Comment je traite un patient infecté par le VIH aux ... · Primo-infection symptomatique (neurologique : méningite ou paralysie faciale) Femme enceinte - Possible si : Age de plus

Comment je traite un patient infecté par le

VIH aux différents stades de la maladie ?

Tristan FERRY

[email protected]

Service de Maladies Infectieuses et Tropicales Hôpital de la Croix-Rousse,

Université Claude Bernard Lyon1, Lyon

Unité INSERM U851, Pathogénie Bactérienne et Immunité Innée, Centre National de Référence des Staphylocoques,

Faculté de Médecine Laennec, Lyon

Qu

an

tité

Activation immune

Virémie

Lymphocytes CD4+ circulants

Lymphocytes CD4+ muqueux

4–8

semaines

Aiguë

5-15 ans

Chronique 2-3 ans

SIDA

Les différents stades

Primoinfection et réservoir

Primoinfection et réservoir

• Le réservoir s’établie pendant la phase de primoinfection

• Présence du génome viral dans les tissus – Tube digestif

– Tissu lymphoïde (plaque de payer)

– Tissu cérébral

Thérapeutique aux différents stades

• Initiations de traitement « usuelles » – Stade SIDA

• Traitement de l’infection opportuniste

• Traitement antirétroviral

– Stade d’infection chronique

• Switch pour multirésistance

• Simplification thérapeutiques ou « allègement »

• Intensification thérapeutique pour espérer réduire le réservoir – Dès la primoinfection

– Au cours de l’infection chronique chez le patient indétectable

Sont exclus de la présentation :

- co-infection VIH/hépatites

- femmes enceintes












- femmes enceintes

PIs

NNRTIs

NRTIs

Fusion Inhibitors (FIs)

Inhibiteur du CCR5

Inhibiteur d’intégrase

Les ARV depuis 1987…

AZT ddI

ddC d4T

SQV

3TC

RTV

IDV

NVP

NFV

DLV

EFV

ABC APV

LPV/

RTV TDF

TPV DRV

ATV

FPV

ENF

FTC

0

5

10

15

20

25

1987 2010

MRV

RTG

Efficacité partielle

Résistance

1996 HAART

HIGHLY ACTIVE ART

RPV

Molécules disponibles en 2012

NNRTIs

Efavirenz (EFV)

Nevirapine (NVP)

Etravirine (ETV)

Rilpivirine (RPV)

PIs

Ritonavir (RTV)

Fosamprenavir (FPV)

Indinavir (IDV)

Saquinavir (SQV hgc)

Tipranavir (TPV)

Lopinavir/ritonavir (LPV/RTV)

Atazanavir (ATV)

Darunavir (DRV)

Didanosine (ddI) Stavudine (D4T) Zidovudine (AZT)

Abacavir (ABC) Lamivudine (3TC) Emtricitabine (FTC) Tenofovir (TDF)

3TC/ABC/AZT 3TC/ABC 3TC/AZT FTC/TDF

NRTIs

Fusion Inhibitors (FIs)

Enfuvirtide (ENF)

Inhibiteur d’intégrase

Raltegravir (RTG)*

Inhibiteur du CCR5

Maraviroc (MRV)*

La trithérapie ou HAART basée sur un

“backbone” : association de 2 NRTI

N R

T

I

N R

T

I

N R

T

I

N R

T

I

N N R T I I P boosté

HAART Backbone

=

2 NRTI

Inhibiteurs nucléosidiques de la RT




NRTIs

Activité antirétrovirale

Inhibe la transcriptase inverse du VIH

Arrêt de l’élongation de l’ADN

Avantages

Peu d’interaction médicamenteuses

Peu de prise par jour

Formes combinées

Mais…

Toxicité « familiale » par inhibition de l’ADN pol mitochondriale Toxicité spécifique de chacune des molécules




NRTIs

Kivexa ®

Truvada ®

Inhibiteurs nucléosidiques de la RT

NNRTIs

Efavirenz (EFV)

Nevirapine (NVP)

Etravirine (ETV)

Rilpivirine (RPV)

Activité antirétrovirale Inhibe la transcriptase inverse du VIH

Altère sa capacité à synthétiser l’ADN

Avantages ½ longue (EFV)

Peu de toxicité au long terme

Mais… Toxicité immédiate « familiale » Hypersensibilité Rash

Toxicité immédiate spécifique (EFV) Inducteur enzymatique Faible barrière génétique 1 seule mutation suffit à conférer une résistance « à toute la famille »

Vertiges Cauchemars Sd dépressif

Inhibiteurs NON nucléosidiques de la RT

Molécules disponibles en 2012

NNRTIs

Efavirenz (EFV)

Nevirapine (NVP)

Etravirine (ETV)*



3TC/ABC/AZT 3TC/ABC 3TC/ZDV FTC/TDF

NRTIs

Kivexa ®

Truvada ®

Atripla ®

Inhibiteurs de protéase PIs

Ritonavir (RTV)

Fosamprenavir (FPV)

Indinavir (IDV)


Tipranavir (TPV)


Atazanavir (ATV)

Darunavir (DRV)

Activité antirétrovirale

Inhibe la protéase

Avantages

Barrière génétique élevée

Mais… Nécessite d’être boosté (1/2 vie courte) Toxicité « familiale » : troubles digestifs dyslipidémie hyperglycémie lipodystrophie

Inhibiteur enzymatique

Utilisation du ritonavir comme booster • Le ritonavir est le plus puissant inhibiteur du CYP3A4

• Augmente la concentration des autres IP lorsqu’il est utilisé à petites doses (100 mg/prise) en diminuant leur métabolisme par le CYP3A

• Le boost réduit la survenue de résistance aux IP

• Le boost réduit également la survenue de résistance aux INRT

Kempf DJ, et al. J Infect Dis 2004;189:51-60.

Incidence de la résistance après traitement initial par HAART avec IP boosté ou non

NNRTI IP boosté

M184V 35,3% 21%

K65R 5,3% 0%

≥ 1 TAM 1,5% 0,6%

Résistance

IP ou NNRTI

53% 0,9%

p< 0,001

P= 0,01

p< 0,001

P= 0,62

R. GUPTA et al ; CID 2008 , 47, 712-22

IP boostés versus INNRTI

PIs

Ritonavir (RTV)

Fosamprenavir (FPV)

Indinavir (IDV)


Tipranavir (TPV)


Atazanavir (ATV)

Darunavir (DRV)

Inhibiteurs de protéase

PIs

Ritonavir (RTV)

Fosamprenavir (FPV)

Indinavir (IDV)


Tipranavir (TPV)


Atazanavir (ATV)

Darunavir (DRV)


PIs

Ritonavir (RTV)

Fosamprenavir (FPV)

Indinavir (IDV)


Tipranavir (TPV)


Atazanavir (ATV)

Darunavir (DRV)


Les objectifs du traitement ARV

Charge virale indétectable (<50 copies/mL):

◦ Maximalise la restauration immunitaire,

◦ Minimise le risque de transmission,

◦ Minimise la pression de sélection.

CD4+ > 500/mm3 :

◦ Pendant plus de 3 ans, mortalité identique à

celles des personnes VIH séronégatives.

Amélioration de la tolérance du traitement et

de la qualité de vie

Mortality in HIV+ Pts Similar to General Population When CD4 > 500 for 5-7 Yrs

• Overall mortality in HIV-infected patients 7-fold higher than general population

• After 6th year of follow-up, mortality among patients with CD4+ cell counts ≥ 500 cells/mm3 comparable to that of the general population

Lewden C, et al. J Acquir Immune Defic Syndr. 2007;46:72-77.

Truncation for Duration of Follow-up, Yrs

Median Time Spent With CD4+ Cell Count ≥ 500 cells/mm3 After Truncated

Duration of Follow-up, Yrs (IQR)

Deaths, n SMR (95% CI)

0 (n = 1208) 4.5 (2.1-7.0) 37 2.5 (1.8-3.5)

1 (n = 1156) 4.2 (2.1-6.4) 29 2.1 (1.4-3.1)

2 (n = 1083) 4.0 (2.1-5.6) 26 2.2 (1.4-3.2)

3 (n = 1031) 3.5 (1.8-4.8) 22 2.1 (1.3-3.2)

4 (n = 967) 3.0 (1.5-3.8) 18 2.1 (1.3-3.4)

5 (n = 864) 2.4 (1.4-3.0) 12 1.9 (1.0-3.2)

6 (n = 763) 1.6 (1.0-2.2) 2 0.5 (0.1-1.6)

7 (n = 610) 0.9 (0.5-1.3) 1 0.5 (0.0-2.6)

Les objectifs du traitement ARV

Test de génotypage pour guider le choix des ARV (7-10 j)

M1 : charge virale doit diminuer d’au moins 2 log10,

M3 : charge virale doit être < 400 copies/mL,

M6 : charge virale doit être indétectable (<50 copies/mL)

Quand débuter le traitement ARV en 2013

Stade C, après le traitement de l’IO

Stade B (candidose oropharyngé, zona, etc.),

Stade A (asymptomatique):

◦ < 350 CD4+/mm3 (ou 15%),

◦ < 500 CD4+/mm3, nouveauté 2010

◦ > 500 CD4+/mm3, non recommandé

- Sauf si :

Primo-infection symptomatique (neurologique : méningite ou paralysie faciale)

Femme enceinte

- Possible si :

◦Age de plus de 50 ans, FRCV,

◦Charge virales > 5 log10, Co-infection VHB ou VHC,

◦Baisse rapide des CD4, HIV-associated nephropathy (HIVAN)

1ère intention EFV+TDF+FTC Si pas de R et si pas Psy, observance et rein OK

ABC+3TC Si HLA B5701-

TDF+FTC Si rein OK

+

NNRTI

RTV/ATV

RTV/DRV

RTV/LPV

IP

Preferred/Recommended

Regimens: DHHS and IAS-USA

*IAS-USA: based on extensive clinical experience. †DHHS: should not be used in first trimester of pregnancy or in women trying to conceive or not using

effective and consistent contraception. ǂDHHS: should not be used in patients who require > 20 mg omeprazole equivalent per day. §IAS-USA: based on data that indicate that this agent is comparable to key third agents but more limited

experience in naive patients.

EFV*† ATV/RTV*ǂ

DRV/RTV§ RAL§

TDF/FTC +

DHHS Guidelines. October 2011. Thompson MA, et al. JAMA. 2010;304;321-333.

ECHO/THRIVE: Rilpivirine vs Efavirenz in

Treatment-Naive Patients

• D/C due to AE more common with EFV vs RPV: 8.5% vs 4.1%

• More virologic failures with RPV vs EFV: 14% vs 7.6%

– Difference due to more VF between Wks 0-48 at HIV-1 RNA > 100,000; VF similar Wks 48-96

– NRTI mutations more common with VF on RPV vs EFV

– Cross-resistance to ETR more common with RPV failure (E138K mutation)

100

80

60

40

20

0

HIV

-1 R

NA

< 5

0 c/

mL

(%)

78%

78%

RPV 25 mg QD (n = 686) EFV 600 mg QD (n = 682)

Wks

0 4 8 12 16 24 32 40 48 60 72 84 96 2

84%

82%

Cohen C, et al. AIDS 2010. Abstract THLBB206. Cohen C, et al. Lancet. 2011;378:229-237.

Molina JM, et al. Lancet. 2011;378:238-246. Cohen C, et al. CROI 2012. Abstract 626.

ECHO, THRIVE: Response to RPV vs EFV

in Patients With High VL, Low CD4

• Reduced response to RPV vs EFV at VL > 100,000 copies/mL and

CD4+ cell counts < 200 cells/mm³

-3.6 (-9.8 to +2.5)

> 100,000 copies/mL

125/ 165

121/ 153

246/ 318

149/ 181

136/ 171

285/ 352

77 81 79 80

76 82

Pat

ien

ts (

%)

40

0

100

20

80

60

Pooled THRIVE ECHO

HIV-1 RNA < 50 copies/mL at Wk 48 by Baseline VL

6.6 (1.6-11.5)

≤ 100,000 copies/mL

162/ 181

170/ 187

332/ 368

136/ 163

140/ 167

276/ 330

90 83

91 84

90 84

Pat

ien

ts (

%)

40

0

100

20

80

60

ECHO THRIVE Pooled

EFV Rilpivirine

Cohen C, et al. AIDS 2010. Abstract THLBB206. Cohen C, et al. Lancet. 2011;378:229-237.

Molina JM, et al. Lancet. 2011;378:238-246. Cohen C, et al. CROI 2012. Abstract 626.

Elvitegravir/Cobicistat/TDF/FTC vs

EFV/TDF/FTC in Treatment-Naive Patients

• Multicenter, randomized, double-blinded, active-

controlled phase III study

Sax P, et al. Lancet. 2012 Jun 30;379:2439-48.

HIV-infected treatment-naive patients with HIV-1 RNA ≥ 5000 copies/mL,

any CD4+ cell count, CrCl ≥ 70 mL/min

(N = 700)

Wk 48

primary analysis

Elvitegravir/Cobicistat/TDF/FTC QD

+ EFV/TDF/FTC placebo QD

(n = 348)

EFV/TDF/FTC QD + Elvitegravir/Cobicistat/TDF/FTC placebo QD

(n = 352)

Planned follow-up

to Wk 192 Stratified by

baseline HIV-1 RNA

> or ≤ 100,000 copies/mL

Elvitegravir/Cobicistat Regimen Noninferior

to EFV Regimen at Wk 48

• Greater CD4+ count increase with EVG/COBI vs EFV: 239 vs 206 cells/mm3 (P = .009)

• Among pts with confirmed virologic failure or rebound, resistance detected in 8/14 pts in

EVG/COBI arm vs 8/17 pts in EFV arm

– Primary integrase mutations and primary NNRTI mutations observed in 7 and 8 pts in EVG/COBI and

EFV arms, respectively

– All 8 pts in EVG/COBI arm had M184V/I mutation vs 2 pts in EFV arm; 3 and 2 had K65R, respectively

84 82

HIV-1 RNA > 100,000 c/mL

90 85

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk

48

(%

)

88

Overall HIV-1 RNA ≤ 100,000 c/mL

84 EVG/COBI/FTC/TDF (n = 348)

EFV/FTC/TDF (n = 352)


Safety of Elvitegravir/Cobicistat

Regimen vs EFV Regimen • Significantly greater incidence of nausea with EVG/COBI regimen

• Significantly greater incidence of sleep disturbance, dizziness, rash

with EFV regimen

• 1.4% of patients discontinued EVG/COBI regimen due to renal

abnormalities vs no patients on EFV regimen

– Significantly greater increase in median serum creatinine from

baseline to Wk 48 in EVG/COBI group: 0.14 vs 0.01 mg/dL (P <

.001)

– Majority of increase in serum creatinine clearance occurred

within

2 wks of starting treatment and progressed minimally over time

• Significantly greater increases in total, LDL, and HDL cholesterol

from baseline to Wk 48 in EFV vs EVG/COBI groups (all P ≤ .001)


Elvitegravir/Cobicistat/TDF/FTC vs ATV/RTV

+ TDF/FTC in Naive Patients

• Multicenter, randomized, double-blinded, active-controlled

phase III study

DeJesus E, et al. Lancet. 2012 Jun 30;379:2429-38

HIV-infected treatment-naive patients,

HIV-1 RNA ≥ 5000 copies/mL, any CD4+ cell count,

CrCl ≥ 70 mL/min

(N = 708)

Wk 48

primary analysis

Elvitegravir/Cobicistat/TDF/FTC QD

+ ATV/RTV + FTC/TDF placebo QD

(n = 353)

ATV/RTV + TDF/FTC QD + Elvitegravir/Cobicistat/TDF/FTC placebo QD

(n = 355)

Planned follow-up

to Wk 192 Stratified by

baseline HIV-1 RNA

> or ≤ 100,000 copies/mL

85 82

93 90 90

87

HIV-1 RNA > 100,000 c/mL

0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk

48

(%

)

Overall HIV-1 RNA ≤ 100,000 c/mL

EVG/COBI/|TDF/FTC (n = 353)

ATV/RTV + TDF/FTC (n = 355)

Elvitegravir/Cobicistat Regimen Noninferior

to ATV/RTV Regimen at Wk 48

• Similar CD4+ cell count increases in both study arms at Wk 48

• Among pts with confirmed virologic failure or rebound, resistance detected in

5/12 pts in EVG/COBI arm vs 0/8 pts in ATV/RTV arm

– 4/5 pts in EVG/COBI arm had M184V/I mutation; 4 had primary integrase mutations


Safety of Elvitegravir/Cobicistat

Regimen vs ATV/RTV Regimen • Similar rates of grade 3/4 adverse events between arms: 13% in

EVG/COBI and 14% in ATV/RTV arm

– Most common adverse events: diarrhea, nausea

• Grade 3/4 hyperbilirubinemia more common in ATV/RTV group:

58% vs 1%

• Significantly greater increase in median serum creatinine from

baseline to Wk 48 in EVG/COBI group: 0.12 vs 0.08 mg/dL (P <

.001)

– Majority of increase in serum creatinine clearance occurred within 2 wks

of starting treatment and progressed minimally over time

• Significantly greater increase in median triglycerides from baseline

to Wk 48 in ATV/RTV group: 23 vs 8 mg/dL (P = .006); otherwise no

difference in lipid values


Les thérapeutiques “de départ” en 2013

Regimen Advantages Disadvantages

EFV based Simplicity

(1 pill once daily) CNS effects may thwart adherence (if concerns about

follow-up)

PI based Once-daily dosing If irregular adherence, least

concern about resistance at VF

No single-tablet regimen or coformulations with NRTIs

Possibility of visible adverse effects that would disclose status

RAL based Minimal adverse effects Few drug-drug interactions

Twice-daily dosing No single-tablet regimen or coformulations with

NRTIs

RPV based Simplicity

(1 pill once daily) Minimal adverse effects

Food requirements Less effective at high HIV-1 RNA count

EVG/COBI based

Simplicity (1 pill once daily)

Minimal adverse effects

Only short-term data available More 2-class resistance in VF than EFV Effect on creatine clearance but no effect on GFR Drug-drug interactions similar to RTV












- femmes enceintes

• Essai ANRS139, multicentrique

non comparatif

• 103 patients, médiane CD4 à J0 :

255/mm3, médiane CV à J0 : 4

log10 c/ml (IQR : 3,6 - 4,6)

• 83 % des patients reçoivent

également des INTI, 12 % ENF

• 14 % reçoivent uniquement la

trithérapie RAL + ETR + DRV/r

(sans autre ARV)

Darunavir (Prézista®) - TMC-114 Une affinité très forte pour la protéase par rapport aux autres IP - jusqu’à 100 fois supérieure pour les virus sauvages !!! - 1.5 fois supérieure pour les virus multirésistants Sélection de mutations plus difficile Une puissance élevée, Grande flexibilité, 2 énantiomères = 2 cibles Naïfs : 800/100 1x/j, Expérimentés : 600/100 2x/j Dierynck et al J. Virol 2007

D’après A.Y. Kovalevsky et al ; J. Mol. Biol. ; 2006 ; 363(1) ; 161-73

LES DEUX ENANTIOMERES DU DARUNAVIR SE FIXENT A DES SITES DIFFERENTS DE LA PROTEASE












- femmes enceintes

Reasons to Consider

Treatment Simplification

• Improve adherence, convenience, and quality of life – Reduce number of doses

– Reduce number of pills

– Reduce number of drugs

– Reduce costs

• Many physicians fear simplification out of perceived risk of tolerability issues and loss of virologic suppression

• However, if simplification is not effective, reverting back to the previous regimen is an option if carefully managed

Claxton AJ, et al. Clin Ther. 2001;23:1296-1310.

Adherence Inversely Related to

Number of Doses per Day

Studies of Electronic Monitoring of Adherence

Mean

Do

se-T

akin

g

Ad

he

ren

ce (

%)

71

0

20

40

80

100

Overall

79

QD

69

BID

65

TID

51

QID

60

P = .008

P < .001

P = .001

Stone VE, et al. J Acquir Immune Defic Syndr. 2004;36:808-816.

HIV-positive patients on ART including ≥ 3 antiretrovirals (N = 299) 6 US cities Self-report questionnaire with aid of facilitator

Not Helpful at All Pills/Day Dosing

Frequency Food Rules Biggest Pill

Extremely Helpful

0

20

40

60

80

100

Mean Relative Impact of Regimen

Features on Adherence

ARV Agents Approved for Once-Daily

Dosing and Fixed-Dose Combinations

Agents Approved for Once-Daily Dosing

Class US EU

NRTIs

ABC 3TC ddI FTC TDF

ABC 3TC ddI FTC TDF

NNRTIs EFV

NVP-XR EFV

NVP-XR

PIs

ATV/RTV FPV/RTV (for tx-naive patients only)

DRV/RTV (for tx-naive patients or tx-exp patients without DRV resistance mutations) LPV/RTV (for tx-naive patients only)

ATV/RTV DRV/RTV (for tx-naive patients or tx-exp patients

without DRV resistance mutations) LPV/RTV (if necessary)

Approved Once-Daily Fixed-Dose Combinations

Class US EU

NRTIs TDF/FTC ABC/3TC

TDF/FTC ABC/3TC

PIs LPV/RTV LPV/RTV

Two drug classes EFV/TDF/FTC RPV/TDF/FTC

EFV/TDF/FTC RPV/TDF/FTC

DHHS Guidelines, October 2011.

• Patients without a history of treatment

failure or drug-resistant virus

• Patients receiving complex regimens

– However, for some forms of treatment

simplification (eg, boosted PI monotherapy),

good adherence is a prerequisite

Optimal Candidates for Treatment

Simplification

• In patients with controlled viremia, simplifying treatment to improve quality of life should be considered[1-4]

• When switching treatment, for whatever reason, maintenance of virologic suppression remains the main concern

• Efficacy and likely adherence to the new regimen should be considered

• Numerous clinical trials have studied the efficacy, safety, and tolerability of a switch in patients with stable virologic suppression

1. DHHS Guidelines, October 2011. 2. GeSIDA Guidelines, January 2012. 3. EACS Guidelines, 2011.

4. Thompson MA, et al. JAMA. 2010;304;321-333.

Summary and Additional

Considerations

Within-Class Simplifications

• Preserves unused drug classes for potential future use

• Types of simplifications

– PI substitutions

• Simplification from twice-daily PI to once-daily PI

• Simplification from boosted PI to unboosted PI

– NNRTI substitutions

• Simplification to agents with reduced dosing frequency or

coformulated agents

– NRTI substitutions

• Simplification to agents with reduced dosing frequency or

coformulated agents

Rubio R, et al. HIV Med. 2010;11:545-553.

SIMPATAZ: Simplification From PI-

Based Therapy to ATV/RTV

• 183 virologically suppressed patients enrolled in multicenter, prospective,

noninterventional study

– Physician recommended treatment simplification

• At Mo 12, 95% of patients on treatment maintained undetectable HIV-1 RNA

• Overall AE rate low

– 3.8% of patients experienced moderate to severe AEs, judged related to ATV/RTV

– Only 1 discontinuation judged related to ATV/RTV AE

• Total cholesterol, triglycerides, and LDL cholesterol all improved significantly

• Proportion of patients classifying themselves as highly satisfied with

their antiretroviral therapy regimen increased significantly from baseline

to Month 12 after switch (47% vs 91%; P < .001)

Squires K, et al. HIV Clin trials 2012;13:233-44

ARIES: Switch From a RTV-

Boosted PI to Unboosted ATV

P = .390

0

20

40

60

80

100

ATV

HIV

-1 R

NA

< 5

0 c

/mL

at

Wk

14

4 (

%)

77 73

ATV/RTV

515 virologically suppressed treatment-naive patients with no evidence of virologic failure during 36-wk induction phase of ATV/RTV + ABC/3TC randomized to switch to unboosted ATV or no change for 48 wks

Tx-Related Grade 2-4 AEs, %

ATV (n = 189)

ATV/RTV ( n = 180)

BL to Wk 36 26 30

Hyperbilirubinemia 13 13

Diarrhea 4 3

Nausea 3 2

Wk 36 to Wk 144 13 23

Hyperbilirubinemia* 6 14

*P = .0232

Changes in median lipid levels from randomization to Wk 144 more favorable with ATV vs ATV/RTV therapy

Out-of-Class Simplifications

• Can be useful option for patients with

tolerability issues

• Strategies

– Simplification from PI-based regimen to RAL

– Simplification from PI-based regimen to

NNRTI-based regimen

• NVP-based regimens

• EFV/FTC/TDF

• RPV/FTC/TDF

Lipoatrophie - lipodystrophie

Lipo-atrophie: NRTI (d4T > ddI > AZT, 3TC,

abacavir), pas d’anomalies métaboliques.

Toxicité mitochondriale

Lipodystrophie:

antiprotéases (IP) et

anomalies métaboliques

Courtesy Bernard Hirschel et Alexandra Calmy, HCUGE

AZT/3TC/NELFI AZT/DDI/NELFI AZT/DDI/EFZ AZT/DDI/LOPIr

Eron J, et al. Lancet. 2010;375:396-407.

SWITCHMRK-1 and -2: Switch From Stable

LPV/RTV to RAL-Based HAART

• Predefined criteria for noninferiority: lower limit of the 95% CI

for treatment difference > -12%

RAL + ARVs, n LPV/RTV + ARVs, n

50

60

70

80

90

100

0 4

Wks

HIV

-1 R

NA

< 5

0 c

/mL

(%)

8 12 24

87%

81%

∆: -6.6 (95% CI: -14.4 to 1.2)

Protocol 032 Protocol 033

50

60

70

80

90

100

0 4

Wks

8 12 24

∆: -5.8 (95% CI: -12.2 to 0.2)

94%

88%

HIV

-1 R

NA

< 5

0 c/

mL

(%)

Non-infériorité non atteinte mais backbone fragile…..

Eron J, et al. Lancet. 2010;375:396-407.

SWITCHMRK -1 and -2: Significant

Decrease in Lipids With Switch to RAL

Mean

Ch

an

ge F

rom

Baselin

e

at

Wk 1

2 (

%)

-50

-40

-30

-20

-10

0

10

20 RAL + ARVs

LPV/RTV + ARVs Protocol 032 Protocol 033

*

NS nps -12.8

0.7

-15.2

2.3

-41.5

3.6

-2.4

2.1

-0.9

0.8

NS nps -12.4

1.3 2.9

8.2 4.0

0.6

-0.6 -2.5

-14.8

-42.8

Fasting

Cholesterol Fasting

Non-

HDL-C

Fasting

TG†

Fasting LDL-C

Fasting

HDL-C

Fasting

Cholesterol Fasting

Non-

HDL-C

Fasting

TG† Fasting

LDL-C

Fasting

HDL-C

*P < .0001; †median change from BL at Wk 12, %.

*

*

* *

*

Switches That Reduce the Number

of Active Drugs in a Regimen

• Reduces drug exposure and may improve tolerability of regimen

• Strategies – Boosted PI monotherapy

• Avoids NRTI toxicities; reduces costs

– Ongoing clinical trials of switches to boosted PI + 3TC only

• Simplification from 2 NRTIs plus a third agent to ATV/RTV + 3TC as maintenance therapy (SALT)[1]

• Simplification from LPV/RTV plus 2 NRTIs to LPV/RTV + 3TC[2]

1. ClinicalTrials.gov. NCT01307488. 2. ClinicalTrials.gov. NCT01471821.

Efficacité LPV/RTV en monothérapie selon la situation clinique

MONARK[1]

Initial therapy M03-613[2]

Induction/Maintenance

0

20

40

60

80

100

0 16 32 Wk

48 0 16 32 48 64 80 96 Wk Wk

36 48 12

MONET[3]

Simplification

Discontinued

On study, HIV-1 RNA > 400

On study, HIV-1 RNA 50-400

On study, HIV-1 RNA < 50

1. Delfraissy JF, et al. AIDS. 2008;22:385-393. 2. Cameron DW, et al. J Infect Dis. 2008;198:234-240.Published by University of Chicago. 3. Arribas J, et al. J Acquir Immune Defic Syndr. 2005;40:280-287.

0 24

Pat

ien

ts (

%)

Studies of ATV/RTV Monotherapy

Study ATARITMO[1] ACTG 5201[2] Karlström[3] OREY[4]

Results 2 pts (7%) with VF at Wk 24 (1 d/c, 1 protocol violation)

5 pts with virologic “blips”

34 simplified to ATV/RTV monotherapy

88% (30) did not experience VF at Wk 48 after simplification

1 pt with VL = 508 at final visit

Stopped at 15 pts

5 VFs

No pts completing 72 wks on monotherapy without VF

9/14 (64%) with virologic success after median 36 wks

21% with tx failure

12% with virologic rebound

Resistance Not tested in plasma samples

5 pts genotyped

No major PI RAMs

No low frequency ATV resistance variants detected

3 pts genotyped

No PI resistance mutations

7 pts genotyped 1 pt with ATV

resistance mutation N88S at Wk 48

1 additional pt with N88S + M46L after Wk 48

1. Vernazza P, et al. AIDS. 2007;21:1309-1315. 2. Wilkin T, et al. J Infect Dis. 2009;199:866-871. 3. Karlström O, et al. J Acquir Immune Defic Syndr. 2007;44:417-422. 4. Pulido F, et al. EACS 2009. Abstract PS4/6.

EACS 2011[1] IAS-USA 2010[2] DHHS 2011[3]

PI/RTV monotherapy

with BID LPV/RTV or

QD DRV/RTV might

represent an option in

patients with intolerance

to NRTI or for treatment

simplification

Therefore, PI/RTV

monotherapy is not

recommended except in

exceptional

circumstances when

other drugs cannot be

considered for reasons of

toxicity/tolerability

In aggregate, boosted PI

monotherapy as initial or

as simplification treatment

has been somewhat less

effective in achieving

complete virologic

suppression and avoiding

resistance. Therefore, this

strategy cannot be

recommended outside of

a clinical trial

1. EACS Guidelines version 6, 2011. 2. Thompson MA, et al. JAMA. 2010;304;321-333.

3. DHHS Guidelines, 2011.

Guidelines Differ Regarding PI

Monotherapy

Reasons to Consider Treatment

Simplification • Improve adherence, convenience, and quality of life: active

simplification

– Reduce number of doses

– Reduce number of pills

– Reduce number of drugs

– Reduce costs

• In patients with controlled viremia and no tolerability issues,

simplifying treatment to improve quality of life should be considered

• Many physicians fear simplification out of perceived risk of

tolerability issues and loss of virologic suppression

• However, if simplification is not effective, reverting back to the

previous regimen is an option if carefully managed

Potential Benefits of Treatment

Simplification • Several highly convenient regimens available, including newer

agents and reformulations/coformulations of older drugs with

less frequent dosing and less toxicity

– Regimens with lower pill burdens and less frequent daily dosing

are associated with better adherence

• When switching treatment, for whatever reason, maintenance

of virologic suppression remains the main concern

– Studies have identified simplification strategies that usually

maintain virologic suppression and often reduce adverse events

• Previous use of suboptimal therapy may reduce likelihood of

effective treatment response












- femmes enceintes

69 patients sous HAART

avec CV < 50 c/ml

depuis plus d’un an

HAART + RAL (intensification)

HAART poursuivi (témoin)

n = 45

n = 24

Randomisation 2 : 1 S24

- Augmentation transitoire

de l’ADN épisomale non

intégré après 2 et 4 chez

29% des patients

intensifiés

- Activation CD8 plus

importante

Le plus dur reste à faire…. Cibler le réservoir !

Conclusion

• Les acquis :

– Simplicité des traitement de première ligne

– Possibilité de simplification thérapeutiques

• A venir (espoir d’éradication) :

– Intensification lors de la primoinfection

– Intensification lors de l’infection chronique

J Acquir Immune Defic Syndr. 2012 Dec 15;61:557-564

http://www.ncbi.nlm.nih.gov.gate2.inist.fr/pubmed?term=marimuno

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