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