AIDS: il ruolo del medico e le più attuali

strategie terapeuticheDott. Renato Maserati

Coordinatore Servizi Ambulatoriali e Responsabile Ambulatorio AIDS, Fondazione

IRCCS Policlinico “San Matteo”. Professore a Contratto Facoltà di Medicina

Università di Pavia

Il principio di base della terapia antiretrovirale

E’ il virus, stupido!!!

IMMUNE DESTRUCTION AND HIV: TWO DIFFERENT MODELS

HIV

CD4+ Cells

INFECTION

IMMUNE DESTRUCTION

AIDS

HIV

CD4+ Cells

INFECTION

IMMUNE DESTRUCTION

AIDS

soluble factorscytokinesapoptosisanti MHC Ab

????

Observational data: likelihood of developing AIDS by 3 years after becoming infected with

HIV (untreated patients)

0102030405060708090

100

bDNA>30k

bDNA10K-30K

3K-10K 501-3K >=500

Plasma viral load (copies)

CD4>750CD4 501-750351-500201-350<=200

Mellors jW, Munoz A, Gigorni JV et al Ann. Intern Med 1997

EFV

1987 1991 1992 1994 1995 1996 1997 1998 1999 20001988 1989 1990

NRTI

2001 2002 2003 2004 2005 2006

Fusion Inhibitor

2007 2008 2009

R5 Antagonist

Integrase Inhibitor

NNRTI

Significant Advances Have Been Made in Antiretroviral Therapy

AZT

ETV

CBV

ddI d4T

ddC

3TC

Trizivir

NVP

DLV

TDF

ENF

FTC

Truvada

Atripla

RAL

MVC

ABC

DRV

PI RTV

SQV

APVIDV

LPVNFV ATV

TPV

fAPV

1993

Antiretroviral Agents 1987-2008

U.S. Food and Drug Administration. HIV/AIDS historical time line: 1981-2008.Lexiva [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.Intelence [package insert]. Yardley, PA: Tibotec, Inc; 2008.

Il paradigma della ARV Il paradigma della ARV (1985 – 1996)(1985 – 1996)

VOGLIO VIVERE….VOGLIO VIVERE….

- mortalita’ elevata- alto livello di frustrazione nella lotta contro HIV- farmaci con una attivita’ antivirale deludente - basso livello di accettabilita’ della terapia da parte dei pazienti e delle loro associazioni

VOGLIO VIVERE…VOGLIO VIVERE… …BENE!…BENE!

Il paradigma della ARV Il paradigma della ARV (1998 – oggi)(1998 – oggi)

- una buona attivita’ antiretrovirale e’ la norma- comodita’ di assunzione e bassa tossicita’- emergono altre problematiche

“Lipodystrophy Syndrome”

No generally accepted case definition of syndrome(s)

Initial reports suggested clustering of:

– Central fat accumulation/adiposity

– Lipoatrophy/fat wasting

– Dyslipidemia

– Insulin resistance/type 2 diabetes mellitus

Recent cross-sectional epidemiological data question linkage of lipoatrophy and fat accumulation

Fram J Acquir Immune Defic Syndr 2005;40:121-131

Abdominal MRI Scans

Control subject Increased Visceral Fat

HIV Therapies Target Different Stages of the Viral Life Cycle

ss = single-stranded; ds = double-stranded.

Adapted from Agrawal L et al. Curr Pharm Des. 2006;12:2031-2055.

Entry and Fusion Inhibitors

Integrase Inhibitors

Protease InhibitorsReverse Transcriptase Inhibitors

NRTIs NNRTIs

Nucleocapsid

ss RNA

Translation

TranscriptionIntegration

Nucleus

Cytosol

ReverseTranscription

Gp120/gp41CD4

Co-receptor (CCR5, CXCR4)

ds DNA

Mature HIV Virion

HIV Virion

Maturation Inhibitors

Non nucleosidicinhibitors NVP, EFV, DLV No need of activation in the cell

Nucleotidic and nucleosidic inhibitors:

AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active

Reverse transcriptase inhibitors

Guanosine

ABC- MP

CBV-MP

CBV-DP

CBV-TP

ABC

Adenosine Phosphotransferase

Cytosolic Enzyme

Kinase

Kinase

Thymidine

ZDV-MP

ZDV

ZDV-DP

d4T

d4T-MP

d4T-DP

Thymidylate Kinase

NDP Kinase

Thymidine Kinase

ZDV-TP d4T-TP

Cytidine

ddC 3TC FTC

ddC-MP

ddC-DP

3TC-MP

3TC-DP

NDP Kinase

CMP/dCMP Kinase

Deoxycytidine Kinase

ddC-TP 3TC-TP

Adenosine

ddI - MP

ddA-MP

ddA-DP

ddI

5’ Nucleotidase

Adenylate Synthetase& Adenylate Lyase

Adenylate Kinase &PRPP Synthetase

Adenylate Kinase &PRPP Synthetase

ddA-TP

Tenofovir

TFV-MP

Tenofovir DF

Diester Hydrolysis

AMP Kinase

NDP Kinase

TFV-DP

FTC-TP

Phosphorylation of NRTIs and NtRTIs

Attivita’ antiretrovirale e farmacoresistenzaAttivita’ antiretrovirale e farmacoresistenza

p

roba

bilit

à di

sel

ezio

nare

una

mut

azio

ne

aumento della soppressione della replicazione virale

monomono

doppiadoppia

triplatripla

Effects of common NRTI mutations

Mutation EffectsM184V Selected by 3TC, FTC → high-level resistance

Also selected by ABC, rarely ddI and ddC

Low-level resistance to ABC

No major effect on ddI (? beneficial effect)

Hypersusceptibility effects for ZDV, d4T and TDF

TAMs Selected by ZDV and d4T (ddI)

Resistance to ZDV, d4T, ddI, ddC, ABC, TDF

↑ number of TAMs = ↑ NRTI cross-resistance

K65R Selected by TDF, ddI, ABC

Resistance to TDF, ABC, 3TC, ddI, ddC

Uncertain effects on susceptibility to d4T

Hypersusceptibility to ZDV

L74V Selected by ABC, ddI

Resistance to ABC, ddI, ddC

Uncertain effects on susceptibility to TDF

Hypersusceptibility to ZDV

Protease Inhibitors

Protease-substrate complex

•Saquinavir (SGC,HGC)*

•Nelfinavir

•Amprenavir*

•Lopinavir §

•Indinavir*

•Ritonavir

•Fos-Amprenavir*

•Tipranavir*

* May be used with ritonavir as a booster

§ Available only in the boosted form

Is HAART so critical in HIV history?AIDS-related Mortality in the USA

1995 1996 1997 1998 1999 2000 2001Year

Dea

ths

per

100

per

son

-yea

rsT

herap

y with

a PI (%

of p

atient-d

ays)

Deaths

Use of PIs

Palella et al. 8th CROI, 2001

40

35

30

25

20

15

10

5

0

100

75

50

25

0

Lopinavir/r 400/100mg BID

Saquinavir/r 1000/100mg BID

Indinavir/r 800/100mg BID

Nelfinavir 1250mg BID

Amprenavir/r

600/100mg BID

Atazanavir 400mg QDQuestions over data

What PI treatments do we now have?

Non nucleosidicinhibitors NVP, EFV, DLV No need of activation in the cell

Nucleotidic and nucleosidic inhibitors:

AZT, ddI, ddC, d4T, 3TC, ABC, TDF, FTCNeed phosphorilation before they become active

Reverse transcriptase inhibitors

0 10 20 30 40 50 60 70 80 90 100% With VL < 50 at Week 48

Boosted PI

NNRTI

NRTI

Unboosted PI

HAART Studies

Bartlett JA et al. Abstract 586, CROI 2005

Previous analysis emphasized relation b/w pill burden and response

Updated analysis: pill burden less important

Highlights efficacy of boosted-PI and NNRTI regimens

HAART Studies: which one?

Le scelte critiche nella HAART

Quando e come iniziare

Individuare i parametri che predicono il successo e l’insuccesso nel singolo paziente a breve termine

Nel medio-lungo periodo: tollerabilità, tossicità, sequenziabilità

Nel paziente multi-trattato: introduzione di nuovi farmaci, terapie “hold-on”

Co-morbidità: epatopatie croniche, diabete, altro

Ruolo di farmacocinetica, genomica, immunologia

Considerations for Initial Regimen

Initial Treatment

Lifestyle

DosingPill Burden

Toxicity

Short TermLong Term

Drug Interactions

Sequencing

Underlying Conditions

HepatitisCV Disease

Perchè i pazienti interrompono la terapia?

Tossicità58.3%

Non aderenza19.6%

Fallimento virologico 14.1%

Altro8.0%

d’Arminio Monforte et al. AIDS 2000; 14:499–507

Cause di interruzione del primo schema HAART a 45 settimane nella coorte ICONA (n = 862)

Adattato da Munk. CPS Info Pack (suppl). POZ 1998.

Gli eventi avversi come determinanti di non aderenza

% d

i paz

ient

i che

han

no s

alta

to u

na d

ose

pe

r un

par

ticol

are

even

to a

vver

so

0

60

Febb

riG

astra

lgia

Ras

h/ps

oria

siVa

riazi

one

form

a co

rpo

Alte

razi

oni g

usto

Neu

ropa

tia/

form

icol

ioD

iarre

aG

as e

gon

fiore

Fatig

ueEm

icra

nia

Nau

sea

Vom

ito

10

20

30

40

50

0 0

11 13 1415 16 17

26 26

36

57

Adverse Effects of NRTIs* Zidovudine (AZT)- headache, GI intolerance, bone marrow suppression

Abacavir - hypersensitivity reaction

Didanosine (ddI) - GI intolerance, pancreatitis, peripheral neuropathy

Stavudine (d4T) - peripheral neuropathy, pancreatitis, lipoatrophy

Zalcitabine (ddC) - peripheral neuropathy, oral ulcers

Lamivudine (3TC) – rare side effects

Emtricitabine (FTC) – side effects uncommon; hyperpigmentation of palms/soles < 2% (non-Whites)

Tenofovir - headache, GI intolerance, renal insufficiency

*Lactic acidosis is a class effect, most strongly associated with d4T/ddI; 3TC, FTC, and tenofovir are active against HBV. Development of HBV resistance may lead to flare of hepatitis.

Adverse Effects of NNRTIs

Rash, including Stevens-Johnson syndrome with nevirapine

Elevated liver enzymes (nevirapine > efavirenz, delavirdine)

– Incidence of hepatotoxicity highest in women with pre-nevirapine CD4 counts >250 cells/mm3 and men with >400 cells/mm3

Efavirenz - neuropsychiatric, teratogenic in primates (FDA Pregnancy Class D)

Acute Adverse Effects of PIs GI intolerance, diarrhea

Hyperbilirubinemia –atazanavir, indinavir

Hepatotoxicity

Increased bleeding in hemophiliacs

Adverse metabolic effects

– Dyslipidemia

– Insulin resistance

– ? Lipodystrophy/fat redistribution

– Atazanavir has favorable metabolic profile

Adverse Effects of Entry Inhibitors

Enfuvirtide (T-20)

– Injection-site reactions

– Hypersensitivity reaction

– Increased incidence of bacterial pneumonia

Come si sta spostando il “pendolo” della terapia ?

Updated DHHS Guidelines: When to Start Treatment

Clinical Category CD4+ Cell

Count

Plasma

HIV-1 RNA

General Guidelines

AIDS-defining illness or severe symptoms*

Any value Any value Treat

Asymptomatic < 200 Any value Treat

Asymptomatic 200-350 Any value Treatment should be offered following full discussion of pros and cons of treatment.

Asymptomatic > 350 ≥ 100,000 Most clinicians recommend deferring therapy, but some clinicians will treat.

Asymptomatic > 350 < 100,000 Defer therapy

CD4+ Count Prior to Therapy Predicts Progression to AIDS

Johns Hopkins HIV Cohort Analysis of CD4+ cell count response

and disease progression in patients who maintained sustained virologic suppression for up to 6 yrs (N = 280)

Only patients with baseline CD4+ count > 350 cells/mm³ returned to near normal CD4+ cell count levels

Rate of progression to AIDS or death was significantly higher over time in patients with CD4+ count < 200 and CD4+ count 201-350 compared with CD4+ count > 350 cells/mm³

Moore RD, et al. IAC 2006. Abstract THPE0109.

0

100

200

300

400

500

600

700

800

900

0 Yr 1 Yr2 Yr3 Yr 4 Yr 5 Yr 6

CD

4+ c

ells

/mm

³

13%

12%

1.5%†

*% Over 6 years of study† P < .05 compared with CD4+ < 200

% Developing AIDS*

> 350

< 200

201- 350

HAART and Survival Based on Initial CD4+ Cell Count

Modeled data from ART Cohort Collaborative

10,855 patients included 934 progressed to AIDS or

died IDUs excluded from model

Sterne J, et al. CROI 2006. Abstract 525.

Progression and Death According to CD4+ Cell Count (cells/mm3)

< 200 vs 201-350

< 350 vs 351-500

Hazard ratio for AIDS (95% CI)

3.68 (3.01-4.51)

1.52

(1.10-2.10)

Hazard ratio for AIDS or death (95% CI)

2.93 (2.41-3.57)

1.26

(0.94-1.68)

Cumulative Probability of AIDS/Death According to CD4+ Cell Count at Initiation of HAART

Years Since Initiation of HAART

0 1 2 3 4 5

0.00

0.02

0.04

0.06

0.08

0.10

0.12

Pro

bab

ility

of

AID

S o

r D

eath

101-200 cells/mm3

201-350 cells/mm3

351-500 cells/mm3

HOPS CohortPrevalence of Mutations in Persons with Virologic Failure after HIV

Suppression, by CD4 Cell Count at HAART Initiation

Uy J, et al., IAS 2007; WEPEB017.

* p-values are for comparisons between CD4 cell count

ranges at HAART initiation

49 50

28

50

31

43

13

22

11 10

0

50

0

10

20

30

40

50

60

Perc

ent (

%)

0-199 cells/mm³ 200-348 cells/mm³ >350 cells/mm³

Any mutation(n=78)

NRTI mutationAmong NRTI-

exposed (n=77)

NNRTI mutationAmong NNRTI-exposed (n=37)

PI mutationAmong PI-

exposed (n=48)

p=0.076* p=0.007 p=0.051 p=0.103

49 50

28

50

31

43

13

22

11 10

0

50

0

10

20

30

40

50

60

Perc

ent (

%)

0-199 cells/mm³ 200-348 cells/mm³ >350 cells/mm³

Any mutation(n=78)

NRTI mutationAmong NRTI-

exposed (n=77)

NNRTI mutationAmong NNRTI-exposed (n=37)

PI mutationAmong PI-

exposed (n=48)

p=0.076* p=0.007 p=0.051 p=0.103

Any mutation(n=78)

NRTI mutationAmong NRTI-

exposed (n=77)

NNRTI mutationAmong NNRTI-exposed (n=37)

PI mutationAmong PI-

exposed (n=48)

p=0.076* p=0.007 p=0.051 p=0.103 Question: Does initiation of HAART at higher CD4 predispose to drug resistance?

Study Eligibility:

– achieved viral load (VL) <1,000suppression

– later had rebound (>1,000)

– had GT performed

Conclusion:Less resistance observed in all ARV classes when therapy started earlier (CD4 >350)

HOPS: Lipoatrophy and CD4+ Nadir

Lichtenstein K, et al. CROI 2002. Poster 684a (T).

30.8

18.2

17.0

13.2

12.0

3.3

0 25 50

Min CD4+ Max CD4+

> 350 > 350

200-349 > 200

< 200

< 200

< 200

< 200

> 500

350-499

200-349

< 200

Incidence of Lipoatrophy (%)

Factors Associated With Peripheral Neuropathy in HIV

1. Lichtenstein K, et al. IAS 2003. Abstract 729. 2. Lichtenstein K, et al. IAS 2003. Abstract 731.

HIV Insight: Incidence of PNP by Nadir CD4 (N = 7980)[2]

HOPS Cohort: PNP Associated With HAART (N = 2178)[1]

14

12

10

8

6

4

2

0

Year

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001

100

80

60

40

20

0

Pa

tie

nts

W

ith

PN

P (

%) P

atie

nts

on

HA

AR

T (%

)

% PNP% on HAART

18

16

14

12

10

8

6

4

2

00-99 100-199 200-349 350-499 ≥ 500

15.5%

11.1%

7.7%

5.1%4.3%

Nadir CD4 Category

P < .0001

Pa

tie

nts

(%

)

Increasing Prevalence of X4- or R5/X4-Tropic Virus at Lower CD4+ Cell Counts

CCR5– Patients with early-stage HIV

disease tend to have pure R5-tropic virus

CXCR4– With advanced disease, X4- or

dual-tropic virus emerges

– Associated with more rapid clinical and immunologic progression

Could CCR5 inhibition select for more virulent X4-tropic virus?

16.0% 16.0% 14.8%

41.9% 40.0%

0

20

40

60

80

> 300

248

Pre

vale

nce

of

X4

or

R5/

X4

(%)

100

201-300

104

101-200

81

51-100

31

< 50

50

CD4+ Cell Count (cells/mm3)

n =

Moyle G, et al. ICAAC 2004. Abstract 1135.

The Case for Earlier Initiation of Therapy

Availability of more potent, easier, and less toxic regimens

Cohort studies showing benefit with earlier therapy

Better response to therapy

Decreased transmission

Preserve R5-tropic virus

Cost-effectiveness

Come scegliere una combinazione HAART iniziale

2006 Guideline Recommendations for Initial HAART Regimen

Recommended Initial Regimens for Antiretroviral-Naive PatientsRecommended Initial Regimens for Antiretroviral-Naive Patients

DHHS Guidelines (May 2006)[1]

NNRTI-based regimen EFV + (3TC or FTC) + (TDF or ZDV)

PI-based regimen LPV/RTV + (3TC or FTC) + ZDV

IAS-USA Guidelines (August 2006)[2]

NNRTI-based regimenEFV*(NVP*)

PI-based regimenLPV/RTV*ATV/RTV*FPV/RTV*SQV/RTV*

*Plus TDF/FTC, ABC/3TC, or ZDV/3TC.

1. DHHS Guidelines. Available at: http://aidsinfo.nih.gov/Guidelines/. Accessed Sept. 15, 2006. . 2. Hammer SM, et al. JAMA. 2006;296:827-843.

Study Follow-up, wks

HIV-1 RNA < 50 c/mL,

%VF, % Any Resistance*,

%

GS 934[1]

EFV + TDF/FTC 144 64 29 68

EFV + ZDV/3TC 144 56 42 76

ACTG 5142[2]

EFV + 2 NRTI 96 89 24 48

LPV/RTV + 2 NRTI 96 77 37 21

KLEAN[3]

FPV/RTV + ABC/3TC 48 66 6 29

LPV/RTV + ABC/3TC 48 65 7 33

Durability of Response to HAART

1. Arribas JR, et al. IAS 2007. Abstract WEPEB029. 2. Riddler S, et al. IAC 2006. Abstract THLB0204. Haubrich RH, et al. HIV Resistance Workshop 2007. Poster 57. 3. Eron J Jr, et al.

Lancet. 2006;368:1238.

*Genotyped patients with virologic failure

% p

atie

nts

wit

h

VL

<50

co

pie

s/m

L a

t w

eek

48

KLEAN: FPV/r vs LPV/r-Naive Virological response

ITT-e: All patients exposed to >1 dose of randomized study medication

66% 65%

89% 88%

n=434 n=444 n=328 n=341

Eron, et al. Lancet 2006; 368 (9534): 476-82.

0

20

40

60

80

100

ITT-e TLOVR Observed

FPV/r

LPV/r

KLEAN: FPV/r vs LPV/r-Naive Grade 3/4 lipid abnormalities

Fasting cholesterol ≥ 300 mg/dL Fasting Triglycerides ≥ 751 mg/dL

11%

9%8% 8%

Eron, et al. Lancet 2006; 368 (9534): 476-82.

(≥ 7.7mmol/l) (≥ 8.4mmol/l)

0

5

10

15

FPV/r

LPV/r

Pat

ien

ts (

%)

ALERT: FPV/r vs ATV/r-Naive Lipid results

FPV/r Baseline

FPV/r Week 24

ATV/r Baseline

ATV/r Week 24Smith K, et al. 46th ICAAC 2006; abstract H-1670a

p < 0.05

0

50

100

150

200

250

Cholesterol LDL HDL TG

n=48 n=38

n=38

n=39

n=48 n=38 n=45 n=39

n=38 n=39

n=48

n=38

n=46 n=39

Med

ian

leve

l (m

g/d

L)

n=46

n=48

1:1 randomization

SQV/r 1000/100 mg bid

+ TDF/FTC

Lopinavir/r 400/100 mg bid

+ TDF/FTC

Prospective, Phase IIIb, randomized, multi-centre, open-label, 2-arm study

N = 337

– 26 North American sites• 8 Canada• 1 Puerto Rico• 17 United States

– 11 French sites

– 1 Thai site

Duration 48 weeks

Inclusion criteria

– Treatment naive– CD4 ≤ 350– HIV RNA > 10,000 copies/ml

Gemini

SQV/r vs LPV/r-Naive

N = 882

– International, open-label trial

Duration: 96 weeks

Inclusion criteria:

– HIV RNA ≥ 5,000 c/mL

– Any CD4 count

Primary efficacy endpoint:VL < 50 c/ml at 48 weeks

Secondary outcomes:

– VL < 50 c/mL at 96 weeks

– VL < 400 c/mL at 48 & 96 weeks

– Safety assessments

Status

– Study start: November 2005

– Fully enrolled

Atazanavir/r300/100 mg qd

+ TDF/FTC

Lopinavir/r 400/100 mg bid

+ TDF/FTC

BMS 138: ATV/r vs. LPV/r + TDF/FTC in ARV-naive patients

1:1 randomization

http://www.clinicaltrials.gov

Metabolic Effects of PIsAgent Lipids Glucose

RTV (full dose) TC/TG insulin resistance

LPV/RTV TC/TG insulin resistance

IDV/RTV TC/TG insulin resistance

NFV LDL/TG, HDL(?) No insulin sensitivity

APV/RTV or FPV/RTV TC/TG No insulin sensitivity

TPV/RTV TC/TG ?

SQV/RTV Little No insulin sensitivity

ATV No No insulin sensitivity

ATV/RTV Little No insulin sensitivity

DRV/RTV ? ?

RTV associated with more pronounced effect on lipids than other PIs

BMS-045: randomized trial of patients with 2 HAART failures

TC HDL-CLDL-C* TG*

*Fasting values.†P < .0001 vs LPV/RTV.

-8†

6

-7

2

-10

1

-4*

30

-15

-5

5

15

25

35

Mea

n C

han

ge

Fro

m

Bas

elin

e to

Wk

48 (

%)

ATV/RTV LPV/RTV

Metabolic Effects of PIs:LPV/RTV vs ATV/RTV

Johnson M, et al. AIDS. 2005;19-685-694.

Il paziente multi-”experienced”

HIV Transmission and the Establishment of HIV Reservoirs

(A)Interactions of HIV envelope glycoproteins, CD4, and CCR5 or CXCR4 coreceptors trigger fusion and entry of HIV.

(B) Outline of the sequence and time course of events involved in viral dissemination.

Fusion inhibitors: T20, (T1249)

•The gp120 subunit binds the CD4 receptor

•Each subunit undergoes a conformational change exposing the region that will bind a transmembrane chemokine receptor

CD4 +chemokine receptors

• Shifts away the steric hindrance of gp 120

• Allows gp 41 to mediate the fusion and entry

DRV/r or TPV/r Versus cPI(s): Week 48: <50 copies/mL With First Use ENF

56%

11% 9%

36%

DRV/r(n = 36)

cPI(s)(n = 35)

TPV/r(n = 123)

cPI(s)(n = 97)

First use of ENF

Pat

ien

ts a

chie

vin

g r

esp

on

se (

%)

20

40

60

80

0

POWER RESIST

Hill A, et al. 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27-30, 2006; San Francisco, Calif. Abstract H-1386.

Virologic Response by Number ofDRV-associated Mutations

De Meyer S, et al. 15th International Drug Resistance Workshop; June 13-17, 2006; Sitges, Spain. Poster 73.

50

1(94)

42

2(113)

22

3(58)

10

≥4(41)

42

All(373)

Number of TMC114 mutations(Number of patients)

Pa

tie

nts

wit

h V

LH

IV R

NA

<5

0 c

op

ies

/mL

at

We

ek

24

(%

)

64

0(67)

100

80

40

60

20

0

V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, L89V

8 7 8 8 9 10 IAS-USA PI mutations

ITT analysis (non-completer = failure)

Etravirine: Primary EndpointChange in VL at 48 weeks

Mea

n c

han

ge

in l

og

10 V

L (

±SE

)

Time (weeks)0

0.5

2 4 8 12 16 20 24

0

–0.5

–1.0

–1.5

–2.5

–2.0

32 40 48

–0.14

–0.88, P = 0.018–1.01, P = 0.002

P values versus active control. SE, standard error.

Active control (n = 40)

400 mg bid (n = 80)

800 mg bid (n = 79)

Relevant NNRTI mutations:

K101P, V179E, V179F, Y181I, Y181V, G190S, M230L

Cohen C, et al. 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0061.

Viral Entry Is the First Part of the HIV Life Cycle and Occurs in 3 Stages

Westby M, van der Ryst E. Antivir Chem Chemother. 2005;16:339-354.

FusionCo-receptor BindingAttachment

Co-receptor Usage of HIV-1 Variants: Defining Tropism

X4R5

CCR5 CXCR4CD4

CD4-Expressing Cells CD4-Expressing Cells CD4-Expressing Cells

CD4 memory CD4 naive

D/M

Adapted from Westby M, van der Ryst E. Antivir Chem Chemother. 2005;16:339-354; and Poveda E et al. AIDS. 2006;20:1359-1367.

Primary endpoint at 24 weeks: Mean change from baseline in HIV-1 RNA

MOTIVATE 1 & 2: Trial Design

1076 ARV-experienced patients

MVC 150 mg† BID(n = 426)

MVC 150 mg† QD (n = 414)

Placebo(n = 209)

R5 HIV-1 infection (44% screen failures)HIV-1-RNA ≥5,000 copies/mL

On stable regimen, or no ARVs for ≥4 weeksResistance to and/or ≥6 months’ experience with ≥1 ARV from 3 classes (≥2 for PIs)

2 identical ongoing phase IIb/III studies

Randomized (1:2:2), double-blind, placebo-controlled

OBT = 3-6 ARVs*Stratified by ENF use and HIV-1 RNA < and ≥5 log

*OBT, optimized background therapy (boosting doses of RTV not counted as an ARV).†Pts receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg of MVC, all others received 300 mg of MVC.

Nelson M, Lalezari J, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 104aLB and 104bLB.

MOTIVATE: Percentage of Patients With Undetectable HIV-1 RNA

MVC QD + OBT (n = 232)MVC BID + OBT (n = 235)

Placebo + OBT (n = 118)

0 4 8 12 16 20 24

20

0

30

40

50

60

70

80

90

100

Time (weeks)2

48.5%42.2%

24.6%

16 20 24

Pat

ien

ts (

%)

0 4 8 12

20

10

0

30

40

50

60

70

80

90

100

Time (weeks)

60.4%54.7%

31.4%

<400 copies/mL <50 copies/mL

P <0.0001*

P <0.0001*P <0.0001*

P = 0.0006*

2

10

HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks.*Versus placebo + OBT.Nelson M, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstract 104aLB.

MERIT: 740 naïve patients randomized to Maraviroc (300 bid) vs EFV (600 OD), both with CBV

VL < 400 copies/mL VL < 50 copies/mL

Pat

ien

ts, %

Pat

ien

ts, %

Time (weeks) Time (weeks)

0

20

40

60

80

100

24 8 16 24 32 40 48 24 8 16 24 32 40 48

70.6%

73.1%69.3%

65.3%

0

20

40

60

80

100

EFV (n = 361) MVC (n = 360)

0 0

Saag M, et al. IAS 2007. Abstract WESS104.

MVC was noninferior to EFV only for < 400 copies/mL endpoint (70.6% vs 73.1%)

CD4+ cell count increases were higher in patients receiving MVC vs EFV (+170 vs +144 cells/mm3)

Recently Approved New or Novel Antiretroviral Agents

Maturevirus

Maraviroc

Entryinhibitors

Reverse transcriptase

inhibitors

EtravirineIntegraseIntegraseinhibitorsinhibitors

RaltegravirRaltegravir

PIs

Darunavir Tipranavir

Percent <400 and <50 Copies/mL(ITT, NC=F)

BENCHMRK 1 & 2

(P<0.001 at Week 16 for all parameters)

Weeks

% o

f P

ati

en

ts <

40

0 C

op

ies

/mL

BENCHMRK 1

Weeks

BENCHMRK 2

RAL <400RAL <50

Placebo <400Placebo <50

Cooper D and Steigbigel R, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Absts. 105aLB and 105bLB.

100

80

60

40

20

0

0 2 4 8 12 16 24

100

80

60

40

20

0

0 2 4 8 12 16 24

*Data from GS-9137 125 mg patients after addition of a PI were excluded.

Zolopa A, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 143LB.

Elvitegravir (GS 9137) 125 mg: The Importance of the Regimen

GS-9137 125 mgwith no active drugs in OBT(n = 26)

Mea

n c

han

ge

fro

m b

ase

lin

e in

H

IV R

NA

lo

g1

0 c

op

ies/

mL

Week

GS-9137 125 mgwith ≥1 activeNRTI or first useof T-20 (n = 47)

0 4 8 12 16 20 24

P <0.001

–0.7

–2.1-2

-1

0

The E92Q IN Mutation Reduces Susceptibility to Multiple Integrase

Inhibitors

DrugWild-type

(HXB2)E92Q

E92Q

S147G

E92Q

S147G

H51Y

E92Q

S147G

H51Y

E157Q

S147G H51Y E157Q

GS-9137

EC50, nM1.3 ± 0.3

42.2 ± 11.2

(32.5)

98.6 ± 23.6

(76.0)

208 ± 32.4

(160)

237 ± 61.6

(182)

10.7 ± 1.1

(8.0)

5.1 ± 1.2

(4.0)

3.3 ± 0.4

(2.5)

MK-0518

EC50, nM5.9 ± 0.6

35.3 ±10.5

(6.0)

45.6 ± 13.7

(7.7)

37.8 ± 6.0

(6.4)

33.7 ± 9.0

(5.7)N/D N/D N/D

L-870,810

EC50, nM0.6 ± 0.2

7.1 ± 1.1

(11.8)

16.6 ± 4.3

(27.7)

13.0 ± 1.5

(21.7)

20.0 ± 4.1

(33.3)N/D N/D N/D

Fold changes: blue: FC <2.5; Yellow: FC ≥2.5 -10; Orange: FC >10.Mean EC50 and standard deviation of n = 3 experiments; N/D, not determined.

EC50 and Fold Change (FC, Relative to Wild-type, HXB2) in Susceptibility to INIs and Control ARV Drugs of IN Site-directed Mutant HIV-1

Jones, et al. 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, Calif. Abstracts 627.

Ingresso di nuovi strumenti di diagnosi e monitoraggio

Potential HLA-B*5701 Screening Implications

Blackn = 100

HLA-B*5701 test

2positive

98negative

Whiten = 100

HLA-B*5701 test

94negative

6positive

Do not treat with ABC

Do not treat with ABC

Appropriate totreat with ABC

Test 100 black patients:

Treat 98 patients at low risk for ABC HSR

Prevent 1 ABC HSR event

Exclude ABC unnecessarily in 1 patient

Test 100 white patients:

Treat 94 patients at low risk for ABC HSR

Prevent 4 ABC HSR events

Exclude ABC unnecessarily in 2 patients

Example shown is based on PPV derived from PREDICT-1 and SHAPE data.

Saag M, et al. IAS 2007. Abstract WEAB305.

Linee guida sull’impiego della farmacocinetica in diverse nazioni

UK BHIVA 2005

Spain 2005

Germany Austria

2004

France 2002

USA DHHS 2006

Unselected, routine

Treatment failure C B B C

Interactions B C B B C

Liver impairment B C B B C

Children B B C

Pregnancy B C

Malabsorption B B C

Once-daily C B C

Toxicity B / C C B B C

Adherence C

CB recommended consider

Utilita’ del TDM (1)

Spesso il dato che si ottiene dal TDM rientra nel “range terapeutico indicato dal laboratorio e/o dalla letteratura

Se il livello è “normale”..

– Vengono escluse interazioni significative

– Bisogna cercare una spiegazione alternativa a fenomeni di tossicità o fallimento

Utilita’ del TDM (2)

PROBLEMA / SITUAZIONE

– Terapia efficace

– Fallimento

– Tossicità

– Aderenza

– Coinfezione HCV o HBV

– Interazioni

– Pz. speciali

COSA AGGIUNGE TDM?

livello ancora basso?spiega e/o previenepreviene? dose?misura oggettivaIndividualizzazione; dose?accerta, ottimizzaindividualizza in gravide,

bambini, insuff. organo

Final Consideration on PK and ARVs

The management of HIV/AIDS patients is centered on optimizing their drug regimen. What do you think is a better correlate with clinical

outcomes?

Drug concentration

Time (hours)12 24

?

ADERENZA

Factors Affecting Adherence

Important to recognize factors that influence adherence However, physicians’ ability to identify patients who will or will not be

adherent is limited

Race, sex, and socioeconomic status are not independent risk factors for nonadherence

Factors associated with

increased adherence

Patient belief in HAART

Physician experience

Social supports

Regular office visits

Factors associated with

nonadherence

Active injection-drug use

Active alcohol abuse

Active psychiatric disease (especially depression)

Younger age

Chaotic lifestyle

Low functional literacy

Why Do Patients Miss Doses?

0 10 20 30 40 50 60

52Too busy/simply forgot46Away from home

45Change in daily routine27Felt depressed/overwhelmed

20Took drug holiday/medication break20Ran out of medication

19Too many pills19Worried about becoming 'immune'

18Felt drug was too toxic17Wanted to avoid side effects17Didn't want others to notice

16Reminder of HIV infection14Confused about dosage direction

13Didn't think it was improving health10To make it last longer9Were told the medicine is no good

Reasons given for missing

antiretroviral doses(structured questionnaire)

POSSIBLE INTERVENTIONS

Simplify dosing schedule

Decrease pill burden

Other

%

Gifford et al. JAIDS 2000;23:386–395.

Patient Preferences in Antiretroviral Regimens

4 most important regimen issues for patients

– Total number of pills per day

– Dosing frequency

– Dietary restrictions

– Side effects The ideal regimen from a patient perspective:

– 2 or fewer small pills per day

– Dosed all together, once daily

– No dietary restrictions

– No adverse effects

Moyle et al. 6th Intl Congress on Drug Ther in HIV Inf 2002. Abstract 99.

Fewer Patients Forget to Take QD Regimens

0

Pat

ien

ts F

org

etti

ng

to

T

ake

HA

AR

T (

%)

7166 63

40

10

20

30

40

50

60

70

80

TID+ TID BID QD

• Forgetting rates reported by 438 of 504 patients in standardized interviews• Patients answered the APPT-1 pan-European survey

Moyle G. Int J STD AIDS. 2003;14(Suppl 1):34-36.

All at onceDivided and taken twice-a-day

Pat

ien

ts p

refe

rrin

g

sch

edu

le (

%)

> 8 pills 8 pills 6 pills6 pills 4 pills4 pills 3 pills

31

69

38

62 59

41

8484

16

9393

7

0102030405060708090

100

Dosing Preferences By Pill Burden

“If you were to take a certain number of pills each day, how would you prefer them to be administered?”

You and your patient decided “it’s time to start”

Initial treatment

Clinical conditions at baseline

Available drugsDrug drug interactions

Co-morbidity

Treatment schedule

Future options

Resistance pattern at baseline

Patient’s expectations on the outcome

Short term side effects

Pill burden

Long term side effects

PK

General Principles of Client-Centered Counselling

The focus of counselling should be client’s concerns and interest explore the personal meaning that a client gives to issues

Context is important assess the physical and emotional circumstances under which HIV risk behaviors take place

Individualize sessions Impact of counselling will be enhanced when based on specific needs and unique situations of individual clients

modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003

General Principles of Client-Centered Counselling

Take a neutral stance maintain a nonjudgmental manner when discussing sexual practices, substance abuse and other personal issues

Remember you limits information alone does not lead to behavior changes, that are a complex process requiring interventions based on client’s personal circumstances.

modified from: Ed Wolf, UCSF Enhanced Counselling Skills Training: The single Session Risk Assessment and Test Disclosure, September 2003