Nuevos paradigmas en el TARV
Anton Pozniak MD FRCPChelsea and Westminster HospitalLondonUK PK /SSR Research
New Paradigms Paradigm 1. Start Earlier to prevent Cancer?
Paradigm 2. Start with an NNRTI or PI/r-or should that be integrase?
Paradigm 3. Avoid nucleosides?-potency and tolerability
Paradigm 4. No more nucleosides
Paradigm 5. No more nucleosides and no more ritonavir
Paradigm 6. Baseline resistance is important
Paradigm 7. Check for Resistance before switching for failure or to simplify
Paradigm 8. Virological failure a paradigm for the minority?
Paradigm 9. Can Increase the CD4 with immune modulators but no clinical gain
Paradigm 10. New treatments seem more attractive than the old
Paradigm 1. Start Earlier ?
This means you have to
– diagnose HIV earlier and
– convince patients treatment will be good for them and
– they have to take it lifelong - for themselves and the Public health?
Consequences of this are financial, Social, health service capacity, patient well-being .
Need safe tolerable low toxicity drugs with high barrier to resistance and at least the promise of such drugs being developed that are better than the current compounds
NA-ACCORD: Survival Benefit With Earlier vs Deferred HAART
Kitahata MM, et al. ICAAC/IDSA 2008. Abstract H-896b.
Increased relative hazard of death with deferral of HAART remained unchanged when adjusted for IDU or for HCV coinfection, which were both independent predictors of mortality
Parameter Associated With Risk of Death Relative Hazard (95% CI)
Older age (per 10 years)
BL CD4+ cell count (per 100 cells/mm3 increase)
1.6
1.0 2.50.1
Deferral of HAART until < 350 cells/mm3 (vs starting at 350-500 cells/mm3)
Female sex
0.9
1.7
1.1
P Value
< .001
.290
< .001
.083
ART CC: Supports Initiating ART at CD4 Threshold of 350 cells/mm3
Analysis of 15 cohorts from US and Europe (ART Cohort Collaboration) N = 24,444
•Sterne J, et al. CROI 2009. Abstract 72LB
0.5
1.0
2.0
4.0
500 400 300 100
CD4 Threshold (cells/mm3)
HR
fo
r A
IDS
or
De
ath
*
200 0
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.
HIV,Cancer and Predictive factors FHDH-ANRS CO4 study
Cancer
Hodgkin's lymphoma, lung,, and liver cancer
Kaposi's sarcoma and non-Hodgkin lymphoma
Cervical cancer
Anal cancer
Predictive factors
Current CD4 cell count
Current CD4 cell count, current viral load, and absence of cART
Current CD4 cell count and absence of cART
Time CD4 count <200 cells /μL and viral load >5 log10 copies / mL.
•Guiguet , M et al lancet Oncology epub oct 2009
Paradigm 2. Start with an NNRTI or PI/r-or should that be integrase?
Guidelines are mixed on this but there is only one large randomised Trial that can inform us
Consequences of this are we are in a data free zone concerning the other Pis which have outperformed Kaletra
We also have good data on integrase but relatively short term data on toxicity and bd dosing and lack of co-formulation need to be addressed
What’s best a PI/r or an NNRTI?ACTG 5142: EFV vs. LPV/r
Results: 96 wks EFV LPV/r EFV/LPV/r
n=253 n=253 n=250
VL <50 c/mL 89%* 77% 83%CD4 count* +241 +285 +268Resistance 48%* 4% 68%Gr 3-4 ADR 18% 19% 20%
*P= <0.05
•Riddler SA. 16th IAC THLP0204
f
ACTG 5142: Lipoatrophy at Week 96
Haubrich R, et al. CROI 2007. Abstract 38. Reproduced with permission.
NRTI-Containing Regimens
EFV + 2 NRTIsLPV/RTV + 2 NRTIsEFV + LPV/RTV
Lipoatrophy defined as > 20% loss of extremity fat by DEXA
Drug-Associated Risk for Lipoatrophy at Week 96 (Logistic Regression)*
Factor OR (95% CI) P Value
EFV vs LPV/RTV 2.7 (1.5-4.6) < .001
d4T vs ZDV 1.9 (1.1-3.5) .029
TDF vs ZDV 0.24 (0.12-0.50) < .001
*Excludes NRTI-sparing arm.
Overall TDF
12
d4T
51
ZDV
40
17
6
33
16
0
15
30
45
60
9
32
Pat
ien
ts W
ith
L
ipo
atr
op
hy
(%)
Boosted PIs in ARV-Naive Patients: Which to use ?
010203040506070
8090
100
*P < .05
Pat
ien
ts W
ith
HIV
-1
RN
A <
50
cop
ies/
mL
(%
)
Ortiz R, et al. AIDS. 2008;22:1389-1397.. Molina JM, et al. Lancet. 2008;372:646-655.
440443
CASTLE[4]
(ITT) 48-Wk Noninferiority
ATV/RTV300/100
QD
LPV/RTV400/100
BID
76 7878*
ARTEMIS[3]
(ITT) 48-Wk Noninferiority
LPV/RTV†
400/100 BID or800/200
QD
DRV/RTV
800/100 QD
84*
444 343170 167
346n =
STARTMRK: Does the initial change in VL mean anything?
•Patients with HIV RNA <50 c/mL Through 96 Weeks (Non-Completer = Failure)
•100
•80
•60
•40
•20•0 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%
•Lennox J, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-924b.
•Non-inferiority
•P-Value <0.001
•RAL + TDF/FTC •EFV + TDF/FTC
Paradigm 3. We still want nucleosides but we have problems
-potency and tolerability
Guidelines are mixed on this but there are large cohorts that confuse us us
Consequences of this are we are in a data rich zone but only in quantity and not of sufficient quality to help make up our mind
Toxicity and potency are issues that need to be resolved
Abacavir and potencyACTG 5202: ABC/3TC vs TDF/FTC + EFV or ATV/RTV
Randomized, double-blind, open-label phase IIIb study
Sax PE, et al. IAC 2008. Abstract THAB0303.
TDF/FTC* 300/200 mg QD +EFV† 600 mg QD
ABC/3TC* 600/300 mg QD + EFV† 600 mg QD
Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL
TDF/FTC* 300/200 QD + ATV/RTV† 300/100 mg QD
ABC/3TC* 600/300 mg QD +ATV/RTV† 300/100 mg QD*Double blind.
†Open label.
Week 96primary endpoint
HIV-infected patients with HIV-1 RNA
> 1000 copies/mL
(N = 1858)
Abacavir A5202: Time to Virologic Failure (ITT)
No Significant Differences in Response to ABC/3TC by BL HIV-1 RNA in 6 Trials-so we wait for Assert-EACS and 5202 CROI!!HIV-1 RNA < 50 copies/mL at Week 48, % (n)
Third Drug
BL HIV-1 RNA < 100,000 copies/mL
BL HIV-1 RNA ≥ 100,000 copies/mL
CNA30021 EFV 65 (217) 67 (167)
CNA30024 EFV 72 (198) 67 (126)
ESS30009 EFV 67 (123) 61 (46)
SHARE ATV/RTV 76 (49) 77 (62)
KLEAN FPV/RTV 67 (197) 65 (237)
KLEAN LPV/RTV 64 (209) 66 (235)
HEAT
ABC/3TC LPV/RTV 67 (188) 57 (155)
TDF/FTC LPV/RTV 62 (205) 60 (140)
Pappa K, et al. ICAAC/IDSA 2008. Abstract 1251.
Abacavir and cardiac diseaseD:A:D: Recent and/or Cumulative Antiretroviral Exposure and Risk of MI
•Lundgren JD, et al. CROI 2009. Abstract 44LB..
# PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157# MI: 523 331 148 40 554 221 139
1.9
1.5
1.2
1.0
0.8
0.6ZDV ddI ddC d4T 3TC ABC TDF
# PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221
IDV NFV LPV/RTV SQV NVP EFV
PI† NNRTI1.2
1.13
1.0
1.1
0.9
1.9
1.5
1.2
1.0
0.8
0.6
*Current or within last 6 months. †Approximate test for heterogeneity: P = 0.02
NRTI
VA cohort Cumulative ABC Use Not Significantly Associated With MI
Events during period of observation
– 278 MIs; rate: 3.69 (95% CI: 3.28-4.15) per 1000 pt-yrs
– 868 CVAs; rate: 11.68 (95% CI: 10.93-12.48) per 1000 pt-yrs
•Bedimo R, et al. IAS 2009. Abstract MOAB202. Graphic used with permission.
MI
HR
per
Yr
of
Exp
osu
re
1.8
1.6
1.4
1.2
1.0
0.8
Unadjusted
Adjusted for MDRDAdjusted for traditional risk factors
1.27
1.09
1.44
1.23
1.02
1.39
1.18
0.99
1.29
P = .056 .113 .191 .146 .702 .866 < .0001 < .0001 .002
HAART With ABC(3881 Pt-Yrs)
HAART With Other NRTIs(25,077 Pt-Yrs)
Mono/Dual ARVs(6642 Pt-Yrs)
French Hospital database Association with boosted PI but not ABC if adjusted for cocaine
and other drug use!!
So what to do?
Preferentially use tenofovir??Abandon nukes??
Tenofovir and the ageing population- BMD Decreases With Age
Ch
ang
e in
Bo
ne
Vo
lum
e (%
)
Women
Men
Peak
Relative influence on peak bone mass (men):40% to 83% genetic 27% to 60% environmental 0.5%-1.0% reduction in
bone volume/year
Age (Years)Orwoll ES, et al. Endocr Rev. 1995;16:87-116.
0
0.2
0.4
0.6
0.8
1.0
0 30 60 8010 4020 50 70
0.1
0.3
0.5
0.7
0.9
Tenofovir and the ageing population-Chronic Kidney Disease Prevalence in General Population Increases With Age
Hallan SI, et al. Br Med J. 2006; 333:1047.
Age (Years)
0
5
10
15
20
25
30
0 20s 30s 40s 50s 60s 70s 80s > 90
Pre
vale
nce
(%
)
GFR (mL/min/1.73 m2):
10s
45-59 30-44 < 30
Tenofovir and Kidney Recovery of eGFR After TDF Cessation 26 HIV+ men changed from TDF because of eGFR <60
Median pr-TDF eGFR 72mL/min/1.73m2, post TDF eGFR 49
38% recovered to baseline, median time to pre-TDF eGFR = 15 months
•Wever K, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. TUPEB177.
•eGFR recovery after TDF change
•0
•20
•40
•60
•80
•100
• eG
FR
(M
DR
D)
•0
•10 •20 •30 •40
•Time after TDF change (months)
•Fitted values
•Time to pre-TDF eGFR
•0•0 •40•40•10•10 •30•30•20•20•0.00•0.00
•1.00•1.00
•0.25•0.25
•0.50•0.50
•0.75•0.75
• Pro
po
rtio
n o
f p
ati
en
ts• P
rop
ort
ion
of
pa
tie
nts
•Time after TDF change (months)•Time after TDF change (months)
Paradigm 4. No more nucleosides
Guidelines are mixed on this but there are large cohorts that confuse us us
Consequences of this are we are in a data rich zone but only in quantity and not of sufficient quality to help make up our mind
Toxicity and potency are issues that need to be resolved
We could forget the nukes and ignore the problem for a while at least!!
•HIV-infected pts taking
2 NRTIs + either NNRTI or boosted PI at
screening; no prior use of DRV; HIV-1 RNA
< 50 c/mL for at least 6 mos; no history of
virologic failure
•(N = 256)
•DRV/RTV 800/100 mg QD •+ 2 NRTIs*•(n = 129)
•DRV/RTV 800/100 mg QD •(n = 127)
Wk 96planned follow-up
•*NRTIs optimized at BL.
Wk 48 primary endpoint
•Arribas JR, et al. IAS 2009. Abstract TUAB106LB.
MONET Trial: Simplification to DRV/RTV Monotherapy in Suppressed Pts
Mean duration of therapy longer in monotherapy group: 7.4 vs 6.4 yrs in the DRV/RTV + 2 NRTIs arm
MONET Trial: 48-Wk Efficacy Results (ITT, TLOVR, Switch = Failure)
DRV/RTV monotherapy noninferior to DRV/RTV HAART at Wk 48
1 pt with virologic failure in each arm developed primary PI and/or multiclass mutations
Drug Resistance, n DRV Mono(n = 127)
DRV + 2 NRTIs
(n = 129)
Pts with 1 genotype 13 22
No primary PI, DRV, or NRTI mutations
12 21
M184V 1 0
Primary PI mutations 1 1
DRV RAMs 0 1
•Arribas JR, et al. IAS 2009. Abstract TUAB106LB.
HIV
-1 R
NA
< 5
0 c/
mL
at
Wk
48 (
%)
40
0
100
20
80
Overall (ITT)
85.3*84.3
60
DRVRTV mono arm (n = 127)DRV/RTV + 2 NRTIs arm (n = 129)
*Noninferiority definition: Δ lower limit < 12%; lower limit 95% CI: -1.0% to -9.9%
Adverse events similar between groups
DRV/RTV600/100 mg BID
+ 2 NRTIs(n = 113)
DRV/RTV Monotherapy600/100 mg BID
(n = 112†)
DRV-naive HIV-infected pts on HAART with HIV-1 RNA < 400 c/mL for ≥ 18 mos,
HIV-1 RNA < 50 c/mL at entry, no previous PI
failure, and CD4+ cell count ≥ 200 cells/mm3
(N = 226)
Wk 48 primary
endpoint
DRV/RTV600/100 mg BID
+ 2 NRTIs(N = 226)
Induction phase to
Wk 0*Begin induction phase at Wk -8
Follow-up to Wk 96
*Pts eligible for randomization into maintenance phase if HIV-1 RNA < 50 c/mL at Wk 8.†1 pt not eligible for randomization; ITT-E population = 225.
•Katlama C, et al. IAS 2009. Abstract WELBB102.
MONOI Study: DRV/RTV Monotherapy vs Triple Therapy in Suppressed Pts
MONOI: 48 Wk Outcomes With DRV/RTV Monotherapy vs Triple Therapy
DRV/RTV monotherapy met criteria for noninferior virologic efficacy vs DRV/RTV + 2 NRTIs at Wk 48 in PP analysis, but not in ITT-E analysis
– PP population = all pts from ITT population except pts who d/c tx without virologic failure or SAE (n = 10) or pts withdrawn without virologic failure or SAE (n = 6)
Virologic failure in 3 pts (2.7%) on monotherapy vs 0 on standard therapy
– Low DRV drug levels noted in 1 pt
– No DRV RAMs in any pt with virologic failure
– All 3 pts regained HIV-1 RNA < 50 c/mL on reintroduction of 2 NRTIs
Virologic Response at Wk 48, %*
DRV/RTV
DRV/RTV+ 2 NRTIs
Δ Lower Limit of 90% CI
PP analysis (n = 204)
94.1 99.0 -4.9 -9.0
ITT-E analysis (n = 225)
87.5 92.0 -4.5 -11.0
•Katlama C, et al. IAS 2009. Abstract WELBB102.
Virologic failure defined as consecutive HIV-1 RNA > 400 c/mL or treatment modification or discontinuation
Number of eventsDRV/r + 2 NRTIs
n=15
DRV/r
n=14
• MONOI Serious Adverse events
• *one HIV encephalitis and one neurological symptoms possibly related to HIV, both possibly related to study treatments
• HIV RNA CSF:580 cp/ml and 330 cp/ml
•2 •2•Infections•Psychiatric events•CNS disorders•Cardiovascular •Cancer
•Lipodystrophy•Surgery
•GI disorders•Hepatic transaminases increase
•CPK
•1 •0•1 •3*•2 •1•0 •3•0 •1•6 •3•1 •0•1 •1•1 •0
Nuke Free -The PROGRESS study
Proportion of Subjects with Plasma VL <40 copies/mL, %
LPV/r+RAL LPV/r+TDF/FTC P-value N,total
Week 2 33.3 (28/84) 9.9 (8/81) <0.001 165
Week 8 77.4 (48/62) 38.5 (25/65) <0.001 127
•T Podsadecki 15th BHIVA . UK. 2009. Poster 31 •T Podsadecki 15th BHIVA . UK. 2009. Poster 31
Are FTC and 3TC so safe that we can include them in Nuke free
regimens eg boosted PI plus 3TC? But....More pills more cost
Paradigm 5. No more nucleosides and no more ritonavir
Using atazanavir to boost raltegravir
GS9350 a new booster-no paradigm shift yet!!
Raltegravir + Atazanavir Study to explore RAL + ATV combination regimen
– Results:
– 92.6% response rate <50c/mL; (n=2 with virologic failure)
– 1 rebound with RAL mutations,
– 1 with ongoing low level viremia < 200 c/mL
– No significant AEs
•Pts on HAART•(N=27)
•Pts on HAART•(N=27)
•ATV 200 mg BID•RAL 400 mg BID•ATV 200 mg BID•RAL 400 mg BID
•24 week analysis
•Baseline Characteristics:•16/27 VL <50 c/mL•CD4 median 417 cells/mm3
•22 on PI regimen (10 on ATV)
•Ripamonti D, et al. 5th IAS; Cape Town, South Africa; July 19-22, 2009; Abst. MOPEB067.
•Entry Criteria:•RAL Naïve•No Hx PI mutations•No PPIs
•Conclusion: Novel dual BID regimen undergoing further study at this and higher doses of ATV BID
Dual Maintenance Therapy with Raltegravir 400 mg BID with Atazanavir 400 mg QD in Patients with no Prior PI Resistance and
Intolerance to Other ARV Regimens: Preliminary Report
PJ Ruane, et al ICAAC 2009 Poster H-914
Raltegravir + Atazanavir
Results• Primary Virological Endpoint (Week 24) % < 400 copies/mL (ITT M=F):
• 93% (27/29)
• Secondary Virological Endpoint (Week 24) % < 48 copies/mL (ITT M=F): 83% (24/29)
– Virological results : A “blip” (48-400 copies/mL) was measured in 4 subjects at baseline (range 51-91 copies/mL) and in 7 subjects (range 48-83 copies/mL) up to Week 24. All blip results were measured by TaqMan®.
– CD4 Results: mean CD4 cell count did not change
– ATZ PK (N=18): Mean plasma C24 ATV level was 62.3 ng/mL (95% CI: 41.0–84.7 ng/mL); median was 62.8 ng/mL (range 0–158 ng/mL). ATV levels in 4 subjects were < 20 ng/mL, 2 of these had levels = 0). Viral loads in these 4 subjects were < 48 copies/mL at all times
Compliance: 90% of subjects showed > 85% compliance as assessed by RAL pill countsRuane et al, H-914 ICAAC2009
Paradigm 6. Baseline resistance is important?
Can we be clever in the way we measure resistance?
– Moving away from population sequencing
CDC Survey: Drug-Resistant HIV Among Newly Diagnosed PatientsType of Resistance
Prevalence of Drug Resistance, %
1998[1] (N = 257)
1999[1]
(N = 239)2000[1] (N = 299)
2003-2004[2]
(N = 633)2003-2006[3]
(N = 3130)
Any drug 5.5 8.8 10.7 14.5 10.4
NRTI 5.1 7.1 7.7 7.1 3.6
NNRTI 0.4 2.1 1.7 8.4 6.9
PI 0 0.8 3.0 2.8 2.4
≥ 2 drug classes 0 1.3 1.3 3.1 1.9
1. Bennett D, et al. CROI 2002. Abstract 372. 2. Bennett D, et al. CROI 2005. Abstract 674.3. Wheeler W, et al. CROI 2007. Abstract 648.
Low frequency variants: Impact on Virologic Response with NNRTI
• What is the threshold of a low frequency resistance variant that is clinically significant for NNRTI- or PI-based HAART?
• Analysis of GS-934All baseline samples w/o detectable NNRTI resistance AS-PCR* with sensitivity down to 0.5%
• 16/476 (3.4%) + K103N by AS-PCR
• 6/16 (38%) had virologic failure• Threshold for failure: ≥2% (2,000 copies of HIV)
• GS-934: Multivariate logistic regression to predict risk of VF
•Goodman D, et al. Antiviral Therapy 2009;14 Suppl 1: A43
•*Allele-specific PCR
Baseline ParameterOdds Ratio
(95% CI)
P-Value
Chi-Square test
K103N ≥2,0%
K103N detectable and <2,%
47.4 (5.2, 429.2)
1.19 (0.15, 9.71)
0.0006
0.8703
BL HIV RNA >100,000 0.98 (0.51, 1.88) 0.9471
BL CD4 ≥200 cells/mm3 0.60 (0.31, 1,16) 0.1282
Treatment arm 0.75 (0.40, 1.41) 0.3695
Paradigm 7. Check for Resistance before switching whether its for failure or to simplify
Etravirine + NRTIs after NNRTI-based regimen
•TMC125•Control
•0
•-•1
•-•2
•Weeks
•0
•4 •8 •12 •16•59 •56 •46 •36 •29•59•n (TMC125)=
•57 •55 •49 •33 •29•57•n (control)=
• Ch
ang
e in
lo
g v
iral
lo
ad (
mea
n)
•Ruxrungtham K, et al HIV Medicine 2008;9:883-896.
•Initial 1.3 log decline in viral load was not sustained past 8 weeks, because of baseline mutations 28.8% had 3 or more NNRTI mutations and 35% 3 or more NRTI
SWITCHMRK -1 and -2: Switch From Stable LPV/RTV- to RAL-Based HAART
•Switch to RAL* •(Protocol 032: n = 174; •Protocol 033: n = 176)
•Continue LPV/RTV* (Protocol 032: n = 174; •Protocol 033: n = 178)
HIV-infected patients with undetectable
HIV-1 RNA for ≥ 3 months
on LPV/RTV-based regimen
(Protocol 032: N = 348; Protocol 033: N = 354)
HIV-1 RNA < 50 copies/mL at
Week 24
Stratified by duration of previous LPV/RTV therapy
(≤ vs > 1 yr)
Mean change in lipids at Week 12
*All patients continued treatment with background regimen including at least 2 NRTIs. No exclusion for number of previous regimens or history of previous virologic failure.
Median previous antiretroviral drugs, n (range)
Ral5.0 (4.0-16.0)
LOP/r5.0 (2.0-15.0)
RAL5.5 (3.0-13.0)
LOP/r6.0 (4.0-14.0)
SWITCHMRK -1 and -2: Switch From Stable LPV/RTV- to RAL-Based HAART
Virologic Outcomes at Wk 24, NC = F
RAL + ARVs, n 174 166 169 173 172 176 176 176 176 175
LPV/RTV + ARVs, n 174 171 171 171 174 178 178 177 177 178
50
60
70
80
90
100
0 4Weeks
HIV
-1 R
NA
< 5
0 c/
mL
(%
)
8 12 24
87%
81%
∆ : -6.6 (95% CI: -14.4 to 1.2)
Protocol 032 Protocol 033
50
60
70
80
90
100
0 4Weeks
8 12 24
∆ : -5.8 (95% CI: -12.2 to 0.2)
94%
88%
HIV
-1 R
NA
< 5
0 c/
mL
(%
)
Eron J, et al. CROI 2009. Abstract 70aLB. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.
Median previous antiretroviral drugs, n (range)
Ral5.0 (4.0-16.0)
LOP/r5.0 (2.0-15.0)
RAL5.5 (3.0-13.0)
LOP/r6.0 (4.0-14.0)
Paradigm 8. Managing Virological failure a strategy for the minority?
Do we always need a boosted PI in salvage?
•30
•90
•0
•60
•120
•RR*: 1.46113.6
•RR*: 0.5415.1
•1998-99 •2004-05
Incidence of Second VF Declining Over Time
•1996-97
•In
cid
ence
per
10
0 P
atie
nt-
Yea
r
•RR*: 0.5117.9
•RR*: 0.8241.5
•REF70.7
•2000-01 •2002-03
•Deeks S, et al. CROI 2008. Abstract 41.
•*Adjusted for time from HAART initiation, sex, age, AIDS, CD4+ cell count, HIV-1 RNA level at HAART initiation and switch, and type of HAART.
Goals for Treatment Experienced Patients
“Goal of new regimen...plasma HIV RNA < 50 copies/mL after six months”
Currently available drugs can achieve the same efficacy in treatment-experienced patients as in treatment-naïve patients
Management of Treatment-Experienced Patients
RulesUse at least 2 preferably 3 active
drugs based on all resistance testing and history
Use a new classEnsure good adherence
RAL + MVC + ETR in Triple Class– Experienced Patients-nuke free again Nonrandomized cohort study
0
100
200
300
Mea
n C
D4+
Cel
l Co
un
t
Incr
ease
(ce
lls/m
m3 )
Nozza S, et al. Glasgow 2008. Abstract P45. Reproduced with permission.
RAL + MVC + ETR (n = 28)
RAL + MVC or ETR (n = 20)
RAL + MVC or ETR + PI (n = 28)
RAL + PI (n = 19)
0
20
40
60
80
100
BL 4 12 24 36 48
Wks
HIV
-1 R
NA
< 5
0 c/
mL
, %
Regimen
Paradigm 9. You can Increase the CD4 with immune modulators but with no clinical gain Can you do better with
CCR5 inhibitors
ESPRIT: IL-2 Treatment Associated Increased CD4+ Cell Count HIV-infected patients receiving antiretroviral therapy with CD4+ cell counts ≥ 300 cells/mm3 N = 4111
Losso M, et al. CROI 2009. Abstract 90aLB. Graphic reproduced with permission.
•1 •2 •3 •4 •5 •6
•100
•200
•300
•400
•500
•600
•700
•800
Years
•0•0
•7
•Time Spent< 300 cells/mm3
> 600 cells/mm3
•ART + IL-26%
57%
•ART9%
36%•Avg difference: 160 cells/mm3; P < .001
•ART + IL-2ART (control)
•No. PtsART + IL-2
ART•2071 1846 1829 1797 1757 1721 1410 8782040 1928 1861 1803 1739 1648 1350 824
• CD
4+ C
ell C
ou
nt
(cel
ls/m
m3 )
ESPRIT: No Significant Effect of IL-2 on Incidence of OI or Death
Addition of IL-2 associated with significantly more grade 4 adverse events
•1 •2 •3 •4 •5 •6
•5
•10
•15
• Cu
mu
lati
ve P
rob
abili
ty
(x 1
00)
of
Eve
nt
Years•0
•0•7
•ART + IL-2ART
•8
•2071 2030 1997 1947 1909 1873 1552 971 3222040 2003 1962 1918 1883 1825 1483 910 272
•No. PtsART+ IL-2
ART
HR: 0.93 (95% CI: 0.75-1.16)
Losso M, et al. CROI 2009. Abstract 90aLB. Graphic reproduced with permission.
Will IL-7 be better?INSPIRE: Immunologic Effects of IL-7
Background on IL-7– Important in thymopoesis and CD4+ cell
maturation– Inverse correlation with CD4+ count
Study design– Phase II dose escalation: 10, 20, 30 µg/kg – Doses given on days 0, 7, 14– N=10/arm; 8 active:2 placebo– Enrollment criteria: On ART >12 mos.,
VL<50 c/mL, CD4 100-400 cells/mm3
Efficacy– Increases in CD8+ cells– Increases in naïve, central memory, and
effector memory CD4+ and CD8+ T cells– Increase in thymic emigrants
Safety– No SAEs– 4 blips in 20 mg/kg dose
•Changes in CD4+ Counts•1200
•1000
•800
•600
•400
•200
•0•Baseline •D7 •D14 •D21 •D28 •W12
•IL-7
• Med
ian
cel
ls/m
m3
•P=0.006, CYT107 10µg/kg, n=7
•P=0.004, CYT107 20µg/kg, n=8
•Placebo, n=4
•P=0.006, CYT107 10µg/kg, n=7
•P=0.004, CYT107 20µg/kg, n=8
•Placebo, n=4
•Levy Y, et al. 49th ICAAC; San Francisco, CA; Sept. 12-15, 2009; Abst. H-1230a.
•IL-7 20 μg/kg •IL-7 10 μg/kg
•Placebo
CCR5 inhibitors MERIT
CD4+ cell count increases were significantly higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)
? Due to CD4 cells remaining in circulation and unable to traffic into the tissues?
Paradigm 10. New treatments seem more attractive than the old.
New drugs
Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation
– another Berlin patient
Anti tat Ribozyme tharapy
Long acting therapies
New TargetsTetherin
Generics-old drugs with a new price
New Treatment paradigms
Anton Pozniak MD FRCPChelsea and Westminster HospitalLondonUK
•
•PK /SSR Research