversies in the Treatment of HIV/AIDS
Paul E. Sax, MDPaul E. Sax, MD
Clinical Director, Division of Infectious Diseases and HIV Program
Brigham and Women’s HospitalAssociate Professor of Medicine
Harvard Medical SchoolBoston, Massachusetts
2
Faculty:Content Development and Training
Calvin J. Cohen, MD, MSResearch Director, CRI New England
Clinical Instructor, Harvard Medical SchoolBoston, Massachusetts
Edwin DeJesus, MD, FACPInfectious Disease Consultants
Medical Director, Orlando Immunology CenterOrlando, Florida
Paul E. Sax, MDClinical Director, Division of Infectious Diseases and HIV Program
Brigham and Women's HospitalAssociate Professor of Medicine, Harvard Medical School
Boston, Massachusetts
Learning Objectives (CME, CE, CPE) At the completion of this educational activity, participants
should be able to:— Describe and discuss current controversies regarding
HIV treatment— Identify key studies that potentially can improve
outcomes with HIV treatment — Summarize the clinical data supporting methods for
improving the health and management of HIV-infected patients
4
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
5
2009 DHHS Guidelines: Recommendations for Initiation of ART in Naïve Patients
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.
Strength of Recommendation: A = Strong; B = Moderate; C = Optional Quality of Evidence for Recommendation: I = data from randomized controlled trials; II = data from well-designed nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = expert opinion
Note: HIV RNA >100,000 c/mL and decline of CD4+ count > 100 cells/mm3 per year favor starting ART
Clinical CategoryCD4 Cell Count
(cells/mm3)2009 DHHSGuidelines Strength-Quality
AIDS-defining illness Any value TreatA-I
Asymptomatic
<350 Treat
350 to 500 Treat A/B-II: 55% A vs. 45% B
>500 Treat/Optional B/C-III: 50% B vs. 50% C
Pregnancy, HIV-associated nephropathy, HIV/HBV when HBV treatment indicated
Any value Treat A-III
6
SMART: Influence of CD4+ Count and Treatment on Clinical Event Rate
Last CD4+ Cell Count (cells/mL)
<250 250–349
350–499 ≥500 Overall
Immediate ART
Person-yrs (%)*
10 (2.6)
30 (7.9)
109 (28.8)
230 (60.7)
379(100)
Rate** 10.4 6.7 1.8 0.0 1.3
Deferred ART
Person-yrs (%)*
19 (6.4)
65 (21.7)
118 (39.5)
97 (32.4) 299 (100)
Rate** 16.0 9.2 7.6 3.1 7.0
Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.Emery S et al. 4th IAS, Sydney, 2007. Abstract WEPEB018.
Opportunistic Disease and Death
Cum
. Pro
babi
lity
(X10
0) 25
Months
Deferred ARTImmediate ART
HR = 4.38 (95%CI, 1.45–13.2); P=.009
5
20
10
15
00 84 12 16 20 24 28 32 36
Serious Non-AIDS (CV, Renal, CA)
HR = 7.05 (95% CI, 1.58–31.5); P=.01
36
Cum
. Pro
babi
lity
(X10
0)
Deferred ARTImmediate ART
5
20
10
25
15
00 84 12 16 20 24 28 32
Months *Time spent in the CD4+ cell count category censored at event**per 100 person years
7
NA-ACCORD: Risk of Death with ART Deferral
351-500 CD4+ >500 CD4+
RR 95% CI P RR 95% CI P
Deferral of ART 1.7 1.3, 2.3 <0.001 1.9 1.4, 2.8 <0.001
Female Sex 1.2 0.9, 1.6 0.24 1.9 1.3, 2.6 <0.001
Older Age(per 10 years) 1.7 1.5, 1.9 <0.001 1.8 1.6, 2.1 <0.001
Baseline CD4 count (per 100 cells/mm3) 1.1 0.7, 1.8 0.59 0.9 0.9, 1.0 0.03
● HIV RNA was not an independent predictor of mortality● Exclusion of IDU or HCV did not affect overall relative risk● Rate of virologic suppression (<500 c/ml) higher in pts who started ART earlier
Kitahata M, et al. New Engl J Med 2009;360:1815-26.
8
ART-CC: When Should ART be Started?
Hazard ratios for AIDS or death, adjusted for lead time/unseen events
Sterne J, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 72LB.
44
Haz
ard
Rat
io f
or
AID
S o
r D
eath
Haz
ard
Rat
io f
or
AID
S o
r D
eath
22.5.5
11
500500 400400 300300 200200 100100 00CD4 Threshold (cells/mm3)CD4 Threshold (cells/mm3)
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)
9
Magnitude of increase in CD4 cell count greatest if therapy started at low CD4 cell counts, but greater likelihood of CD4 cell count
normalization with earlier therapy
1. Moore R, et al. Clin Infect Dis. 2007;44(3):441-446; 2. Gras L, et al. J Acquir Immune Defic Syndr. 2007;45(2):183-192.
Likelihood of Achieving a Normal CD4 Cell Count Depends on Where You Start
1000
800
600
400
200
0
0 48 96 144 192 240 288 336
ATHENA National Cohort2
Weeks From Starting ART
<5050-200200-350350-500≥500
Years on ART
Johns Hopkins HIV Clinical Cohort1
Mea
n C
D4
Cel
l C
ou
nt
(cel
ls/m
m3)
0 1 2 3 4 5
200
400
600
800
0
1000
<200
201-350
>350
10
● Patients initiating ART should be willing and able to commit to lifelong treatment and understand the benefits and risks of ART and the importance of adherence
● Patients and clinicians may defer therapy based on clinical or personal circumstances
● The decision to defer should depend on CD4 count and viral load
● Deferring therapy may be considered for:- Adherence barriers- Comorbidities that complicate or prohibit ART- Elite controllers/Long-term nonprogressors
2009 DHHS Guidelines: Conditions Where Deferral of Therapy Might be Considered
Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision December 1, 2009.
11
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
12
DHHS Guidelines: TDF/FTC a part of all Preferred Regimens for Treatment-Naïve Patients
Preferred Regimens
• EFV/TDF/FTC• ATV/r + TDF/FTC• DRV/r (once daily) + TDF/FTC• RAL + TDF/FTC[Pregnant Women Only: LPV/r (twice daily) + ZDV/3TC]
AlternativeRegimens
• EFV + (ABC or ZDV)/3TC• NVP + ZDV/3TC• ATV/r + (ABC or ZDV)/3TC• FPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• LPV/r (once or twice daily) + either [(ABC or ZDV)/3TC1] or TDF/FTC• SQV/r + TDF/FTC
AcceptableRegimens
• EFV + ddI + (3TC or FTC)• ATV + (ABC or ZDV)/3TC
InsufficientData
• MVC + ZDV/3TC• RAL + (ABC or ZDV)/3TC• (DRV/r or SQV/r) + (ABC or ZDV)/3TC
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
13
Studies Comparing ABC/3TC and TDF/FTC
A5202 HEAT ASSERT
Sponsor NIAID GSK GSK
Sample Size 1858 (797 HIV RNA > 100,000 c/mL)
688 385
Blinding Double-Blind Double-Blind None
3rd Drug EFV or ATV/r LPV/r QD EFV
Primary Endpoint Time to Virologic Failure*
<50 c/mL at 48 wks Change in GFR at wk 48 by MDRD
HLA-B*5701 Testing Permitted, not required No Required, only negative pts enrolled
Key Results For those with HIV RNA >100,000 c/mL, study stopped early due to higher rate of virologic failure with ABC/3TC
ABC/3TC non-inferior
No difference in eGFR; proportion <50 c/mL favored TDF/FTC (71% vs. 59%; difference 11.6%, 95% CI 2.2-21.1); Total hip and lumbar spine BMD decline more with TDF/FTC
*Confirmed >1000 c/mL between wks 16-24, >200 c/mL wk 24 on)
14
No. at Risk
ABC-3TC 398 363 313 267 222 188 137 87 49 20
TDF-FTC 399 361 321 284 236 204 160 104 65 23
A5202: Time to Virologic Failure in Patients with Baseline HIV RNA >100,000 c/mL
Sax PE, et al. NEJM 2009;361:2230-2240.
0
20
40
60
80
100
0 12 24 36 48 60 72 84 96 108
Weeks since Randomization
Pro
ba
bil
ity
of
No
Vir
olo
gic
F
ail
ure
(%
)
TDF-FTC (26 events)
ABC-3TC (57 events)
P<0.001, log-rank testHazard ratio, 2.33 (95% CI, 1.46-3.72)
Probability of No Virologic Failure
15
A5202: Virologic Failure According to Baseline Characteristics
Sax PE, et al. NEJM 2009;361:2230-2240.
ABC-3TC
(N=398)
TDF-FTC
(N=399)
Sub GroupEvents/person-yr at risk (Events per 100
person-yr)Hazard ratio (95%)
P Value for interaction
Overall 57/398 (14.82) 26/399 (6.34) 2.33 (1.46-3.72) <0.001
Sex 0.04
Male 50/331 (15.41) 18/345 (5.24) 3.00 (1.74-5.17)
Female 7/67 (11.63) 8/54 (11.97) 0.85 (0.30-2.39)
Age 0.07
30yr 3.24 (1.73-6.08)
40yr 2.08 (1.28-3.39)
Race or ethnic group 0.55
White 18/170 (10.33) 8/202 (3.63) 2.82 (1.22-6.53)
Black 26/112 (26.71) 12/94 (13.93) 1.94 (0.96-3.90)
Hispanic 9/103 (8.87) 6/93 (6.59) 1.35 (0.48-3.83)
HIV-1 RNA 0.20
5.5 log10 copies/mL 2.64 (1.58-4.40)
6.0 log10 copies/mL 3.39 (1.60-7.22)
CD4 count 0.007
50 cells/mm3 3.54 (1.97-6.36)
200 cells/mm3 1.68 (0.98-2.88)
Genotype tested at screen 0.02
Yes 22/175 (14.05) 3/166 (1.99) 7.21 (2.15-24.20)
No 35/223 (15.35) 23/233 (8.88) 1.71 (1.00-2.91)
0.04 1.00 25.00
ABC-3TC Better TDF-FTC Better
16
HEAT: Virologic Failure by Baseline HIV-1 RNA Using A5202 Efficacy Endpoint
8790 9087
0
20
40
60
80
100
<100,000 ≥100,000
ABC/3TC
TDF/FTC
Perc
ent w
ithou
t Viro
logi
c Fa
ilure
n = 188 155 140205
Pappa K, et al. 17th IAC, Mexico City, 2008. Abst. THAB0304.Young B, et al. 48th ICAAC/46th IDSA, Washington, DC, 2008. Abst. H-1233.
41%
63%
18%
19%18%
4%22%
15%
0%
20%
40%
60%
80%
100%
ABC/3TC TDF/FTC
Pro
po
rtio
n o
f S
ub
ject
s w
ith
VF
≥500,000 c/mL
250,000 - <500,000 c/mL
100,000 - <250,000 c/mL
<100,000 c/mL
~59%~59%
~37%~37%
17
ASSERT: Proportion of Subjects with HIV-1 RNA <400 and <50 copies/ml by Visit (TLOVR)
Observed analysis: ≥90% in both arms achieved <50c/ml at Week 48
77%71%67%59%
CD4 cell count increase 150 c/mm3 at Wk 48 in both arms
Pro
po
rtio
n(%
)
0
10
20
30
40
50
60
70
100
0 24 48
Week
36124
80
90
W48 difference for % <400 cps/ml was 9.5% (95% CI: 0.6,18.4)
W48 difference for % <50 cps/ml was 11.6% (95% CI: 2.2, 21.1)
ABC/3TC FDC QD: HIV-1 RNA <400 copies /mL TDF/FTC QD: HIV-1 RNA <400 copies /mL
ABC/3TC FDC QD: HIV-1 RNA <50 copies /mL TDF/FTC QD: HIV-1 RNA <50 copies /mL
Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1.
18
ASSERT: Adjusted Mean Change in eGFR (MDRD)
Subjects at Visit
TDF/FTC QDABC/3TC QD 192 158 144
193 176 167
Ch
an
ge
fro
m B
L i
n G
RF
by
MD
RD
(m
L/m
in/1
.73
m2
)
-8
-6
-4
-2
0
2
4
6
8
0 24 48
Week36124
172181
155173
135159
ABC/3TC QD TDF/FTC QD
Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1.
nAdjusted
Mean S.E. Diff.95% CI forDifference P-value
ABC/3TC FDC QD 174 0.22 0.890
TDF/FTC FDC QD 184 1.18 0.828 0.953(-1.445, 3.351)
0.435
19
ASSERT: % Change from Baseline in Hip and Spine Bone Mineral Density
Stellbrink H-J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 10/1.
ABC/3TC: -1.90%TDF/FTC: -3.55%= -1.68 ; 95% CI (-2.26, -1.09)
ABC/3TC: -1.59%TDF/FTC: -2.41%= -0.84 ; 95% CI (-1.61, -0.06)
SubjectsABC/3TC: 176 134 117 182 141 125TDF/FTC: 180 156 138 183 165 143
0
-1
- 2
- 3
- 4
0 24 48
Total Hip0
-1
- 2
- 3
- 4
0 24
P<0.001
Lumbar Spine
48
P=0.036
week week
% c
han
ge
in B
MD
% c
han
ge
in B
MD
20
D:A:D Study: NRTIs and Risk of MI
Lundgren J, et al. 16th CROI, Montreal, Canada, 2009. Abstract 44LB.; Sabin C, et al. Lancet. 2008;371:1417-26..
* Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddC)
ZDV ddI ddC d4T 3TC ABC TDF#PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157#MI: 523 331 148 405 554 221 139
1.9
1.5
1.2
1
0.8
0.6
Recent Exposure*: yes/noCumulative Exposure: per year
**
Rel
ativ
e R
isk
of
MI (
95%
CI)
Adjusting for eGFR does not change ABC MI finding:Adjusted RR 1.89; 95% CI (1.46 – 2.44; p=0.0001)
21
VA Case Registry: Use of ABC or VA Case Registry: Use of ABC or TDF in Last Regimen and Risk of MITDF in Last Regimen and Risk of MI
Bedimo R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOAB202.
Unadjusted HR of AMI for each PY of exposure to each one of the categoriesAdjusted for estimated GFR prior to regimen onset (by MDRD method)
NRTI in last regimenduring obs. period
ABC TFV Both ABC and TFV
Haz
ard
rat
io
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
22
DHHS Guidelines:Criteria for Preferred PI
● The following criteria distinguish between preferred and alternative PIs:1. Superior or noninferior virologic efficacy compared to another
PI regimen, with at least 48-week data published;2. No more than 100mg of ritonavir per day;3. Once-daily dosing;4. Low pill count; and5. Good tolerability
● Using these criteria, ATV/r QD and DRV/r QD are preferred PIs
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
23
DRV/r and ATV/r in ARV-Naïve Patients: Higher Response Rates than LPV/r
Adapted from: 1. Mills A, et al. AIDS May 29, 2009 [Epub ahead of print]; 2. Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d
*Estimated difference in response vs LPV/r for superiority: ITT = 8.3% (95% CI 1.8;14.7, P=0.012)
ARTEMIS1
(ITT, TLOVR)*96 weeks
LPV/r QD or BID
DRV/r 800/100 QD
79
71
n=343n=346
0
20
40
60
80
100
CASTLE2
(ITT, NC=F)96 weeks
ATV/r300/100 QD
LPV/r400/100 BID
6874
0
20
40
60
80
100
n=443 n=440Pat
ien
t P
erce
nt
<50
co
pie
s/m
L
24
ARTEMIS: DRV/r Better Tolerated than LPV/r
Grade 2–4 adverse events*≥2% incidence, n (%)
DRV/r (N=343)
LPV/r (N=346)
Mean exposure (weeks) 95.0 91.4
Any grade 2–4 AE at least possibly related 80 (23) 119 (34)
GI AEs (all AEs) 23 (7) 52 (15)
Diarrhea 14 (4)‡ 38 (11)
Nausea 6 (2) 10 (3)
Rash (all types) 9 (3) 5 (1)
*Excludes laboratory abnormalities reported as adverse events; ‡p<0.001 vs LPV/r; no other AEs showed a statistically significant difference between the two treatment arms
Mills A, et al. AIDS May 29, 2009 [Epub ahead of print].
25
CASTLE:ATV/r Better Tolerated than LPV/r
a Through 96 weeksb Excluding lab abnormalities reported as AEs
Molina J-M, et al. 48th ICAAC/46th IDSA , Washington, DC, 2008. Abst. H-1250d.
ATV/rn = 441n (%)
LPV/rn = 437n (%)
Serious Adverse Events (SAEs) 63 (14) 50 (11)
Grade 2-4 treatment-related AEsa 133 (30) 140 (32)
Grade 2-4 treatment-related AEs 3%a,b
Jaundice 18 (4) 0
Nausea 18 (4) 33 (8)
Diarrhea 11 (2) 54 (12)
26
Comparing PI Lipid Profiles
*Significantly different from LPV/r: P<0.0001 ATV/r vs. LPV/r; p<0.001 DRV/r vs. LPV/r (TC+TG)
Molina J, et al. 48th ICAAC/46th IDSA. Abst. H-1250d; Mills A, et al. Ibid. Abst. H-1250c; Walmsley S, et al. 11th EACS. Abst. PS1/4; Pulido F, et al. 47th ICAAC. Abst. H-361.
Mean (CASTLE) or Median (ARTEMIS)Total Cholesterol and Triglyceride Level Increases at 96 Weeks
*
100 mg RTV QD
200 mg RTV QD
** *19
14
26
18
36
55
35
56
0
10
20
30
40
50
60
Total Cholesterol Triglycerides
CASTLE: ATV/r + TDF/FTC
ARTEMIS: DRV/r + TDF/FTC
CASTLE: LPV/r + TDF/FTC
ARTEMIS: LPV/r + TDF/FTC
Lip
id V
alu
es
mg
/dl
27
D:A:DExposure to PIs and Risk of MI
D:A:D Study includes 33,308 patients, 580 with MI
Lundgren J, et al. CROI 2009, abstract 44, 2/8/2009
1.9
1.131.1
1
0.9
MI
RR
Per
Yea
r (9
5%C
I)
IDV NFV LPV/r SQV
68,469298
56,529197
37,136150
44,657221
PYFU:MI:
PI*
* Approximate test for heterogeneity: P=0.02Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents
28
Cumulative exposure (per additional year)
No. exposed
No. exposed
cases OR [ 95% CI ] P value
Saquinavir 324 92 0.96 0.80 – 1.15 0.669
Indinavir 497 146 1.10 0.98 – 1.24 0.117
Nelfinavir 453 131 1.12 0.98 – 1.28 0.110
Lopinavir 290 94 1.37 1.09 – 1.72 0.006
Amprenavir/Fosamprenavir 117 46 1.52 1.19 – 1.95 0.001
ANRS:Exposure to PIs and Risk of MI
● Nested, case-control study to evaluate association between risk of MI exposure to NRTIs and PIs
● Over 115,000 HIV-infected patients enrolled between 1989 and 2006- Cases: 289 Patients with a first definite or probable MI prospectively
reported between January, 2000 and December, 2006- Matched Controls: For each MI case, up to 5 controls with no history
of MI matched for age, sex and clinical center
Lang S, et al .16th CROI; Montreal, Canada; February 8-11, 2009. Abst . 43LB.
Note: Insufficient number of pts on DRV/r and ATV/r to assess those agents
29
RAL: Pros and Cons
● PROs- New class
- No baseline resistance in ARV-naïve pts
- Well Tolerated
- Relatively few significant drug interactions
- Established efficacy in experienced pts
- No apparent teratogenicity
- No lipoatrophy based on early (48 week) data
● CONs- BID
- No long-term data
- No randomized data with NRTIs other than TDF/FTC
- PK/PD relationship unclear
- Resistance data still emerging
- No second generation agent available
30
100
80
60
40
20
00 8 16 24 32 40 48 60 72 84 96
Immunologic: 240 vs. 225 cells/mm3 (95% CI -13,+42)
Study Week
% P
ati
en
ts w
ith
HIV
RN
A L
ev
els
<5
0 C
op
ies
/mL
86%
82%
81%
79%
Non-inferiorityP-Value <0.001
STARTMRK: RAL and EFV Have Similar Virologic Efficacy Through 96 Weeks
Patients with HIV RNA <50 c/mL Through 96 Weeks (Non-Completer = Failure)
Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.
RAL + TDF/FTC EFV + TDF/FTC
31
STARTMRK: Adverse Events
● Overall adverse events similar between arms● CNS events higher in EFV arm, but
- were transient, mild and occurred within first 48 weeks- Led to few discontinuations- Rates of depression were similar between groups
AEs RAL (%) EFV (%) P value
Overall AE 266 (94.7) 275 (97.5) 0.086
Drug Related AE 132 (47) 220 (78) <0.01
Serious Clinical AE 40 (14) 34 (12) 0.457
Deaths 3 (1) 0
Malignancies 3 (1) 11 (4)
CNS 81 (29) 171 (61) <0.001
Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.
32
STARTMRK: Mean Change in Metabolic Parameters to Week 96
Change in TC/HDL ratio was RAL -0.18 and EFV -0.04 (p=0.192)Change in TC/HDL ratio was RAL -0.18 and EFV -0.04 (p=0.192)
-10
-5
0
5
10
15
20
25
30
35
40
45
T Chol HDL LDL TG
Mea
n C
han
ge
(mg
/dl)
RAL + TDF/FTC EFV + TDF/FTC
P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001 P<0.001P<0.001
Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.
33
STARTMRK: Mean Change in DEXA Morphological Parameters to Week 48
0
5
10
15
20
25
Appendicular Trunk Total
Me
an
% C
ha
ng
e in
Fa
t fr
om
B
as
elin
e
RAL + TDF/FTC EFV + TDF/FTC
DeJesus E, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1571.
34
Recent Studies Comparing Non-Preferred to Preferred ARVs
Overall virologic failures: NVP QD 11.2%, NVP BID 12.8%, ATV/r 14.0%
Pat
ien
ts (
%)
wit
h H
IV R
NA
<50
c/m
L
ITT: 95% CI= -5.9% to 9.8%; p=0.63
67 65
0
20
40
60
80
100
ATV/rNVP (QD/BID)
1. Soriano V, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924c;2. Heera J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009. Abst. TUAB103.
ARTEN: Comparison of NVP and ATV/r in ARV-naïve pts starting at CD4+ <400 (Men)
and <250 (Women) (N=569)1
MERIT-ES: Comparison of EFV and MVC in ARV-Naïve Patients with an R5 screening
result by enhanced Trofile assay2
6259
0
20
40
60
80
100
MVCEFV
Week 48 <50 c/mL Week 96 <50 c/mL
• D/C for AEs: 15.5% EFV vs. 6.1% MVC
• Virologic failures: 5.9% EFV vs. 12.5% MVC
Pat
ien
ts (
%)
wit
h H
IV R
NA
<50
c/m
L
35
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
36
Potential Treatment Simplification Strategies
● Substitution of co-formulation for individual agents (e.g., EFV + TDF/FTC to EFV/TDF/FTC)
● Substitution for a single component of the regimen (e.g., ENF to RAL) to improve tolerability or decrease/prevent toxicity
● Dose or regimen de-escalation (e.g., Discontinuation of RTV or PI/r monotherapy)
● Maximizing the use of PK properties to achieve less drug exposure (e.g., FOTO)
37
Simplification Improves Adherence
* Using the Mixed Effect ModelDeJesus E, et al. ICAAC, San Francisco, 2009. # H1572
Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*Analysis of Three Once-daily HAART Regimens by Daily Pill Burden*
QD
do
seQ
D d
ose
TDF + FTC + EFV TDF/FTC + EFV TDF/FTC/EFV
0 192144Week 9648
3 pills 1 pill2 pills
Extension phaseExtension phase
Daily Pill Burden Comparison P Value
1 vs. 2 0.2304
1 vs. 3 0.0005
2 vs. 3 0.0262
Once-Daily RegimensTDF + FTC + EFV
(n=238)TDF/FTC + EFV
(n=162)TDF/FTC/EFV
(n=157)
Daily Pill Burden 3 2 1
Dose Duration (study wks) BL → 96 97 - 144 145 – 240
Mean Adherance Rate (%) 95.6 97.0 97.9
38
EASIER: Quality of Life After Switch from Enfuvirtide to Raltegravir
Boulet T, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PE 7.2/2.
ENF + OBT HIV RNA <400 c/mL(Stable > 3 mos.)
Screening Randomization 1:1SWITCH RAL + OBT
MAINTENANCE ENF +OBTRAL + OBT
–W4 –W1 D0 W24 W48
-1.3
-5.3-4.7
2
5.84.8
-6
-4
-2
0
2
4
6
8
Significant Changes in Quality of Life From BaselineMaintenance Arm RAL arm
Physical Summary Pain Social Functioning
P=0.003 P=0.02P=0.001
Me
an
sc
ore
ch
an
ge
fro
m B
as
eli
ne
to
We
ek
24
BetterHRQoL
WorseHRQoL
39
SWITCHMRK 1 & 2:Study Design
● Identical, multicenter, double-blind, randomized, active-controlled studies
● Enrolled pts with HIV RNA <50 c/mL on LPV/r BID regimen in combination with at least 2 NRTIs- No limit on number of prior
ART regimens- Prior virologic failure not an
exclusion- No lipid lowering therapy
for at least 12 weeks
● Randomized (1:1) to continue LPV/r or switch to RAL
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
SWITCHMRK 1 SWITCHMRK 2
RAL
(N=174)
LPV/r
(N=174)
RAL
(N=176)
LPV/r
(N=178)
HIV RNA
≤ 50 c/mL94.3% 92.5% 96.0% 95.5%
Mean CD4 (cells/mm3) 478 508 471 482
LPV/r ≤ 1 yr 16.7% 17.8% 17.6% 18.5%
Median yrs prior ART(min, max)
3.3
(0.3, 22.3)
3.6 (0.5,
20.2)
3.7 (0.5,19.2)
4.6 (0.6,16.3
)
Median # prior ART(min, max)
5.0
(4.0, 16.0)
5.0 (2.0, 5.0)
5.5 (3.0,13.0)
6.0 (4.0,14.0
)
40
● Statistically significant improvements in total cholesterol, non-HDL cholesterol and triglycerides were observed following switch to RAL
● Further Analysis underway to assess factors associated with failure after switch to RAL- Previous Resistance: 84% with confirmed HIV RNA >50 c/mL) in the RAL group were not on 1st
ART regimen; 66% with history of VF on prior regimen(s)- NRTI Backbone: Virologic failure rate higher on ABC/3TC than TDF/FTC
SWITCHMRK 1 and 2:Virologic Outcomes (NC = F)
Eron J, et al. 16th CROI, Montreal, Canada, 2009. Abst. 70aLB.
Per
cen
t H
IV R
NA
<50
Co
pie
s/m
L
50
60
70
80
90
100SWITCHMRK 1
0 4 8 12 24Weeks
81%
87%
(95% CI) : -6.6 (-14.4, 1.2)
0 4 8 12 24Weeks
94%
88%
(95% CI) : -5.8 (-12.2, 0.2)
SWITCHMRK 2
41
SWITCHMRK 1 and 2:Lower Response with ABC than TDF
http://www.emea.europa.eu/humandocs/PDFs/EPAR/isentress/Isentress-H-860-II-10-AR.pdf
Study 032: <50 copies/mL (Observed Failure)* Difference in percent
response
% (95 CI)
Raltegravir Lopinavir/r
Population n/N % (95 CI) n/N % (95 CI)
Total 139/154 90.3 (84.4, 94.4) 152/162 93.8 (88.9, 97.0) -3.6 (-10.0, 2.5)
Concurrent background ART
TDF** 72/79 91.1 (82.6, 96.4) 69/75 92.0 (83.4, 97.0) -0.9 (-10.4, 8.8)
ABC** 20/25 80.0 (59.3, 93.2) 22/23 95.7 (78.1, 99.9) -15.7 (-35.9, 4.1)**The difference in response was similar in study 033 (-12.9 % for ABC vs -4.6% for TDF)**plus FTC or 3TC
42
MONET: Simplification to DRV/r QD Monotherapy
Arribas J, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUAB106.
N=2562NRTIs + PI/r or NNRTI
HIV RNA<50 X 6 monthsNo h/o VF; DRV naive
N=2562NRTIs + PI/r or NNRTI
HIV RNA<50 X 6 monthsNo h/o VF; DRV naive
DRV/r 800/100 mg QD + 2 NRTI* (n = 129)
DRV/r 800/100 mg QD (n = 127)
96 wks96 wks
DRV/r + 2NRTIs DRV/r
HIV RNA < 50copies / mL, ITT, TLOVER,S=F 85.3% 84.3%
HIV RNA < 50 at last visit 97.7% 97.6%
Primary PI mutation 1 1
Grade 2-4 GI AEs ≥ 2% incidence 3.9% 5.5%
Grade 2-4 GI AEs ≥ 2% incidence( all types ) 1.6% 1.6%
ALT > 5 x ULN 1.6% 4.8%
Total Cholesterol > 300mg / dL, sustained 1.6% 4.8%
43
IMANI III: Lopinavir/r QD Monotherapy
● 48 week open-label pilot study
● Evaluated efficacy, safety and tolerability of LPV/r QD monotherapy in pts with undetectable VL while in active follow-up post IMANI I or after completion of IMANI II (LPV/r BID in ARV-naïve patients)
LPV/r QD monotherapy for simplification: Caution warranted until results from larger ongoing
studies evaluated
Gathe J, et al. 12th EACS; Cologne, Germany; November 11-14, 2009. Abst. PS 4/5.
IMANI III
31 Subjects
IMANI I
4 Subjects
IMANI II
27 Subjects
2 protocol defined
failures at Week 36
1 LFTU at
Week 48
27 Subjects
Week 48
SubjectBaseline
Mutations Week VLOn Treatment
Mutations
007 L63P 36 4,145M461, I54V, I62V, L63P,
V82A
021L63P, A71T
36 3,582L10V, V32I,
M46I/W, I47V, L63P, A71T
44
DHHS Guidelines:Regimen Simplification
● Switching patients with an extensive treatment history from LPV/r to RAL should be done with caution
● RAL can safely substitute for ENF in patients not previously treated with integrase inhibitors
● Any drug substitution may introduce unanticipated adverse effects or drug-drug interactions
● PI/r monotherapy studies have reported mixed results and should not be regarded as a clinical strategy until further data are available
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
45
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
46
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm
2009 DHHS Guidelines: Opt-out Testing
● Patients must be identified early in the course of HIV infection, making earlier initiation of therapy an option
● Most HIV-infected patients are not diagnosed until they are at much later stages of disease
● For the current treatment guidelines to have maximum impact, opt-out testing per current CDC recommendations is essential
47
CDC Recommendation for HIV Testing in Adults and Adolescents
● Routine, voluntary, HIV screening for all persons aged 13–64 years, not based on risk
● Opt-out HIV screening• Opportunity to ask questions and option to decline
● Consent for HIV test is part of general consent for care• Separate consent not recommended• Prevention counseling not required in conjunction with HIV screening
● Low-prevalence setting• If yield from screening <0.1%, continued routine screening not warranted
Branson BM et al. MMWR Recomm Rep. 2006;55(RR-14):1-17.
48
Removing Written Consent Increases HIV Testing Rates
● After HIV testing opt-out policy change, rate of HIV tests per 1000 patient-visits increased 4.38 (CI, 2.17–6.60, p<0.001)
● No increase in ordering of other tests (hematocrit or creatinine) or of HIV testing in control setting without policy change
● Increase occurred across all patient populations and led to a rise in newly-diagnosed HIV
Zetola PLoS One. 2008;3(7):e2591
20
15
10
5
0
HIV
Te
sts
per
1,0
00
pat
ien
t -v
ts
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
SFGH HIV Tests
50
40
30
10
0Te
sts
per
1,0
00 v
isit
s
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
Creatinine Tests
20
20
15
10
5
0
HIV
Te
sts
per
1
0,0
00
Lab
ora
tory
t
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
Control University-based Medical Center HIV Tests
Hematocrit Tests
50
40
30
10
0Te
sts
per
1,0
00 v
isit
s
0 6 12 18 24 30 36
MonthsJuly 2004 June 2007
Before Policy After Policy
20
49
Changing HIV Testing Laws: Impact on Survival
● Comparison of diagnosis rates in states with opt-out vs. opt-in testing
● In states with opt-out testing, HIV is diagnosed at a higher CD4 cell count better treatment outcomes
● Computer-based simulation model of HIV disease applied to these data
● If all remaining states switched to opt-out, potential national survival gain would be > 600,000 life years
April M, et al. 47th IDSA Meeting, Philadelphia, 2009. Abst. 1254
50
HIV Testing Expansion: Earlier Diagnosis, Higher CD4 Counts
● Program to expand testing in medical and jail settings in Washington, DC began in 2006
● Since program began, patients diagnosed with higher CD4 counts at initial testing
● During first 18 months of program, increase in median CD4+ count at diagnosis to 332 cells/mm3
Median CD4+ Countat Time of Testing
215
187 198220
262
332
183
0
50
100
150
200
250
300
350
2001 2002 2003 2004 2005 2006 2007
Year of HIV Diagnosis
Me
dia
n C
D4
Co
un
t
Hader S, et al. 16th CROI; 2009; Montreal. Abstract 57.
51
Adoption of Opt-out Testing
Opt in Opt out
Written consent required: n= 8 (MA, MI, NE, OR, NY, PA, WI, RI)
Mahajan AP, et al. Ann Intern Med 2009;150:263-9.
52
Why is Opt-out Screening Not Being Implemented in All States?
● Need to reduce stigma and discrimination before universal testing
● Before universal testing there must be universal prevention counseling for HIV-negative and treatment and care for HIV-positive
● Broad testing leading to increase in numbers of HIV- positive patients entering into care could potentially have grave consequences due to a lack of funding and healthcare resources
● While it is everyone’s human right to know their HIV status, they also have the right to decide when and where they will be HIV tested
The Global Network of People living with HIV, Scaling up HIV Testing: Different perspectives; http://www.gnpplus.net/component/option,com_docman/task,cat_view/gid,245/Itemid,53/?mosmsg=You+are+trying+to+access+from+a+non-authorized+domain.+%28search.yahoo.com%29; Accessed 12/10/09
53
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
54
First Positive HIV Vaccine Trial
● 16,401 patients enrolled from 2003-2005 in Thailand in placebo-controlled trial
● Intervention: Canarypox ALVAC-HIV and glycoprotein 120 AIDSVAX B/E (“boost)
● Intervention reduced infection by 30%
Rerks-Ngarm S et al. N Engl J Med 2009.
0.00.10.20.30.40.50.60.70.80.91.0
0 0.5 1 1.5 2 2.5 3 3.5
Years
Prob
abili
ty o
f HIV
-I In
fect
ion
(%)
PlaceboPlacebo
VaccineVaccine
Intention-to-analysisIntention-to-analysis Modified Intention-to-analysisModified Intention-to-analysis
0.00.10.20.30.40.50.60.70.80.91.0
0 0.5 1 1.5 2 2.5 3 3.5
Years
Prob
abili
ty o
f HIV
-I In
fect
ion
(%)
P<0.05
55
Many PrEP Trials Pending
Study/Location
Sponsor/ Funder
Population (mode of exposure) Intervention arms (s)
Status/ExpectedCompletion
US Extended Safety Trial (CDC 4323)United States
CDC 400 gay/men and other men who have sex with men (penile/rectal)
Daily oral TDF Fully enrolled/2009Fully enrolled July 2007Final data analysis Q1/10
Bangkok Tenofovir Study(CDC 4370)Thailand
CDC 2,400 injecting drug users (parenteral)
Daily oral TDF Enrolling/20101st interim analysis Q4/09
CAPRISA 004South Africa
CAPRISA, FHI, CONRAD, USAID,LIFElab
1,200 heterosexual women (vaginal)
Coitally dependent topical tenofovir gel
Fully enrolled/20101st interim analysis in Q4/082nd interim analysis in Q3/09
iPrExBrazil, Ecuador, Peru,South Africa, Thailand, US
NH, BMGF 3,000 gay men and other men who have sex with men (penile/rectal)
Daily oral TDF/FTC Enrolling/20111st interim analysis in Q4/09
TDF2 (CDC 4940)Botswana
CDC 2,000 heterosexual men and women (penile and vaginal)
Daily oral TDF/FTC
(switched from TDF Q1 2007)
Enrolling 2012
Partners PrEPKenya, Uganda
BMGF 3,900 serodiscordant heterosexual couples (penile and vaginal)
Daily oral TDF & daily oral TDF/FTC
Enrolling 2012
FEM-PrEPKenay, Malawi, South Africa, Tanzania, Zambia
FHI, USAID, BMGF
3,900 heterosexual women (vaginal)
Daily oral TDF/FTC Enrolling 2012
VOICE (MTN 003)South Africa, Uganda, Zambia, Zimbabwe, additional sites to be determined
MTN, NIH 5,000 heterosexual women (vaginal)
Daily oral TDF; daily oral TDF/FTC; daily topical tenofovir gel
Enrolling 2013
IAVI E001 and E002Kenya, Uganda
IAVI 150 serodiscordant couples and at-risk men and women (vaginal and penile/rectal)
Daily oral TDF/FTC; intermittent oral TDF/FTC (twice weekly – coital dosing)
Planning/2010Anticipated start Q3/2009
Ongoing ARV based Prevention (Oral PrEP and Topical Microbicide) Trials (September 2009)
BMGF-BI & Melinda Gates Foundation; CAPRISA – Centre for the AIDS Programme of Research in South Africa; CDC – US Centers for Disease Control and Prevention; FHI – Family Health International; FTC – emtricitabine; IAVI – International AIDS Vaccine Initiative; MTN – Microbicide Trials Network; NIH – US National Institute of Health; Q1-4 – quarters 1-4; TDF – tenofovir disoproxil fumarate; USAID – United States Agency for International Development
56
A Major PrEP Issue:Is it Cost-Effective in the US?
● Computer simulation of HIV acquisition, detection, and care to model PrEP among MSM at high risk of HIV in US
● Model assumed 50% PrEP efficacy and TDF/FTC $753/month● Base-case: $298,000/Quality-adjusted life year (QALY) – not
generally considered cost-effective by US standards
Paltiel AD, et al. Clin Infect Dis 2009;48:806-815..
$0 $100,000 $200,000 $300,000 $400,000 $500,000+ $0 $100,000 $200,000 $300,000 $400,000 $500,000+
TDF Resistance (0%-100%)
ART Efficency Reduction (0%-15%)
PrEP Toxicity (None Extreme scenario)
Cohort age (30-34)
HIV Testing Frequency (Never-Annual)
PrEP Cost Multiplier (0.1-1.0)
HIV Injection Incidence Multiplier (0.3-2.0)
PrEP Efficiency (90%-20%)
Incremental Cost per QALY
57
2009 DHHS Guidelines: Preventing Secondary Transmission of HIV
● Essential tools for prevention of sexual and blood-borne transmission of HIV include:- Consistent and effective use of ARV therapy, resulting in a
sustained reduction in viral load;- Consistent condom usage;- Safer sexual and drug use practices; and- Detection and treatment of STIs
● Medical visits provide an opportunity to:- Reinforce HIV prevention messages;- Discuss sexual- and drug-related risk behaviors;- Diagnose and treat intercurrent STIs; and
- Develop open communication between provider and patient
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
58
HIIV Treatment Reduces the Risk of Transmission
ARV StatusCY
ObservationNo. LinkedInfections
InfectionRate (C-Y)
Infection RateRatio (95% CI)
Not on ARV 5,062 171 3.4/100 ---
On ARV 547 4 0.7/100 0.21 (0.08, 0.59)
On ARV –conservative*
547 6 1.0/100 0.32 (0.14, 0.73)
● Sexual risk behaviors lower in those on ART (19% vs 25%, P<0.05)● Both ART and change in behavior independently reduced HIV
transmission
*Includes 2 partners who seroconverted in the same 3-month interval when the HIV-infected partner initiated ARVs
2,993 couples were followed for a median of 512 days
HIV-free Survival of HIV-negative partners,by ARV status of HIV+ Partner
0
2073920
500
1035475
1000
598256
1500
25269
2000
806
2500
00
0.0
0.2
0.4
0.6
0.8
1.0
Su
rviv
al P
rob
ab
ilit
y
Days
Off ARV On ARV
CensoredLogrank P<.0001
Sullivan P, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 52bLB.
59
Potential Impact of “Test and Treat” Strategy on HIV Epidemic and Use of ART
Granich R, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPL101.
Strategy: Universal ARTART if CD4+ <350 cells/mm3No ART
0.0000.0050.0100.0150.020
Inc
ide
nc
e/y
ea
r
0.00
0.05
0.10
0.15
Pre
va
len
ce
0.00
0.05
0.10
0.15
1980 2000 2020 20400.000
0.005
0.010
Mo
rta
lity
/ye
ar
0.000
0.005
0.010
1980 2000 2020 2040
HIV ART
Pro
po
rtio
n o
f ad
ole
scen
ts a
nd
ad
ult
s 15
yea
rs o
r o
lder
0.0000.0010.0020.0030.0040.005
60
Concerns Regarding Using “Test and Treat” Strategy
1. Crepaz N et al. JAMA 2004;292:224-236; 2. Vernazza PL, et al. AIDS 2000;14:117-21; 3. Marcelin, A-G, et al. AIDS 2008;22:1673-81.
HIV RNA detected in semen of 7/145 (5%) of men with VL <40 c/mL
#
HIV RNA in seminal
plasma (c/mL) ARV combination
1 940 ZDV, 3TC, IDV, RTV
2 257 3TC, EFV, LPV/r
3 1230 ZDV, 3TC, LPV/r
4 255 TDF, FTC, AZT
5 802 ZDV, 3TC, IDV, RTV
6 267 FTC, ATV, RTV
7 620 TDF, FTC, EFV
HIV in semen in ARV naïve and ARV treated men with VL <400
0%
20%
40%
60%
80%
100%
HIV-RNA HIV-DNA
Pe
rce
nta
ge
of
pa
tie
ns
wit
h
de
tec
tab
le H
IV i
n s
em
en Controls (drug naïve ) n=55
Effective treatment n=114
P<0.0001P<0.0001
P<0.01P<0.01
● Patients who believe that ART or an undetectable viral load protects against transmitting HIV have higher rates of unprotected sex (OR 1.82; 95% CI, 1.52-2.17)1
● While HIV RNA significantly lower in semen of pts on ART with an undetectable plasma HIV RNA, still detectable in some2,3
61
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities
62
Life Expectancy of ARV-treated Patients by CD4 Nadir
Depending on when HAART is started, life expectancyduring modern HAART era is 10 to 30 years less than that
in uninfected patients
CD4+ Nadir (cells/mm3) < 100 100-200 >200
Life expectancy at age 20 (years)
32 42 50
ART-Cohort Collaboration. Lancet. 2008;372:293-299 (see also Lohse N, et al. Ann Intern Med. 2007;146:87-95 and Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77.)
Life Expectancy by CD4+ Nadir When HAART Started
63
Kaplan RC, et al. Clin Infect Dis. 2007; 5:074-1081.
Traditional Health Related Risk Factors More Prevalent Among HIV-positive Patients
0 10 20 30 40 50 60 70 80
0 10 20 30 40 50 60 70 80
Prevalence, % (95% CI)
High LDL Level
Low HDL Level
HighTriglycerides Level
Hypertension
Smoking
Overweightor Obese
Diabetes
HIV+ Men
HIV- Men
HIV- Women
HIV+ Women
64
Many Non-AIDS Events Appear to be Higher in Treated HIV Disease than Controls
● Cardiovascular disease1-4
● Cancer (non-AIDS)● Bone fractures/osteopenia5,6
● Left ventricular dysfunction● Liver failure7
● Kidney failure● Cognitive decline (controversial)8
● Frailty9
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
65
Many Factors Contribute to Non-AIDS Events Being More Common In HIV
Behavior
Pre-HAARTHarm
HAARTToxicity
PersistentImmuneDefects
PrematureAging
Deeks and Phillips, BMJ 2009
66
Association Between Current CD4 Cell Count and Non-AIDS Complications
StudyNon-AIDS
malignancies Renal disease/death CVD events/deathLiver disease/
death
FIRST Yes Yes Trend, NS No
D:A:D Yes Yes Trend, NS Yes
CASCADE Yes NA Yes Yes
SMART Trend, NS Trend, NS Trend, NS Yes
Phillips A, et al. 15th CROI; 2008; Boston. Abstract 8.
Is Lower Current CD4 Cell Count Significantly Associated With Increased Risk of non-AIDS Events?
67
DHHS Guidelines: T-cell Activation and Inflammation
● Early untreated HIV infection associated with sustained high-level inflammation and T-cell activation which are associated with disease progression
● ART results in a rapid, but often incomplete, decrease in most markers of HIV-associated immune activation- Persistent inflammation, as represented by levels of IL-6, may be
associated with risk of death
● These observations support earlier use of ART:- Treatment decreases the level of inflammation and T-cell
activation; and- Degree of residual inflammation and/or T-cell dysfunction during
ART is higher in patients with lower CD4 cell nadirs and earlier treatment may result in less residual immunological perturbations
Adapted from US Department of Health and Human Services Guidelines; Revised December 1, 2009.Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf
68
Current Clinical Controversies in the Treatment of HIV/AIDS
1. When to Start: 2009 DHHS Guidelines
2. What to Start: 2009 DHHS Guidelines
3. Benefits and Limits of Simplification
4. Adoption of Opt-out Testing
5. Potential Strategies for HIV Prevention
6. The Importance of Non-AIDS Co-Morbidities