Mitä tapahtui HIV -medisiinassa...

Mitä tapahtui

HIV-medisiinassa 2009 ?HIV-medisiinassa 2009 ?

Jarmo Oksi

dos, el

TYKS

Slide and text citations

• Clinical Care Options

www.clinicalcareoptions.com

• 12th European AIDS Conference /EACS11/2009 Cologne, Germany (website)

• IAS 2009, Cape Town, South Africa (website)• IAS 2009, Cape Town, South Africa (website)

• Journal Watch AIDS Clinical Care from the publishers of The New England Journal of Medicine

• www.who.int/hiv/pub/arv/rapid_advice_art.pdf

• www.aidsinfo.nih.gov

• www.europeanaidsclinicalsociety.org

New IDSA -guidelines: Primary

care for HIV-infected patientsAberg JA et al.CID 2009 Sep 1; 49:651

• Uudistuksina edelliseen (2004):

• HIV nyt krooninen kontrolloitu sairaus -> yleisen terveyden hoito ja seulonta: ikääntymiseen liittyvät

• Syfiliksen yhteydessä herkästi liq (ainakin jos neurol tai silmäoireita tai myöhäinen latentti syfilis)

• Virtsa-analyysi ja Krea-clearence suositeltavia ikääntymiseen liittyvät

sairaudet, syöpäseulonnat ym.

• Uusi HIV dg -> aina syytä tutkia lääkeresistenssi

• VZV-rokote niille jotka eivät vesirokkoa ole sairastaneet (CD4-taso >200)

clearence suositeltavia (munuaiskomplikaatioiden riski itse infektiossa ja eräillä lääkkeillä kuten TDF)

• HLAB5701 määritys ennen ABC –aloitusta

• Coreceptor tropismin testaus ennen maraviroc-aloitusta

ACP (American College of Physicians):

broad screening for HIV

Qaseem et al Ann Int Med 2009 Jan 20

• 10% - 25% of people who test HIV+ report no high-risk behaviors !!

• Almost half of all newly diagnosed pts are identiefied late in their illness …late in their illness …

• People unaware of their infection -> transmit 20 000 infections /year (USA)

• Screening is cost-effective even in low-risk communities!

• If 4000 consecutive, routine HIV tests are negative, the community prevalence is probably < 0,1% (low-risk population)

Life expectancy for HIV-infected

patients in the U.S.Harrison et al. J AIDS 2009 Sep 2

• CDC investigators, HIV surveillance data from 25 states

• 1996-2005 a total of > 220 000 pts w new HIV+ (55% black,

• Average life expectancy increased by 12 years during study period (from 10,5 years to 22,5 years in 2005)

• Greater in women than men (23,6 vs 22,0 yrs in 2005)HIV+ (55% black,

36% white, 9% hispanic) (75% men)

• 33% w CD4 <200

• By the end of 2007 10 366 (4,7%) have died

(23,6 vs 22,0 yrs in 2005)

• Worst among IVDU (15,2 in 2005)

• Racial/ethnic differencies especially among men (whites 25,5; hispanics 22,6; blacks 19,9 yrs in 2005).

• White women: 21,4 yrs.

No increase in transmitted

resistance in EuropeJ Infect Dis 2009 Nov 15; 200:1503

• 20 European countries 2002-2006

• N=2687 treatment-naïve pts, VL>1000 c/ml

• Prevalence of transmitted

• Stabilization of transmitted drug resistance at • Prevalence of transmitted

resistance 8,4%

• NRTIs 4,7%PIs 2,9%NNRTIs 2,3%

• Declining trend (ns); significantly declining of transmitted resistance to PIs

resistance at <10%

Seronegatiivinen HIV-infektioBártolo et al Rapid clinical progression to AIDS and death in a persistently seronegative

HIV-1 infected heterosexiual young man. AIDS 2009 Nov 13; 23:2359

• aiemmin terve 20 v mies

• 3 kk seksisuhde seksityöläiseen joka myös IVDU (kuoli 6kk:ssa, HIV-va +)

• painonlasku ja ”fatigue”

• 6 kk kuluessa CD4 ad 52, HIV-va neg edelleen

• Seerumin p24 ag + ja plasman VL sopivat HIV-infektioon

• Kuoli AIDSiin 6kk kuluessa • painonlasku ja ”fatigue”

• HIV-1 ja HIV-2 va neg

• 3 kk kuluttua sammas, CD4 232, HIV-va neg

• Kuoli AIDSiin 6kk kuluessa tutkimuksiin hakeutumisesta

• Phylogeneettiset tutkimukset osoittivat B/G rekombinantin variantin, CCR5-tropic. Eli myös tähän tropismiin voi liittyä nopeasti progredioiva tilanne

Long-term nonprogressors and HIV

controllers: definitions and prevalenceGrabar et al.: Prevalence and comparative characteristics of long-term

nonprogressors and HIV controller patients in the French Hospital Database on HIV.

AIDS 2009 Jun 1; 23:1163

• Of 46 880 pts who were followed prospectively, only 903 (2%) met inclusion criteria:- asymptomatic

• Four categories of clinically stable pts:- LTNP Long-term nonprogressors:HIV+ for >8 yrs and a CD4 nadir >500- Elite LTNPs: HIV+ for >8 yrs, CD4 nadir >600 and a positive CD4 count slope- HIV controllers: HIV+ for >10 yrs and 90% of measured VLs <500 c/mlinclusion criteria:

- asymptomatic- ART-naïve- known date of HIV dg- documented visit 2005- at least 3 measurements of CD4 count and VL during the previous 5 yrs

90% of measured VLs <500 c/ml- Elite HIV controllers: HIV+ for >10 yrs, 90% of measured VLs <500 c/ml, and the most recently measured VL <50 c/ml

• Of the 903 pts- 202 LTNPs- 25 elite LTNPs- 101 HIV controllers- 69 as elite HIV controllers

• Of the 25 elite LNPS 10 were also HIV controllers and 8 elite HIV controllers

• Of the 69 elite HIV controllers 32 were LTNPs and 8 were elite LTNPs

HIV rokote- ja mikrobisidi-tutkimuksissa

käänne parempaanNEJM 2009; 361:2209. Abstract 48LB CROI 2009

• 2008 näytti siltä, että kaikki mikrobisidi- ja rokotetutkimukset aina epäonnistuvat positiivisen efektin saamisen suhteen (miesten ympärileikkaus toki preventiona

• HPTN 035 trial (n>3000) (principal investigator Abdool Karim, S)- Africa & USA

ympärileikkaus toki preventiona näytti tehokkaalta)

• Thai RV144 trial (n>16 000) - ALVAC-HIV + AIDSVAX B/E vaccines, ITT analysis- vaccine recipients vs placebo had a 31% lower rate of HIV infection- which component responsible: either of the vaccines or poxvirus vector?

- Africa & USA- PRO 2000 gel was 30% effective in preventing HIV infection- strongest effect in women with low rates of condom use and high rates of gel use

Kantasolusiirto paransi HIV-infektion

NEJM 2009; 360:692• Case report

• HIV-infected man w AML

• Both CCR5 and CXCR4 –tropic viral variants

• Allogeneic stem-cell transplant-> drug-free virologic control

• Donor was (HLA-identical) and homozygous for the CCR5 delta32 alleleallele

• After transplantation: - absence of HIV-specific T cell responses- decline of HIV-specific ab responses- persistent lack of detectable virus (HIV-1 RNA and proviral DNA) in blood, BM, and rectal mucosa (where CCR5-expressing macrophages persisted)

• Role of immunosuppression for the prevention of GVHD ?

• Future? –> research in area of gene therapy directed at decreasiing the expression or functionality of the CCR5 coreceptor ?

Definitive results: IL-2 does not

benefit HIV-infected patients

NEJM 2009; 361:1548

• IL-2 improves CD4 cell recovery in pts on ART

• But: that benefit does not translate

• SILCAAT:-bl CD4 <300-CD4 cell count greater by 53 in IL-2 group

• ESPRIT:• But: that benefit does not translate into lower risks for disease or death

• 2 large trials: SILCAAT and ESPRIT; follow-up 7-8 years

• ESPRIT:-bl CD4 >300-CD4 cell count greater by 159 in IL-2 group

• Both studies:- no lower rate of death or OI in IL-2 group- higher rates of AEs in IL-2 group

ESPRIT: IL-2 + ART vs ART Alone in

Patients With CD4+ ≥ 300 cells/mm3

Antiretroviral Therapy

+ IL-2*

(n = 2071)HIV-infected patients receiving antiretroviral therapy with CD4+ cell

Median follow-up:

Antiretroviral Therapy

Alone

(n = 2040)

therapy with CD4+ cell counts ≥ 300 cells/mm3

(N = 4111)

*IL-2 induction phase: 3 cycles of 7.5 million IU twice daily for 5 days every 8 weeks. IL-2 maintenance phase: additional IL-2 cycles to maintain CD4+ cell count ≥ 1000 cells/mm3

or 2 x baseline level.

follow-up: 7 yrs

ESPRIT: IL-2 Treatment

Associated With Increased

CD4+ Cell Count

500

600

700

800

ART + IL-2

CD

4+

Ce

ll C

ou

nt

(ce

lls/m

m3)

Losso M, et al. CROI 2009. Abstract 90aLB. Graphic reproduced with permission.

1 2 3 4 5 6

100

200

300

400

500

Years

00

7

Time Spent

< 300 cells/mm3

> 600 cells/mm3

ART +

IL-2

6%

57%

ART

9%

36%

Avg difference: 160 cells/mm3; P < .001

ART + IL-2

ART (control)

No. Pts

ART + IL-2

ART

2071 1846 1829 1797 1757 1721 1410 878

2040 1928 1861 1803 1739 1648 1350 824

CD

4+

Ce

ll C

ou

nt

(ce

lls/m

m

ESPRIT: No Significant Effect of

IL-2 on Incidence of OI or Death

10

15

Cu

mu

lati

ve

Pro

ba

bil

ity

(x 1

00

) o

f E

ve

nt

ART + IL-2

ART

• Addition of IL-2 associated with significantly more grade 4 adverse

events

1 2 3 4 5 6

5

Cu

mu

lati

ve

Pro

ba

bil

ity

(x 1

00

) o

f E

ve

nt

Years0

07

ART

8

2071 2030 1997 1947 1909 1873 1552 971 322

2040 2003 1962 1918 1883 1825 1483 910 272

No. Pts

ART+ IL-2

ART

HR: 0.93 (95% CI: 0.75-1.16)

Losso M, et al. CROI 2009. Abstract 90aLB. Graphic reproduced with permission.

Raltegravir (RAL) - advantages and limitationsLancet 2009 Aug 3; 374:796; Lennox et al; Emery et al

Abstract 70aLB CROI 2009

• RAL - the 1st integrase inhibitor

• Phase II studies for treatment-naïve pts in 2007. Phase III studies presented in ICAAC 2008, now published in Lancet 2009.

• N=566, randomization to EFV qd or RAL bd. Both groups

• 48 week: - 86% of RAL pts- 82% of EFV ptsreached the primary endpoint of VL <50c/ml (significant -> non-inferiority)

• 48 week:Increase in CD4 count significantly or RAL bd. Both groups

received TDF + FTC.Half of the pts CD4<200. Half of the pts VL >100 000 c/ml.

Increase in CD4 count significantly greater w RAL than w EFV (CD4 count 189 vs 163)

• Rates of virologic suppression were similar btw RAL vs EFV

• AEs less common w RAL (CNS AEs 10% vs 18%)

• Virtual lack of drug-drug interactions

• Disadvantage: twice-daily use (A study of OD RAL is ongoing)

• RAL now for treatment-naïve pts

STARTMRK: Virologic and

Immunologic Efficacy at Wk 481

RN

A

< 5

0 c

op

ies/m

L (

%)

100

80

8682

∆ 4.2% (95% CI: -2 to 10);P < .001 for noninferiority

Me

an

CD

4+

Ce

ll C

ou

nt

Inc

rea

se

(c

ell

s/m

m3)

250

200189

163

∆: 26 cells/mm3 (95% CI: 4-47)

Lennox J, et al. ICAAC/IDSA 2008. Abstract H896a.

Pts

Wit

h H

IV-1

RN

A

< 5

0 c

op

ies/m

L (

%)

80

60

40

20

0M

ea

n C

D4

+ C

ell

Co

un

t In

cre

as

e (

ce

lls/m

m 200

150

100

50

0

163

RAL EFV RAL EFV

Clinical Role of Integrase

Inhibitors in Treatment-Naive Inhibitors in Treatment-Naive

Patients

CCO (clinicalcareoptions.com)

Summary of RAL Treatment-Naive Data

• Phase II (Protocol 004, N = 198): RAL comparable to EFV

in virologic efficacy at 144 wks

– HIV-1 RNA < 50 copies/mL: 78% RAL vs 76% EFV

– Fewer CNS adverse events with RAL vs EFV

– RAL had less effect on serum lipids vs EFV

• Phase III (STARTMRK, N = 563): noninferior virologic • Phase III (STARTMRK, N = 563): noninferior virologic

efficacy of RAL vs EFV at 96 wks

– HIV-1 RNA < 50 copies/mL: 81% RAL vs 79% EFV

– Fewer CNS adverse events with RAL vs EFV

– Lower cholesterol and triglyceride increases with RAL vs

EFV

1. Gotuzzo E, et al. IAS 2009. Abstract MOPEB030.

2. Lennox J, et al. Lancet. 2009;[Epub ahead of print].

RAL Drug Interactions• Fewer due to alternative metabolism: glucuronidation

(UGT1A1)

• TDF ↑ RAL 49%

• PI interactions

– ATV– ATV

• NNRTI Interactions

– ETR and EFV (RAL AUC ↓ 36%) acceptable

• Rifampin

– 40% reduction in RAL AUC; RAL dose increased to 800 mg BID when

administered with rifampin[1]

– ANRS study (N = 150) of EFV vs RAL 400 mg vs RAL 800 mg for

HIV/TB-coinfected patients[2]

1. Raltegravir package insert.

2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00822315.

Can RAL Be Dosed Once

Daily?• Study ongoing (QDMRK) to determine

safety and efficacy of RAL once daily vs

twice daily

– Treatment-naive patients – Treatment-naive patients

– RAL 400 mg BID vs RAL 800 mg QD, both

plus TDF/FTC

– Estimated enrollment: 750 patients

• Primary outcome: HIV-1 RNA < 50

copies/mL at Wk 48

ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00745823.

RAL Switch Regimens• RAL substituted for ENF in suppressed patients

– Many studies, including 1 randomized,[1] support this

use

– Rarely, unexpected adverse effects may occur

(depression)[2]

• SWITCHMRK[3]• SWITCHMRK

– Predefined criteria for virologic noninferiority not met

– Demonstrated lipid benefits

– When underlying resistance may be present (eg,

experienced patients, transmitted resistance), careful

patient selection needed

– Lower barrier to resistance with RAL vs boosted PIs

1. De Castro N, et al. IAS 2009. Abstract MOPEB066. 2. Harris M, et al. AIDS. 2009;22:1890-1892.

3. Eron J, et al. CROI 2009. Abstract 70aLB.

Principles Guiding Second-Line

Integrase Inhibitor–Containing

Regimens• Key strategy for success with integrase inhibitor–

containing regimens is inclusion of ≥ 2 active agents

• If resistance at VF with first-line NNRTI- or PI-based

regimen involves NRTI-associated mutations, NRTIs in

subsequent regimen cannot be considered fully activesubsequent regimen cannot be considered fully active

– Integrase inhibitor + 2 NRTIs may not be sufficient in

these cases

• In patients who discontinued first-line regimen, negative

genotypic resistance test does not necessarily indicate

absence of resistant viral population

– Particularly for M184V

• Use of RAL + boosted PI merits further study in 2 NRTI +

NNRTI failure patients

BRAVO:

Efficacy of RAL

Without a PI?

• Retrospective cohort (chart

review)

of RAL with or without PI

– PI cohort: 87% DRV, 36% ETR,

10% ENF (mean prior ARV: 4.1)

– No PI cohort: 66% ETR, 17% ENF,

13% MVC (mean prior ARV: 3.8; P

< .01 vs PI cohort)

– Most pts received NRTI TDF + FTC

1 R

NA

< 7

5 c

op

ies/m

L (

%)

80

RAL + Pl (n = 332)

No Pl (n = 110)

100

– Most pts received NRTI TDF + FTC

• GSS (similar between groups) a

significant predictor of Wk 12

response (P = .04)

– Treatment group (PI vs non-PI) and

number of ARVs not predictive of

virologic success

• Additional follow-up needed to

evaluate RAL without PI n = 442 336 373 195

HIV

-1 R

NA

< 7

5 c

op

ies/m

L (

%)

Baseline Wk 4 Wk 12 Wk 240

20

40

60

Skiest D, et al. IAS 2009. Abstract MOPE072. Reproduced with permission.

Maraviroc (MVC) now approved for

use in treatment-naïve patients

• A 96 week analysis (excluding pts w bl

samples w CXCR4-using virus) showed

response rates of 59% for MVC and 63%

for EFVfor EFV

• FDA expanded indications to include

treatment-naïves pts with CCR5-tropic

virus (tropism to be tested!)

• Twice-daily

MVC Another Potential Option

for Treatment-Naive Patients• MERIT-ES: similar virologic efficacy of MVC vs EFV, each with ZDV/3TC, at Wk 96 in

treatment-naive patients with R5-only virus using enhanced sensitivity phenotypic

tropism assay (post-hoc analysis)*

– HIV-1 RNA < 50 copies/mL in 60.5% vs 60.7%, respectively (TLOVR)

• EFV associated with greater lipid effects vs MVC

*MVC currently approved for treatment-experienced patients with resistance to multiple

Heera J, et al. IAS 2009. Abstract TUAB103.

*MVC currently approved for treatment-experienced patients with resistance to multiple antiretrovirals and CCR5-tropic virus.

Patients With Specified Lipid Parameter at Wk 96, % MVC

(n = 360)

EFV

(n = 361)

P Value

Total cholesterol ≥ 200 mg/dL (5.2 mmol/L) 10.8 38.7 < .0001

LDL cholesterol ≥ 130 mg/dL (3.4 mmol/L) 6.3 27.4 < .0001

LDL cholesterol ≥ 160 mg/dL (4.1 mmol/L) 1.5 9.9 < .0001

Triglycerides ≥ 200 mg/dL (2.3 mmol/L) 16.0 19.2 NS

Abacavir and CVD –

more data but no consensus• ACTG 5202 (Sax et al 2008): Shorter

Time to VF in Pts With High HIV-1 RNA on ABC/3TC (Proportion of pts with VF receiving ABC/3TC vs TDF/FTC: 14% vs 7%)

• HEAT randomized double-blind trial

• STEAL (Martin et al, CID 2009 Nov 15; 49:1591randomized, open label study (n=357 virologically suppressed HLAB5701-neg pts, treatment-experienced – switch from NRTIs to TDF/FTC or ABC/3TC): most of pts white men.

96 weeks: • HEAT randomized double-blind trial (n=688, treatment naïve pts) (Smith et al, AIDS 2009 Jul 31; 23:1547):

-48 weeks, VL<50 c/ml:68% w ABC/3TC +LPVr67% w TDF/FTC + LPVr

-96 weeks, VL<50 c/ml:60% vs 58% respectively-similar efficacy also in subgroups w high or low VL, low or better bl CD4 -similar rates of VF, similar drug discontinuations because of AEs

96 weeks: similar efficacy in ITT analysis, VF rates: TDF/FTC 3,9% vs ABC/3TC 5,6%-ABC/3TC: - significantly higher rate of serious

nonAIDS events, mainly CVD events- more likely lipid-lowering medicines

inititated- TDF/FTC: significantly lower bone mineral density

• Pts with high underlying CVD risk: consider an alternative to ABC

HEAT Wk 96: ABC/3TC

Noninferior to TDF/FTC; VF in

14% of Each ArmABC/3TC + LPV/RTV* (n = 343)

TDF/FTC + LPV/RTV* (n = 345)

< 5

0 c

op

ies/m

L (

%)[

1] 100

80

≥ 500,000 copies/mL

250,000 - < 500,000 copies/mL

100,000 - < 250,000 copies/mL

< 100,000 copies/mL

224

15100

80

1. Smith KY, et al. IAC 2008. Abstract LBPE1138. 2.Young B, et al. ICAAC/IDSA 2008. Abstract 1233.

Graphics reproduced with permission.

HIV

-1 R

NA

<

50

co

pie

s/m

L (

%)

80

60

40

20

0

60 58 56 55

MD = F‡M = F†

*LPV/RTV could be switched to FPV/RTV.†NRTI switches allowed.‡NRTI switches counted as failure.

18

VF

(%

)[2]

41

18

22

63

194

15

ABC/3TC(n = 49)

TDF/FTC(n = 48)

80

60

40

20

0

Weighing the Options: TDF/FTC vs ABC/3TCRegimen Advantages Disadvantages

ABC/3TC

• High level of efficacy in clinical trials with EFV or boosted PIs

• Similar efficacy to TDF/FTC in HEAT regardless of BL HIV-1 RNA

• HSR can be safely

• Preferred option only in IAS-USA guidelines

• Potential for HSR reaction to ABC

• Inferior response in pts with BL HIV-1 RNA > 100,000 c/mL in ACTG 5202

• Association with ↑ risk of MI in • HSR can be safely avoided with HLA-B*5701 assay

• Association with ↑ risk of MI in some studies

TDF/FTC

• High level of efficacy in clinical trials with EFV or boosted PIs

• Coformulated with EFV as QD regimen

• Preferred option in DHHS and IAS-USA guidelines

• Caution in pts with renal insufficiency

• Long-term nephrotoxicity and tubular toxicity not fully understood

• Should not be coadministered with other nephrotoxic drugs

• Bone toxicity

BICOMBO: No Difference in CV

Risk Markers After Switch to

ABC vs TDF• Retrospective analysis of subset of virologically suppressed pts who

switched from other NRTI to ABC (n = 46) or TDF (n = 34)

• Markers of inflammation, endothelial dysfunction, insulin resistance,

and hypercoagulability compared at BL and Wk 48

• None of these markers were significantly different between arms at ABC

15

0.1

• None of these markers were significantly different between arms at

Wk 48

Med

ian

Ch

an

ge F

rom

B

L a

t W

k 4

8 (

%)

-5

0

5

10

20

ABC

TDF

-3.9

5.94.0 5.1

-2.8

6.65.2

8.4

-2.0

7.8

-0.4-2.5

8.8

0.050.1

12.6

4.6

15.4

-2.2

P = .26

P = .52

P = .59

P = .12

P = .84P = .96 P = .13

P = .33

P = .69

P = .73

Martinez E, et al. IAS 2009. Abstract MOAB203. Graphic used with permission.

D:A:D: Antiretroviral Exposure

and Risk of MI• Updated analysis of D:A:D study (N = 33,308 from 11

cohorts)

– Earlier analyses of D:A:D study found increased risk

of MI associated with cumulative exposure to PIs and

recent exposure to ABC or ddIrecent exposure to ABC or ddI

– Current report analyzed association between

exposure to 13 antiretroviral drugs with sufficient

follow-up data and risk for MI in HIV-infected patients

– Data on drug exposure and MI risk reported with >

30,000 person-yrs of follow-up available

Lundgren JD, et al. CROI 2009. Abstract 44LB.

D:A:D: Recent and/or

Cumulative Antiretroviral

Exposure and Risk of MI

RR

of

rec

en

t* e

xp

os

ure

ye

s/n

o9

5%

CI

1.9

1.5

1.2

1.0

0.8

0.6

1.9

1.5

1.2

1.0

0.8

NRTI

Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.

# PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157# MI: 523 331 148 40 554 221 139

RR

of

rec

en

t* e

xp

os

ure

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

0.6

*Current or within last 6 mos. †Approximate test for heterogeneity: P = .02

RR

of

cu

mu

lati

ve

e

xp

os

ure

/ye

ar

95

%C

I

Boosted PIs in ARV-Naive Pts:

Virologic Suppression at Wk 48

60

70

80

90

100

Pts

Wit

h H

IV-1

RN

A

< 5

0 c

op

ies

/mL

(%

)

CASTLE[4]

(ITT)

NRTIs: TDF/FTC

76 7878*

KLEAN[1]

(ITT-E, TLOVR)

NRTIs: ABC/3TC

GEMINI[2]

(ITT)

NRTIs: TDF/FTC

ARTEMIS[3]

(ITT)

NRTIs: TDF/FTC

65 66

84*

6564

M05-730[5]

(ITT, NC = F)

NRTIs: TDF/FTC

75 76

0

10

20

30

40

50

This slide is an illustration only and not meant to be a cross-study comparison.

*P < .05 between LPV/RTV QD and DRV/RTV QD; no other significant differences in any comparisons above. †Use of LPV/RTV

BID or QD was not randomized and was dependent on site and pt preference. ‡SGC or tablet until Wk 8; tablet after Wk 8.

Pts

Wit

h H

IV

< 5

0 c

op

ies

/mL

(%

)

1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Ortiz R, et al. AIDS.

2008;22:1389-1397. 4. Molina JM, et al. Lancet. 2008;372:646-655. 5. Gathe J, et al. CROI 2008. Abstract 775.

440443

ATV/RTV

300/100

QD

LPV/RTV

400/100

BID

FPV/RTV

700/100

BID

LPV/RTV

400/100

BID

LPV/RTV†

400/100

BID or

800/200 QD

DRV/RTV

800/100

QD

434444 343

SQV/RTV

1000/100

BID

LPV/RTV

400/100

BID

170 167 346n = 333331

LPV/RTV

800/200

QD‡

LPV/RTV

400/100

BID‡

Study Findings Support

Once-Daily Dosing of Lopinavir/Ritonavir Tablets in

Treatment-Naive IndividualsGathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior

to twice-daily dosing and results in similar safety and tolerability in antiretroviral-naive subjects

through 48 weeks. J Acquir Immune Defic Syndr. 2009;50:474-481

• OD dosing of LPVr tablets noninferior to BID dosing regarding virologic

suppression at 48 weeks when combined with TDF/FTC in treatment-

naive individuals

• Efficacy comparable between OD and BID dosing groups regardless of

baseline HIV-1 RNA or CD4+ cell countbaseline HIV-1 RNA or CD4+ cell count

• Safety and tolerability also comparable between OD and BID dosing

groups

– Similar incidence of diarrhea

– Increases in total cholesterol significantly higher in patients given

twice-daily LPV/RTV

• No new PI resistance mutations identified in any patients with virologic

rebound

Crum-Cianflone N, et al. AIDS. 2009;23:41-50.

M05-730: Wk 48 Response to

LPV/RTV QD vs BID in Naive Pts

LPV/RTV QD

LPV/RTV BID

60

100

80P = .782 P > .999P = .715

� Randomized, open-label 96-wk noninferiority study

� LPV/RTV 800/200 mg (n = 333) vs 400/100 mg (n = 331), both with TDF/FTC

1 R

NA

< 5

0 c

op

ies/m

L(%

)

• No differences in lab abnormalities,

AEs at Wk 48 except ↑ in TC greater

with BID dosing (+34.5 vs +29.0

mg/dL; P = .044)

60

40

0

20

BL VL < 100K173 138

BL VL ≥ 100K160 193

Overall333 331n =

Gathe J, et al. CROI 2008. Abstract 775.

� For first 8 wks, arms divided between tablet and SGC formulations; after 8 wks, all received tablets

� QD noninferior to BID at Wk 48: 76% vs 75% (95% Cl: -5% to 8%)

� CD4+ cell count at Wk 48: +186 (LPV/RTV QD) vs +197 (LPV/RTV BID)

HIV

-1 R

NA

< 5

0 c

op

ies/

Lipid Changes From BL to Wk 48

66

FPV/RTVLPV/RTV

3933

2923

39 41

Me

dia

n C

ha

ng

e (

%)

10

20

30

40

50

60

7060

KLEAN[1]

1720 1820

2926

12

47

P = .0022

LPV/RTVSQV/RTV

GEMINI[2]

Me

dia

n C

ha

ng

e (

%)

10

20

30

40

50

60

70

This slide is an illustration only and not meant to be a cross-study comparison.

1. Eron J Jr, et al. Lancet. 2006;368:476-482. 2. Walmsley SL, et al. J. Infect Dis. 2009;50:367-374. 3. Nelson M, et al. Inter Congress

on Drug Therapy in HIV Infection 2008. Abstract P127. 4. Reprinted from The Lancet, v 372, Molina JM, et al, pp 646-655, Copyright

2008, with permission from Elsevier.

TC LDL HDL TG

Me

dia

n C

ha

ng

e (

%)

0

10

DRV/RTVLPV/RTV

P < .001

P < .001

ARTEMIS[3] P < .0001

ATV/RTV

LPV/RTV

12

24

12 15

2732

13

51

P < .0001

CASTLE[4]

TC LDL HDL TG

Me

dia

n C

ha

ng

e (

%)

0

10

TC LDL HDL TG

Me

dia

n C

ha

ng

e (

%)

0

10

20

30

40

50

60

70

TC LDL HDL TG

Me

dia

n C

ha

ng

e (

%)

0

10

20

30

40

50

60

70

12.419.8

12.6 12.5 9.8

19.4

6.8

57.6

Weighing the Options: Choosing Among Preferred Boosted PIsPI Daily Pill

Burden, Food Requirements

QD? Other Considerations

ATV/RTV 2, with food Yes • Favorable lipid profile• Lowest pill burden of boosted PIs• Daily dose requires only RTV 100 mg/day• Absorption impaired with acid-reducing agents• Associated with rise in unconjugated bilirubin and scleral icterus in 4% to 9% of

pts

DRV/RTV 3, with food Yes • Favorable lipid profile• Relatively low pill burden• Daily dose requires only RTV 100 mg/day• Also highly effective against PI-resistant virus in PI-experienced pts • Rash in ~ 3% of pts; use with caution in pts with sulfa allergy

FPV/RTV 3 or 4, with or Only as • Only BID dosing “preferred” option in DHHS guidelinesFPV/RTV 3 or 4, with or without food

Only as alternati

ve regimen

• Only BID dosing “preferred” option in DHHS guidelines• 700/100 mg BID similar in efficacy and tolerability as BID LPV/RTVSGC• Daily dose requires only RTV 100 mg daily when administered as 1400/100

mg QD• GI adverse effects; rash in ~ 3% of pts; use with caution in pts with sulfa

allergy

LPV/RTV 4, with or without food

Yes • Only coformulated boosted PI• Lower cost than other boosted PIs• Long-term experience• One of recommended agents for pregnancy• Daily dose requires RTV 200 mg/day • More GI adverse effects and triglyceride and total cholesterol elevations than

other boosted PIs that use RTV 100 mg/day

SQV/RTV 6, with food No • Favorable lipid profile• Long-term experience• Only BID dosing “preferred” option in IAS-USA guidelines• Highest pill burden among preferred PI choices

TDF Associated With Increased

Risk for Proximal Renal

Tubulopathy (PRT)• Cross-sectional analysis of Swiss HIV Cohort Study (N = 1202)

• PRT = pathological status of ≥ 3 of the following 4 measures:

fractional excretion (FE) of phosphate or uric acid,

protein/creatinine ratio in urine, euglycemic glucosuria

cGFR median (IQR)

PRTFE (phos) > 20%FE (phos) > 10%and hypophosphatemicNormal function

protein/creatinine ratio in urine, euglycemic glucosuria

� Incidence of PRT highest in patients receiving TDF plus a PI (vs no TDF, no

PI): OR: 7.1 (95% CI: 2.5-19.8; P < .001)TDF+, PI- (n = 320)

103 (88-124)

58% 20%

17%

5%

TDF+, PI+ (n = 426)

97 (80-118)

50%

20%

18%

12%

Fux C, et al. CROI 2009. Abstract 743. Graphics reproduced with permission.

107 (88-127)

78%

9%

11%

TDF-, PI- (n = 221)

2%

Rosiglitazone Improves

Lipoatrophy in Previous ZDV or

d4T Recipients• Patients with clinical lipoatrophy,

≥ 12 mos’ cumulative exposure to

d4T or ZDV, discontinued d4T or

ZDV from current HAART regimen

for ≥ 24 wks prior to study600

800

1000

Ch

an

ge in

Lim

b F

at

at

Wk 4

8 (

g)

P < .001*

P = .018†

Rosiglitazone

Placebo

El-Bajjani D, et al. CROI 2009. Abstract 42LB. Graphic reproduced with permission.

for ≥ 24 wks prior to study

– Randomized to receive

rosiglitazone 4 mg BID (n =

34) or placebo (n = 37) in

addition to current regimen0

200

400

Ch

an

ge in

Lim

b F

at

at

Wk 4

8 (

g)

Rosiglitazone Placebo

*Intragroup comparison. †Intergroup comparison.

P = .03*

n = 29 32

Europe: What to Start 2008

CCO , José Gatell• EFV preferred NNRTI in both EACS and BHIVA

guidelines and preferred over PIs in BHIVA guidelines

• Recent data suggest DRV/RTV and ATV/RTV at least

noninferior to LPV/RTV– Despite long-standing data on LPV/RTV, more lipid or GI AEs than

DRV/RTV or ATV/RTV

– FPV/RTV and SQV/RTV offer no clear benefits over DRV/RTV or

ATV/RTV

• ABC/3TC and TDF/FTC preferred NRTIs in European

guidelines– ABC concerns: higher rates of VF in pts with high BL HIV-1 RNA,

higher cardiovascular risk vs other NRTIs, need for HLA B*5701 testing

– TDF concerns: use with caution in pts with renal disease or elevation of

creatinine

• Agents from new classes (RAL or MVC) not currently

(2008!) recommended in first-line therapy

EACS guidelines 2009: Initial Combination Regimen for

ARV-naïve PatientSelect 1 drug in column A

and 1 NRTI comb in

column B

A B Remarks

Recommended NNRTI-EFV

-NVP

or RTV-

boosted PI

TDF/FTC

ABC/3TC

-co-formulations

-ATV/r 300/100 mg qd

-DRV/r 800/100 mg qd

-LPV/r 400/100 mg bid boosted PI-ATV/r

-DRV/r

-LPV/r

-SQV/r

-LPV/r 400/100 mg bid

or 800/200 mg/qd

-SQV/r 1000/100 mg

bid

Alternative SQV/r

FPV/r

RAL

-ZDV/3TC

-ddI/3TC or

FTC

-SQV/r 2000/100 mg

qd

-FPV/r 700/100 mg bid

or 1400/200 mg qd

-RAL 400 mg bid

-ZDV/3TC co-form

EACS 11/2009

Starting HAART: Starting HAART:

Optimal Timing

2008 DHHS Guidelines: When to Start

Clinical Condition and/or

CD4+ CountRecommendations

• History of AIDS-defining

illness

• CD4+ count ≤ 350 cells/mm3

• Pregnant women Start antiretroviral therapy• Pregnant women

• HIVAN

• HBV coinfection when HBV

treatment is indicated

Start antiretroviral therapy

CD4+ cell count > 350

cells/mm3

Considerations: � Older age

� Comorbidities

� CD4+ count decline > 120

cells/yr

� Serodiscordant relationshipsDHHS guidelines. Available at: http://www.aidsinfo.nih.gov.

2008 IAS-USA Guidelines: When to StartClinical Condition and/or

CD4+ CountRecommendations

Symptomatic HIV infection

Asymptomatic, CD4+ cell count

< 350 cells/mm3

Start antiretroviral therapy

Considerations:

CD4+ count ≥ 350 cells/mm3

Considerations:

• HIV-1 RNA > 100,000

copies/mL

• CD4+ count decline > 100

cells/yr

• HBV or HCV infection

• Cardiovascular disease

• HIV-associated nephropathy� Mother-to-child transmission

� Serodiscordant relationshipsHammer SM, et al. JAMA. 2008;300:555-570.

DHHS 2008: Recommended Regimens for

Treatment-Naive PatientsDHHS Guidelines “Preferred” Regimens, November 2008[1]

NNRTI-based

regimenEFV*

+ TDF/FTCPI-based regimen ATV/RTV QD

DRV/RTV QD

FPV/RTV BID

• IAS-USA 2008 guidelines state that RAL

can be considered for first-line therapy in

select circumstances[2]

FPV/RTV BID

LPV/RTV BID/QD*Except during first trimester of pregnancy or in women with high pregnancy potential.

1. DHHS guidelines. Available at: http://aidsinfo.nih.gov.

2. Hammer S, et al. JAMA. 2008;300:555-570.

WHO updates HIV treatment

recommendations Nov 30, 2009• New WHO recommendations endorse earlier ART

inititation for HIV-infected adolescents and adults and even more-aggressive approach for those coinfected with TB or HBV

• HIV+TB : ART as soon as possible regardless of CD4 countscounts

• HIV + HBV : asap in pts who require treatment for HBV (TDF + either FDC or 3 TC)

• Second-line ART should consist of a ritonavir-boosted PI + 2 NRTI. (ATVr or LPVr are the preferred PIs)

• www.who.int/hiv/pub/arv/rapid_advice_art.pdf

• Full set of guidelines expected in Feb 2010

DHHS 2009 (Dec 1)U.S. Department of Health and Human Services

www.aidsinfo.nih.gov• hoidon aloitus huomattavasti aiemmin !

• CD4 <500 - ”lifelong ART” (CD4 350-500: panelin jäsenistä 55% kannatti ”strong recommendation”) (A/B II)

• perusteena 2 kohorttitutkimusta, joissa kokonaiskuolleisuus todettiin merkitsevästi alemmaksi, jos hoito aloitettiin tällä kriteerillä (NEJM 2009; 360:1815 ja Lancet 2009; 373:1352)2009; 360:1815 ja Lancet 2009; 373:1352)

• ”Recommended regimens”:- EFV + TDF + FTC- ATVr + TDF + FTC- DRVr + TDF + FTC- RAL + TDF + FTC

• ”Alternative regimens”:- LPVr + 2 NRTI (paitsi raskaana oleville naisille ”recommended” LPVr + ZDV + 3TC


www.aidsinfo.nih.gov• HBsAg + -> TDF mukaan

kombinaatioon

• Strength of Recommendation Quality of Evidence

• CD4 yli 500: 50% panelin jäsenistä lähtisi hoitamaan oireettomia (CIII)- kohorttitutkimuksen tuloksetalentuvasta mortaliteetista- lisääntynyt ”non-AIDS defining disease” –riski hoitamattomilla (kardiovask CVD, maligniteetit, munuais- ja maksa-sairaudet).

A: Strong recommendation for the statement B: Moderate recommendation for the statement C: Optional recommendation for the statement I: One or more randomized trials with clinical outcomes and/or validated laboratory endpoints II: One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes III: Expert opinion

munuais- ja maksa-sairaudet).Huom myös HIVAN.- hyvin siedetty ja tehokas ART- preventiovaikutus

• Aloita ART: ”history of an AIDS-defining illness or with a CD4 <350” (AI).


www.aidsinfo.nih.gov• Aikainen ART vähentänee inflammaatiota ja immuuniaktivaatiota, jotka

vaikuttanevat kardiovaskulaarisiin ja muihin komorbiditeetteihin

• Maksimaalinen ja jatkuva VL:n supressio siirtää tai estää- lääkeresistenssiin johtavaa selektiota- säilyttää turvallisen CD4-tason- edesauttaa merkittävästi potilaan kliiniseen hyvinvointiin

• HIV-associated Nephropathy (HIVAN) - most common cause of chronic kidney disease in HIV-pts that may lead to end-stage kidney disease- almost exclusively in black patients and can occur at any CD4 count- ongoing viral replication appears to be directly involved in renal injury- extremely uncommon in virologically suppressed pts - ART in pts with HIVAN associated w both preserved renal function and prolonged survival, and therefore should be started in these patients (AII)

DHHS 2009 (Dec 1) www.aidsinfo.nih.gov

• Co-infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) - more rapid progression of viral hepatitis-related liver disease, including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and fatal hepatic failure- immunodeficiency and a direct interaction of HIV - ART -> preserving or restoring immune function and reducing HIV-related immune activation and inflammation- ARTdrugs active against both HIV and HBV (e.g., tenofovir, lamivudine, emtricitabine) may also

• Conclusion: earliertreatment of HIV/HBV and possibly HIV/HCV coinfection may reduce the risk of liver disease progression (CIII)tenofovir, lamivudine, emtricitabine) may also

prevent the development of significant liver disease by directly suppressing HBV replication- ARTdrugs do not directly inhibit HCV replication. HCV treatment outcomes may be improved if HIV replication is controlled or if CD4 counts are increased- The presence of chronic viral hepatitis increases the risk of ART-induced liver injury; however, the majority of coinfected persons do not develop clinically significant liver injury, particularly those receiving recommended ART - hepatotoxicity is greater in pts w more advanced HIV disease? NVP toxicity is a notable exception: HSR and associated hepatotoxicity more frequent in pts w higher CD4 cell counts.

progression (CIII)

• ARTdrugs active against both HIV and HBV should be started in all patients coinfected with HBV who are also going to receive HBV treatment (AIII)

Outcomes in HIV/HCV-coinfection

• EuroSIDA[1] HIV/HCV-coinfected patients

with high HCV RNA (> 500,000 IU/mL)

had significantly increased incidence of all-

cause death and liver-related death

1. Rockstroh J, et al. CROI 2009. Abstract 101. 2. Montes ML, et al. CROI 2009. Abstract 106.

cause death and liver-related death

• GESIDA/FIPSE[2] Regardless of response,

HCV treatment did not affect survival or

hepatic decompensation in HIV/HCV-

coinfected patients with cirrhosis

– Suggests clinical utility of early intervention to

prevent cirrhosis

ART ja HCV:n maksavaurion progressioPascual-Pareja JF et al. AIDS 2009 May 15

• ART voi vähentää maksan

nekroinflammatorista aktiviteettia HIV/HCV

koinfektiossa potilailla joilla CD4 >350

(biopsian ottoajankohtana)(biopsian ottoajankohtana)

• retrospektiivinen tutkimus – sekottavia

tekijöitä?

• tukee aikaisen ART-aloituksen strategiaa

koinfektiotapauksissa

DHHS 2009 (Dec 1)www.aidsinfo.nih.gov

• CVD: Major cause of mortality among HIVpts>30% of serious non-AIDS conditions and >10% of deaths among HIVpts (Smith C. Association between modifiable and non-modifiable risk factors and specific causes

of death in the HAART era: The Data Collection on Adverse Events of Anti-HIV Drug Study. CROI 2009; Montreal, Canada. Abstract 145 & Mocroft A, Reiss P, Gasiorowski J, et al. Serious fatal and non-fatal non-AIDS-defining illnesses in Europe. CROI 2009; Montreal, Canada. Abstract 707)

• Exposure to specific ARTdrugs linked to a higher risk of CVDCVD

(Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417-1426)Certain HIV treatment regimens are associated with a more atherogenic lipid profile

• Untreated HIV infection may also be associated with an increased risk of CVDCross-sectional studies, pts with HIV have higher levels of markers of inflammationand endothelial dysfunction than HIV-uninfected controls. McComsey G, Smith K, Patel P, et al. Similar reductions in markers of inflammation and endothelial activation after initiation of abacavir/lamivudine or tenofovir/emtricitabine: The HEAT Study. CROI 2009; Montreal, Canada. & Baker JV, Duprez D, Rapkin J, et al. Untreated HIV infection and large and small artery elasticity. J AIDS 2009;52(1):25-31


• CVD - In two randomized trials: markers of inflammation and coagulation increased following treatment interruption(Calmy A, Gayet-Ageron A, Montecucco F, et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS. 2009;23(8):929-939. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e20).

• One study suggests that antiretroviral treatment may improve endothelial function(Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-(Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol. 2008;52(7):569-576)

• SMART: risk of CVD events greater in pts randomized to CD4-guided treatment interruption vs pts w continuous ART. In other studies, ART resulted in marked improvement in parameters associated with CVD, including markers of inflammation (e.g., interleukin 6 [IL-6] and high sensitivity C-reactive protein [hsCRP]) and endothelial dysfunction.

• There is also a modest association between lower CD4 w ART and short-term risk of CVD Phillips AN, Neaton J, Lundgren JD. The role of HIV in serious diseases other than AIDS. AIDS. 2008;22(18):2409-2418.

• CASCADE: the link between CD4 count and fatal CVD events was no longer statistically significant when adjusting for VL.


• CVD - Conclusion:

• The data linking - viremia and endothelial dysfunction and inflammation, - the increased risk of CVD events with treatment interruption- association between CVD and low CD4 count suggest that - association between CVD and low CD4 count suggest that

early control of HIV replication with ART can be used as a strategy to reduce CVD risk (BIII).


• Malignancies Monforte A, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS. 2008;22(16):2143-2153.

• Increased incidence of non-AIDS-associated malignancies in HIVpts(Bedimo RJ, McGinnis KA, Dunlap M, et al. Incidence of non-AIDS-defining malignancies in HIV-infected versus noninfected patients in the HAART era: impact of immunosuppression. J AIDS 2009

• Large cohort studies of pts w ART: link between low CD4 counts (<350−500 ) and the risk of AIDS- and/or non-AIDS-defining malignancy Reekie J, Mocroft A, Engsig F, et al. Relationship between current level of immunodeficiency and non-AIDS-defining malignancies. Paper presented at: 16th CROI 2009; Montreal Canada. Abstract 860a. Bruyand M, Thiebaut R, Lawson-Ayayi S, et al. Role of uncontrolled HIV RNA level and immunodeficiency in the occurrence of malignancy in HIV-infected patients during the combination antiretroviral therapy era: Agence Nationale de Recherche sur le Sida (ANRS) CO3 Aquitaine Cohort. Clin Infect Dis. 2009;49(7):1109-11162009;49(7):1109-1116

• The ANRS C04: Pts w CD4 counts <500 vs >500: protective effect of ART for HIV-associated malignancies. (Guiguet M, Boue F, Cadranel J, et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 2009)

• Cancers associated with chronic viral infections (e.g., HBV, HCV, HPV, EBV, HHV-8) and HIV-associated immunodeficiency (Silverberg MJ, Chao C, Leyden WA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS. 2009;23(17):2337-2345. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.

• HIV viremia itself: risk of non-Hodgkin lymphoma and other AIDS-defining malignancies, independent of other factors (Zoufaly A, Stellbrink HJ, Heiden MA, et al. Cumulative HIV viremia during highly active antiretroviral therapy is a strong predictor of AIDS-related lymphoma. J Infect Dis. 2009;200(1):79-87.


U.S. Department of Health and Human Services

• Malignancies - Conclusion:

Together this evidence

suggests that initiating

ART to suppress HIV ART to suppress HIV

replication and maintain

CD4 counts at above

350–500 may reduce the

risk of both AIDS-defining

and non-AIDS-defining

malignancy (CIII).


• Neurocognitive declineHIV in brain tissue assumed to be the cause of AIDS dementia complex. The improvement of AIDS dementia complex symptoms with ART supported this assumption.

• CASCADE cohort: dramatic decline in the incidence of HIV-associated dementia from 6.49 /1000 py (before 1997) to 0.66 /1000 py (2003−2006), after the widespread use of potent ART. Pts w CD4 >350 associated with the lowest risk of developing HIV-associated dementia. (Bhaskaran K, the lowest risk of developing HIV-associated dementia. (Bhaskaran K, Mussini C, Antinori A, et al. Changes in the incidence and predictors of human immunodeficiency virus-associated dementia in the era of highly active antiretroviral therapy. Ann Neurol. 2008;63(2):213-221)

• Association with less severe neurologic complications: changes in neuropsychological ability, speed of processing, and everyday functioning. Such syndromes also were predicted by a lower pretherapy CD4 nadir and/or by CD4 count while on ART.

• Additional clinical data needed to determine the relative roles of - ongoing HIV replication and - potential neurotoxicity of ARTin the development of HIVAN. Whether early initiation of ART will prevent HIVAN remains unclear.

• However, the neurological complications that may accompany uncontrolled HIV

replication and CD4 depletion suggest a potential benefit of earlier initiation of antiretroviral therapy (CIII).


• Age and treatment-related immune reconstitution

• CD4 cell response to ART: - important predictor of short-term and long-term morbidity and mortality.

• Treatment initiation at an older age is consistently associated with a less robust CD4 count response; associated with a less robust CD4 count response; starting therapy at a younger age may result in better immunologic and perhaps clinical outcomes(CIII).

• The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study group. Response to combination antiretroviral therapy: variation by age. AIDS. 2008;22(12):1463-1473.


• T-cell activation and inflammation• Untreated HIV infection: High-level inflammation and T-cell activation. Risk of subsequent

disease progression: independent of other factors such as VL and CD4 count

• ART: rapid, but often incomplete, decrease in most markers of HIV-associated immune activation. Persistent T-cell activation and/or T-cell dysfunction is particularly evident among patients who delay therapy until later stage disease (CD4 count <350). (Neuhaus J, Jacobs HT, the INSIGHT SMART MaCSG. Markers of inflammation, coagulation, and renal function in HIV-infected adults in the Strategies for Management of ART Study and in 2 large population-based studies, Coronary Artery Risk Development in Young Adults and Multi-Ethnic Study of Atherosclerosis. CROI Artery Risk Development in Young Adults and Multi-Ethnic Study of Atherosclerosis. CROI 2009; Montréal, Canada. Abstract 740. Robbins GK, Spritzler JG, Chan ES, et al. Incomplete reconstitution of T cell subsets on combination antiretroviral therapy in the AIDS Clinical Trials Group protocol 384. Clin Infect Dis. 2009;48(3):350-361

• ART decreases the level of inflammation and T-cell activation, which may be associated with reduced short-term risk of AIDS- and non-AIDS-related morbidity and mortality (Palella F, Gange S, Elion R, et al. Inflammatory markers among abacavir and non-abacavir recipients in the Womens’ Interagency HIV Study and the Multicenter AIDS Cohort Study. CROI 2009; Montreal, Canada. Abstract 150LB. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis. 2009;200(6):973-983 (CIII).


• Prevention of Sexual Transmission• Emerging evidence supports the concept

”treatment as prevention”

• VL low – transmission less common. HIV serodiscordant heterosexual couples.serodiscordant heterosexual couples.(Reynolds S, Makumbi F, Kagaayi J, et al. ART reduced the rate of sexual transmission of HIV among HIV-discordant couples in rural Rakai, Uganda. CROI 2009; Montreal, Canada. Abstract 52a.Sullivan P, Kayitenkore K, Chomba E, et al. Reduction of HIV transmission risk and high risk sex while prescribed ART: Results from discordant couples in Rwanda and Zambia. CROI 2009; Montreal, Canada. Abstract 52bLB)

• Effective ART regardless of CD4 count is likely to reduce transmission to the uninfected sexual partner (BII).

DHHS 2009

RECOMMENDATIONS • • ART should be initiated in all pts

with a history of an AIDS-defining illness, or with CD4 < 350 (AI).

• • ART regardless of CD4 count, in pts with: - pregnancy (AI), - HIV associated nephropathy (AII), - HBV co-infection when treatment

• • For patients with CD4 > 500, 50% of the Panel members favor starting ART (B); 50% view optional (C) in this setting (B/C-III).

• • Pts initiating ART should be willing and able to commit to lifelong treatment, and should - HBV co-infection when treatment

of HBV is indicated (AIII).

• • ART recommended for patients with CD4 350 – 500. 55% of Panel members voted for strong (A) and 45% for moderate recommendation (B) (A/B-II).

lifelong treatment, and should understand the benefits and risks of therapy and the importance of adherence (AIII).

• • Pts may choose to postpone therapy, and providers, on a case-by-case basis, may elect to defer therapy based on clinical and/or psychosocial factors

DHHS 2009: Conditions Favoring

More Rapid Initiation of Therapy

• • Pregnancy (AI)

• • AIDS-defining conditions (AI)

• • Acute opportunistic infections (see discussion below)

• • Lower CD4 counts (e.g., <200) (AI) • • Lower CD4 counts (e.g., <200) (AI)

• • Rapidly declining CD4 counts (e.g., >100 /y) (AIII)

• • Higher viral loads (e.g., >100,000 copies/ml) (BII)

• • HIV-associated nephropathy (AII)

• • HBV coinfection when treatment for HBV is indicated (AIII)

Timing of initiation of antiretroviral therapy in AIDS-free

HIV-1-infected patients: a collaborative analysis of 18

HIV cohort studies.

Sterne JA, May M, Costagliola D, et al. Lancet. 2009;373(9672):1352-1363.

• Ei randomoituja tutkimuksia nyk. lääkekombinaatioilla kun hoitoa aloitettaessa CD4 >350.

• ART Cohort Collaboration (ART-CC), 61 798 py seuranta: pienenevä AIDS:n ja kuoleman riski 5 vuodessa kun hoito aloitetaan CD4 ≥350 vs.200-349 seuranta: pienenevä AIDS:n ja kuoleman riski 5 vuodessa kun hoito aloitetaan CD4 ≥350 vs.200-349 (May M, Sterne JA, Sabin C, et al. Prognosis of HIV-1-infected patients up to 5 years after initiation of HAART: collaborative analysis of prospective studies. AIDS. 2007;21(9):1185-1197)

• Jatkoanalyysissä korkeammillakin CD4-tasoilla todettiin samat asiat: CD4 351-450 vs 251-350 (RR: 1.28, 95% CI: 1.04 to 1.57).

ART CC: Supports Initiating

ART at CD4 Threshold of 350

cells/mm3

• Analysis of 15 cohorts from US and Europe

(ART Cohort Collaboration) N = 24,4444.0

HR

fo

r A

IDS

or

Death

*

*Adjusted for lead-time and unobserved events.

Sterne J, et al. CROI 2009. Abstract 72LB.

Graphic reproduced with permission for educational use only.

0.5

1.0

2.0

500 400 300 100

CD4 Threshold (cells/mm3)

HR

fo

r A

IDS

or

Death

*

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)

Effect of early versus deferred antiretroviral

therapy for HIV on survival.

Kitahata MM, Gange SJ, Abraham AG, et al. N Engl J Med. 2009;360(18):1815-1826

• In a collaboration of North American cohort

studies (NA-ACCORD) that evaluated patients

regardless of whether they had started therapy:

- 6 278 pts w deferred therapy until CD4 <350- 6 278 pts w deferred therapy until CD4 <350

- 2 084 pts w ART w CD4 cells 351-500

• Pts w deferred therapy had an increased risk of

death (RR: 1.69, 95% CI: 1.26 to 2.26) after

adjustment for other factors that differed

between these two groups

NA-ACCORD: Earlier vs Deferred HAART

• NA-ACCORD, established in 2006, includes 22

HIV research cohorts– Current analysis includes 9174 patients with CD4+ cell count

≥ 500 cells/mm3 at study visit between 1996-2006

• Compared outcomes based on treatment

according to following definitions– Immediate treatment: initiated HAART within 1.5 years of first

CD4+ cell count of ≥ 500 cells/mm3

– Deferred treatment: did not initiate HAART within 1.5 years of

first CD4+ cell count of ≥ 500 cells/mm3 but did initiate HAART

within 1.5 years of first CD4+ cell count of < 500 cells/mm3

• Primary outcome: death from any causeKitahata MM, et al. CROI 2009. Abstract 71.

NA-ACCORD: Survival Benefit

of Earlier HAART by Baseline

FactorParameter Associated

With Risk of Death* Relative Hazard† (95% CI) P Value

Deferral of HAART until < 500 cells/mm3

(vs starting at ≥ 500 cells/mm3)1.6 < .001

1.0 2.50.1

Female sex 1.2 .117

Older age (per 10 yrs) 1.6 < .001

Baseline CD4+ cell count

(per 100 cells/mm3 increase)1.0 .696

*All causes of death unspecified. †Stratified by cohort and calendar year.

Kitahata MM, et al. CROI 2009. Abstract 71.

NA-ACCORD: Survival Benefit

With Earlier vs Deferred HAART

Parameter Associated With Risk of Death Relative Hazard (95% CI) P Value


(vs starting at 350-500 cells/mm3)[1] 1.7 < .001

� Female sex 1.1 .290

� Older age (per 10 yrs) 1.6 < .001

1. Kitahata MM, et al. ICAAC/IDSA 2008. Abstract 896b.

2. Kitahata MM, et al. CROI 2009. Abstract 71.

1.0 2.50.1


� Baseline CD4+ cell count * 0.9 .083


(vs starting at ≥ 500 cells/mm3)[2] 1.6 < .001

� Female sex 1.2 .117


� Baseline CD4+ cell count* 1.0 .696

*Per 100 cell/mm3 increase.

NA-ACCORD

• CD4 351 – 500: Ilman ART hoitoa potilaat olivat kuolemanvaarassa 69% todennäköisemmin kuin ne joilla välitön hoito

• CD4 yli 500: Ilman ART hoitoa potilaat olivat kuolemanvaarassa 94% todennäköisemmin kuin ne joilla välitön hoitokuolemanvaarassa 94% todennäköisemmin kuin ne joilla välitön hoito

• Molemmat erot merkitseviä, myös useat comorbiditeetit huomioon ottaen

• Tutkimuksessa ei voitu ottaa huomioon kumulatiivisia ART sivuvaikutuksia pidemmällä tähtäimellä

START Study: Proposed Study

Design• Early treatment pilot study, estimated

enrollment: 4000 patients

Immediate Data

Enrollment

beginning in

early 2009 Immediate

Treatment

Defer Treatment

until CD4+ cell count

< 350 cells/mm³

Treatment-naive

pts with

CD4+ cell count

> 500 cells/mm³

Data

collection at

Mos 1, 4, and

every 4 mos

thereafter for

~ 6 yrs

early 2009

Study endpoints: fatal AIDS or nonfatal serious AIDS events (cardiovascular, liver,

renal, and cancer), and non-AIDS–related deaths

Summary of Observational Cohort

Analyses on When to Initiate HAART• NA-ACCORD[1]: initiating HAART at CD4+ cell count ≥ 500 cells/mm3

provided 60% survival benefit over deferring HAART to CD4+ count < 500

cells/mm3

• ART Cohort Collaboration[2]: analysis supports initiating HAART at CD4+ cell

count threshold of 350 cells/mm3

– Smaller absolute risk of AIDS or death and mortality observed at CD4+ cell counts – Smaller absolute risk of AIDS or death and mortality observed at CD4+ cell counts

> 350 cells/mm3

• NA-ACCORD adjustment for lead-time bias: allowed HAART to be initiated

within 1.5 years after BL CD4+ cell count

• ART CC adjustment for lead-time bias: events prior to HAART initiation

derived from

7 different cohort studies (not ART CC) obtained between 1989 and 1996

– Unobserved events during lead time imputed from historical observational data

– Multiple imputation adjustments for error in lead time and unseen event estimation

1. Kitahata MM, et al. CROI 2009. Abstract 71.

2. Sterne J, et al. CROI 2009. Abstract 72LB.

Summary: When to Start• Guidelines agree ART should be initiated in pts with CD4+ cell

counts < 350 cells/mm3

– Therapy can be considered in several special situations depending on specific

guidelines: high HIV-1 RNA (> 100,000 copies/mL), rapid CD4+ cell count

decline

(> 50-100 cells/mm3/yr), low CD4+ cell count percentage (< 14%), age > 55 yrs,

HCV coinfection, HBV coinfection if HBV treatment is indicated, high risk of

cardiovascular eventscardiovascular events

• Accumulating data from observational cohort analyses suggest

benefits to starting when CD4+ cell counts 350-500 cells/mm3

– Survival benefit

– Fewer AIDS-defining events

• NA-ACCORD data suggest survival benefit of starting ART at

even higher CD4+ cell counts (> 500 cells/mm3)

DHHS 2009: Acute OI

-Immediate ART ?• OIs for which there is no effective

therapy (e.g., cryptosporidiosis, microsporidiosis, PMLE) but for which ART may improve outcome - start as soon as possible (AIII).

• Cryptococcal meningitis or non-tuberculous mycobacterial infections, for which immediate therapy may increase the risk of IRIS, a short delaymay be warranted before initiating ART

• TBC with low CD4, ART within the first 2 months of treatment for tuberculosis appears to confer a significant survival advantage (Velasco M, Castilla V, Sanz J, et al. Effect of simultaneous use of highly active antiretroviral therapy on survival of HIV patients with tuberculosis. J AIDS. 2009;50(2):148-152. Abdool Karim S, Naidoo K, Grobler A, et al. Initiating ART during TB treatment significantly increases survival: results of a randomized controlled clinical trial in TB/HIV-co-infected patients in South Africa. CROI 2009; Montreal, Canada. Abstract 36a.

may be warranted before initiating ART (Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J AIDS. 2009;51(2):130-134) (CIII).

• Pneumocystis jiroveci pneumonia (PCP), early initiation of ART associated with increased survival –ART should not be delayed (AI)

• Clinicians should refer to Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents for more detailed discussion: Kaplan JE, Benson C, Holmes KH, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America.

MMWR Recomm Rep. 2009;58(RR-4):1-207

Significantly Improved Outcomes With

Integrated HIV and TB Treatment

Outcome, % Early ART Sequential ART

• 56% lower rate of death associated with concurrent ART

and TB treatment (early ART)

• Mortality: HR: 0.44 (95% CI: 0.25-0.79; P = .003)– Early ART: 5.4/100 person-yrs

– Sequential ART: 12.1/100 person-yrs

Abdool Karim SS, et al. CROI 2009. Abstract 36a.

Outcome, % Early ART Sequential ART

HIV-1 RNA <1000 copies/mL at

12 mos

91.0* 80.0

TB treatment successful 78.4 73.3

Incidence of IRIS 12.1*† 3.8†

Mortality in MDR-TB patients 20 71

*P < .05†Note: 83% early ART vs 62% sequential ART patients had initiated ART—data provisional.

Summary of Key Conclusions

• Among HIV-infected patients with TB,

simultaneous administration of HAART

and TB treatment significantly improved

survival[1]survival[1]

– Simultaneous HAART/TB treatment reduced

risk of mortality by 63%

• Consistent with data from SAPIT, but

additional data needed[2]

1. Velasco M, et al. J Acquir Immune Defic Syndr. 2009;50:148-152.

2. Abdool Karim SS, et al. CROI 2009. Abstract 36a.

HIV + OI -> early ART

• ACTG 5164 (CROI 2008) and SAPIT (CROI 2009) – the benefits of ART apparent by 6 months, and even earlier

• Retrospective study in Brazil – supports early ART. Benefit of ART on survival of HIV infected pts admitted to ICU (Croda et al. Crit Care Med 2009 May)

• Randomized trial ACTG 5164 (Zolopa et al. Early ART reduces AIDS progression/death in individuals with acute OIs: A multicenter AIDS progression/death in individuals with acute OIs: A multicenter randomized strategy trial. PLoS One 2009 May): - n=282- 14 d after starting treating OI- randomized to ART in 2 days vs in 4-32 weeks- 70% had baseline CD4 < 50- PCP 63%, cryptoc.meningitis 12%, serious bact.infection 12%, toxo 5%, MAC 2%. Multiple OIs 33%- At 48 weeks: AIDS or death 14% vs 24% favoring early ART- IRIS: 8 in early, 12 in delayed group (developed a median of 33 days after ART start)

SAPiT: Optimal Time to Initiate

ART in HIV/TB-Coinfected

Patients

Early ART

ART initiated during intensive or

continuation phase of TB therapyHIV-infected patients (n = 429)

Sequential ART

ART initiated after TB therapy

completed

(n = 213)

HIV-infected patients diagnosed with TB and

CD4+ cell count < 500 cells/mm3

(N = 642)

Primary endpoint: all-cause mortality

0.90

0.95

1.00

Early ART

Sequential ART

SAPiT: Increased Survival With

Concurrent HIV and TB

Treatment

Abdool Karim SS, et al. CROI 2009. Abstract 36a. Graphic reproduced with permission.

0.70

0.75

0.80

0.85

0.90

Su

rviv

al

Months Postrandomization

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Intensive phase of TB

treatment

Post-TB treatmentContinuationphase of TB treatment

Early ART Decreases Survival

in HIV+ Patients With

Cryptococcal Meningitis• HIV-infected African patients diagnosed with cryptococcal meningitis

randomized to receive 10 wks of fluconazole 800 mg QD + ART (n =

26) or fluconazole alone (n = 28)

– After 10 wks, all patients received fluconazole 200 mg QD + ART1.00

Delayed ART

Makadzange AT, et al. CROI 2009. Abstract 36cLB. Graphic reproduced with permission.

• After 2 yrs of follow-up: 23 deaths in early ART group (87% mortality

rate) vs 9 deaths in delayed ART group (37% mortality rate) (P = .002)

• Median survival, early ART vs delayed ART: 35 vs 274 days (P = .028)

0.00

0.25

0.50

0.75

0 200 400 600 800

Time to Death (in Days)

Delayed ART

Early ART

P = .028Su

rviv

al

HIV-infektioon liittyvien neurologisten

ilmentymien kirjo CD4-tason mukaan

Mandell, Principles and Practice of Infectious Diseases 2009

HAND (HIV associated

neurocognitive disorders)

• HAD HIV associated dementia

• MND Mild neurocognitive disorder

• ANI Asymptomatic neurocognitive impairment

CHARTER-kohortti (CNS HIV AntiRetroviral

Therapy Effects Research Project, 2003-2007)

• 1555 HIV-positiivista– Keski-ikä 43 v, 63 %:lla CD4 <200

ennen hoitoa

– Arviointihetkellä • HAART 71 %, keskeyttänyt 14 %,15

%:lla ei koskaan lääkitystä

• CD4 420 (keskiarvo)29 %

48 %

0,30

0,35

0,40

0,45

0,50

Pro

po

rtio

n

• CD4 420 (keskiarvo)

• 52 %:lla neuropsykologinen häiriö (terveisiin kontrolleihin verrattuna) huolimatta tehokkaasta lääkityksestä– >50 %:lla näistä häiriö

oppimisessa (task of learning), toiminnanohjauksessa (executive functioning), mieleen palauttamisessa (recall) ja työmuistissa (working memory)

2 %

21 %

0,00

0,05

0,10

0,15

0,20

0,25

Normal Mild Mod Severe

Global Neuropsychological PerformanceP

rop

ort

ion

Heaton, Abstract 154, 16th CROI 2009

Likvorin pleosytoosin tulkinta

HIV-infektiossaPrice, J Infect Dis 2008

• Lievä pleosytoosi yleistä, kun veren CD4

>50

• Selvitettävä tarkemmin, kun• Selvitettävä tarkemmin, kun

– Li-leuc >20

– Li-leuc >5 ja veren CD4 <50

– Li-leuc >5 ja potilas on lääkehoidossa

No Effect of Acyclovir in

Reducing HIV Transmission• Randomized, double-blind, placebo-

controlled trial of acyclovir 400 mg

BID vs placebo

• 3408 HSV-2/HIV–coinfected

individuals with CD4+ cell count ≥

250 cells/mm3 and HIV-uninfected

partners

� No difference between arms in incidence of HIV infection

– 136 HIV-uninfected individuals acquired HIV-1 infection

– Incidence: 2.8/100 person-yrs (95% CI: 2.3-3.3)

• Acyclovir treatment associated with

lower HIV-1 RNA in plasma and

genital secretions and fewer

episodes of genital ulcers

Episodes, n Acyclo

vir

Placebo

Genital ulcers 217 550

HSV-2–positive

genital ulcers

92 336

Celum C, et al. IAS 2009. Abstract WELBC101.

Outcome Acyclovir Placebo

HIV-1

transmission, n

68 67

• Linked

transmissions*

41 43

• Unlinked

transmissions

25 20

*Viral sequences similar in DNA analysis.

2.3-3.3)

LIFE• ”Life is

a sex-transmitted disease with 100% mortality”

– kuva: www.englishrussia.com

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