Taller UiTB – 2009 Barcelona, a 30 de Noviembre del 2009 ... · Tuberculosis extrapulmonar 80...

Cuando y con qué comenzar el TARGA en paciente con TBCuando y con qué comenzar el TARGA en paciente con TB

Dr. José M. MiróServicio de Enfermedades Infecciosas

Hospital Clínic – IDIBAPSUniversidad de Barcelona

Barcelona

Dr. José M. MiróServicio de Enfermedades Infecciosas

Hospital Clínic – IDIBAPSUniversidad de Barcelona

Barcelona

Taller UiTB – 2009Barcelona, a 30 de Noviembre del 2009

Taller UiTB – 2009Barcelona, a 30 de Noviembre del 2009

Correo electrónico: [email protected] electrónico: [email protected]

• Introducción

• Cuando comenzar el TARGA

• Cual es la mejor pauta de TARGA

• Conclusiones

• Introducción



• Conclusiones

Cuando y con qué comenzar el TARGA en paciente con TB


Late presenters in the HAART era in Spain1,591 ART-naïve patients (2004-05)

Andalusia: 2

Madrid: 5

Valencia: 2

Catalonia: 4

Canary Islands: 1

Balearic Islands: 1

Basque Country: 1La Rioja: 1

.

.

.

..

..

.. .

.

..

.. .. .

Spanish HIV Cohort (CoRIS)

Late presenters in the HAART era in SpainClinical Stage at HIV Diagnosis (N=1,591)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Males Females Total

C (AIDS)

B (Symptomatic)

A (Asymptomatic)

Acute/Early Infection

Caro-Murillo AM and the CoRIS investigators. Enferm Infecc Microbiol Clin. 2007.

~ 20% had C events

Forma de Presentación del Sida CoRIS (N= 477; 2004-07)

Forma de Presentación del Sida CoRIS (N= 477; 2004-07)

IO79% SK

8%

LNH5%

Cervix1%

CDS1%

WS6%

IOSKLNHCervixCDSWS

0

5

10

15

20

25

30

TBC PCP CAN TOX CMV CRI LMP MYC NEU OTR

IO

Infecciones Oportunistas más Frecuentes como forma de Debut del Sida

CoRIS (N= 477; 2004-07)

Infecciones Oportunistas más Frecuentes como forma de Debut del Sida

CoRIS (N= 477; 2004-07)

%

0

5

10

15

20

25

30

35

40

TBC PCP CAN TOX

UDVPHMXHTX

Infecciones Oportunistas más Frecuentes según la Conducta de Riesgo

CoRIS (N= 477; 2004-07)

Infecciones Oportunistas más Frecuentes según la Conducta de Riesgo

CoRIS (N= 477; 2004-07)

%

Evento CEvento C MedianaMediana RIQRIQTuberculosis pulmonarTuberculosis pulmonar 221221 95; 38595; 385Tuberculosis extrapulmonarTuberculosis extrapulmonar 8080 24;13524;135NeumonNeumoníía por a por P. P. jiroveciijirovecii 2929 11;6111;61CandidiasisCandidiasis esofesofáágicagica 3535 12;11112;111ToxoplasmosisToxoplasmosis cerebralcerebral 4949 20;13820;138CriptococosisCriptococosis 2222 8;538;53LMPLMP 100100 61;15161;151Sarcoma de Sarcoma de KaposiKaposi (SK)(SK) 130130 69;27669;276Linfoma no Linfoma no HodgkinHodgkin (LNH)(LNH) 128128 59;26059;260

Linfocitos CD4 & Eventos CCoRIS (N= 477; 2004-07)

Linfocitos CD4 & Eventos CCoRIS (N= 477; 2004-07)

Mortality from HIV and TB coinfections is higher inEastern Europe than in Western Europe and Argentina

The HIV/TB Study Writing Group. AIDS 2009, 23:2485–2495



Use of cART therapy in HIV/TB coinfected patients according to region.





≈10%

Survival within 1 year of TB diagnosis according to region

• Introducción



• Conclusiones

• Introducción



• Conclusiones



1.- Symptomatic patients (B/C events): all cases1.- Symptomatic patients (B/C events): all cases

2.- Asymptomatic patients- CD4 < 350 cels/mm3: Recommended in all cases- CD4 350-500 cels/mm3: Recommended in some situations*- CD4 > 500 cels/mm3: Delayed in general.

2.- Asymptomatic patients- CD4 < 350 cels/mm3: Recommended in all cases- CD4 350-500 cels/mm3: Recommended in some situations*- CD4 > 500 cels/mm3: Delayed in general.

*Liver cirrhosis, chronic C/B hepatitis, Plasma HIV-1 RNA Viral Load > 105 copies/ml; CD4 <14%; Age >55 years; High cardiovascular risk; HIV-related nephropathy.

*Liver cirrhosis, chronic C/B hepatitis, Plasma HIV-1 RNA Viral Load > 105 copies/ml; CD4 <14%; Age >55 years; High cardiovascular risk; HIV-related nephropathy.

2010 Spanish Recommendations for cART in HIV-1-InfectedAntiretroviral Naïve Patients

¿When to start?

Acute therapyAcuteAcute therapytherapy

HAARTHAARTHAART

Timing of HAART in HIV-infected patients with Opportunistic Infections (OIs)


Maintenance therapyMaintenanceMaintenance therapytherapy

- High pill burden- Overlapping side effects- PK interactions- Risk of IRIS/IRD*

IRIS/IRD = Immune restoration disease / Immune reconstitution inflammatory syndrome .IRIS/IRD = Immune restoration disease / Immune reconstitution inflammatory syndrome .

Overlapping side effect profiles of first-lineantituberculosis drugs and antiretroviral drugs

Harries AD et al, Lancet 2006; 367: 944–45

Overlapping side effect profiles of first-lineantituberculosis drugs and antiretroviral drugs

Harries AD et al, Lancet 2006; 367: 944–45Side effectSide effect Possible causesPossible causes

Antituberculosisdrugs

Antituberculosisdrugs

Antiretroviral drugs

Antiretroviral drugs

Skin rash/Fever

GI symptoms (N,V,D)

Hepatitis

Leukopenia, anemia

Peripheral neuropathy

CNS dysfunction

Skin rash/Fever

GI symptoms (N,V,D)

Hepatitis

Leukopenia, anemia

Peripheral neuropathy

CNS dysfunction

PZA, RIT, INH

PZA, RIT, RBT, INH

PZA, RIT, RBT, INH

RBT, RIT

INH

INH

PZA, RIT, INH

PZA, RIT, RBT, INH

PZA, RIT, RBT, INH

RBT, RIT

INH

INH

NVP, EFV, ABC, AMP

AZT, RIT, AMP, IDV

NVP, PIs, immunereconstitution

AZT

D4T, DDI

EFV

NVP, EFV, ABC, AMP

AZT, RIT, AMP, IDV

NVP, PIs, immunereconstitution

AZT

D4T, DDI

EFV

P450 Cytocrom- CYP 3A4 Substrates Inducers Inhibitors Most drugs Rifabutin NNRTI PI

CCR5-inhibitors

Carbamacepine Rifamicines Phenobarbital Phenytoin Corticoids Nevirapine Efavirenz

Imidazoles Cimetidine Ca antagonists Macrolides ISRS Protease inhibitors (PIs) Delavirdine

Imidazoles: Keto>>Itra>FluconazoleMacrolides: Erythro>>Clarithro>>AzithromicinePIs: Ritonavir>>IDV-APV-ATZ-LPV>NFV>Saquinavir

Å Rifampin>Rifapentine>Rifabutin.

PK INTERACTIONSPK INTERACTIONS

PK INTERACTIONSPK INTERACTIONSP450 Inhibition

(fast, hours)P450 Inhibition

(fast, hours)

P450 Induction(slow, days)

P450 Induction(slow, days)Se

rum

leves

Seru

m lev

es

ToxicityToxicity

EfficacyEfficacy

Lüllmann H et al. Pharmacology. 1992.Lüllmann H et al. Pharmacology. 1992.

Normal rangeNormal range

TDM !!!TDM !!!TDM !!!

Paradoxical Reaction of Tuberculoma in a patients with AIDS (IRIS)

Paradoxical Reaction of Tuberculoma in a patients with AIDS (IRIS)

Day 0 Day +15 Anti-TB Rx + AZT

Paradoxical Reaction of Ganglionar Tuberculosis in a patients with AIDS (IRIS)

Paradoxical Reaction of Ganglionar Tuberculosis in a patients with AIDS (IRIS)

Day 0 Day + 50 Anti-TB Rx + + HAART

TB-associated IRIS: Incidence, Risk Factors, and Effectwithin an ART Program in Sub-Saharan Africa

Lawn S et al. AIDS 2007, 21:335–341• Retrospective analysis of a study cohort (N=160 pts) enrolled over 3 years within a community-based cART service in South Africa. Overall IRIS 12% (32% <60 days).

IRIS Management / TreatmentIRIS Management / Treatment

1.- To rule out OI microbiological failure, OI resistance orantimicrobial toxicity.1.- To rule out OI microbiological failure, OI resistance orantimicrobial toxicity.

2.- IRIS treatmentMild/Moderate: Nonsteroidal inflammatory drugs (NSID)Severe: Corticosteroids.

2.- IRIS treatmentMildMild//ModerateModerate: : NonsteroidalNonsteroidal inflammatoryinflammatory drugsdrugs (NSID)(NSID)SevereSevere: : CorticosteroidsCorticosteroids..

3.- In some severe cases, it is recommended to stop antiretroviral therapy (HAART).3.- In some severe cases, it is recommended to stop antiretroviral therapy (HAART).

Acute therapyAcuteAcute therapytherapy

HAARTHAARTHAART



Maintenance therapyMaintenanceMaintenance therapytherapy

HAARTHAARTHAART

- High pill burden- Overlapping side effects- PK interactions- Risk of IRIS/IRD*

- Risk of disease progressionand death in patients withadvanced disease (CD4<50 cells/mm3)

IRIS/IRD = Immune restoration disease / Immune reconstitution inflammatory syndrome .IRIS/IRD = Immune restoration disease / Immune reconstitution inflammatory syndrome .

Prognosis of HIV-1-infected patients starting HAART: a collaborative analysis of prospective studies

ART Cohort Collaboration. Lancet. 2002; 360:119-29.



HIV-1 risk factorHIV-1 risk factorCDC stageCDC stage

CD4+ T cell countCD4+ T cell countHIV Viral LoadHIV Viral Load





Immediate vs. Deferred cART in the Setting of Acute AIDS-Related OIs (ACTG A5164)

Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Epub 2009 May 18.



Study day Study day

EnrollmentEnrollment

Opportunistic infections*Treatment

Starts

Opportunistic infections*Treatment

Starts

Immediate Arm

Start ART

Immediate Arm

Start ART

Deferred ArmStart ART

Deferred ArmStart ART

RecommendedStart window

RecommendedStart window

48wks48

wks

48wks48

wks

-14-14 00 22 2828 4242 8484 224224

Study schemaStudy schema

12 days vs. 45 days

*TB excluded !!!*TB excluded !!!

CharacteristicsCharacteristics TotalTotal ImmediateImmediate DeferredDeferredCD4 CD4 (cells/mm(cells/mm33)) Median (IQR)Median (IQR) 29 (1029 (10--55)55) 31 (1231 (12--5454)) 28 (1028 (10--56)56)HIV RNA HIV RNA (log10)(log10) MMedian edian

(IQR)(IQR)5.075.07

(4.71(4.71--5.63)5.63)5.07 5.07

(4.74(4.74--5.59)5.59)5.085.08

(4.64(4.64--5.64)5.64)No Prior ARTNo Prior ART N (%)N (%) 259 (92)259 (92) 131 (93)131 (93) 128 (91)128 (91)PCPPCP N (%)N (%) 177 (63)177 (63) 88 (62)88 (62) 89 (63)89 (63)BIBI N (%)N (%) 34 (12)34 (12) 17 (12)17 (12) 17 (12)17 (12)Other OIOther OI N (%)N (%) 71 (25)71 (25) 36 (26) 36 (26) 35 (25)35 (25)

CryptoCrypto / / HistoHisto N (%)N (%) 45 (16)45 (16) 20 (14)20 (14) 25 (18)25 (18)Toxoplasmosis Toxoplasmosis N (%)N (%) 113 (5)3 (5) 9 (6)9 (6) 4 (3)4 (3)

CMV CMV N (%)N (%) 6 (2)6 (2) 4 (3)4 (3) 2 (1)2 (1)MAC MAC N (%)N (%) 6 (2)6 (2) 3 (2)3 (2) 3 (2)3 (2)

Multiple OI/BIMultiple OI/BI w/in w/in 30 days30 days 33%33% 32%32% 33%33%







Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Epub 2009 May 18.Zolopa AR, et al. PLoS ONE. 2009;4(5):e5575. Epub 2009 May 18.

Results Through 48 WeeksResults Through 48 Weeks

No difference in primary endpoint of No difference in primary endpoint of virologicvirologic suppressionsuppressionNo difference in IRIS (10 immediate, 13 deferred) or need for ARNo difference in IRIS (10 immediate, 13 deferred) or need for ART changesT changes

Prob

abilit

y of s

urviv

ing

with

out

deat

h/ne

w AI

DS d

efin

ing

even

tPr

obab

ility o

f sur

vivin

g wi

thou

tde

ath/

new

AIDS

def

inin

g ev

ent

Immediate ARTDeferred ARTImmediate ARTDeferred ART

000.00.0

0.20.2

1.001.00

44 88 1212 1616 2020 2424 2828 3232 3636 4040 4444 4848

0.10.1

0.90.9

0.80.8

0.70.7

0.60.60.50.5

0.40.4

0.30.3

116116

9494

HR=0.5399%CI (0.25,1.09)P=0.023

HR=0.5399%CI (0.25,1.09)P=0.023

Early cART ⇒ less new AIDS events or death

MonthsMonths

Retrospective cohort study of 188 patients in U.K. (1996-1999). Median CD4 cell count at TB diagnosis of 90 cells/µL (IQR: 30;180). Retrospective cohort study of 188 patients in U.K. (1996-1999). Median CD4 cell count at TB diagnosis of 90 cells/µL (IQR: 30;180).

Treatment of TB in HIV-infected persons in the cART eraDean GL et al. AIDS 2002, 16:75-83

Treatment of TB in HIV-infected persons in the cART eraDean GL et al. AIDS 2002, 16:75-83

Adverse events (AE) occurred in 54% of patients, the majority withinthe first 2 months. One-third of whom changed or interrupted HIV and/or TB medication.

Adverse events (AE) occurred in 54% of patients, the majority withinthe first 2 months. One-third of whom changed or interrupted HIV and/or TB medication.

ADIADICD4: - >100 cells/µL

- <100 cells/µLHAART: - Yes

- No HAART

CD4: - >100 cells/µL- <100 cells/µL

HAART: - Yes- No HAART

91928598

91928598

9 (10%)18 (20%)3 (3.5%)

24 (24.5%)

9 (10%)18 (20%)3 (3.5%)

24 (24.5%)

No.No. p-valuep-value=0.07

<0.001

=0.07

<0.001

Prospective cohort study of 49 patients in Brazil (1999-202). Mean CD4 cell count at TB diagnosis of 101±128 cells/µL. Prospective cohort study of 49 patients in Brazil (1999-202). Mean CD4 cell count at TB diagnosis of 101±128 cells/µL.

Efavirenz-based ART in HIV Patients on Rifampin for TBPedral-Sampaio DB et al. BJID 2004; 8: 211-6

Efavirenz-based ART in HIV Patients on Rifampin for TBPedral-Sampaio DB et al. BJID 2004; 8: 211-6

Late cART>3 weeks

N=36

Late cART>3 weeks

N=36CD4 (cells/µL)Plasma VL (log10/mL)Extrapulmonary TBToxicity (liver, rash)IRISDeaths

CD4 (cells/µL)Plasma VL (log10/mL)Extrapulmonary TBToxicity (liver, rash)IRISDeaths

95 ± 985.8 ± 0.4

77%37%0%23%

95 ± 985.8 ± 0.4

77%37%0%23%

103 ± 1405.5 ± 0.7

42%7%19%3%

103 ± 1405.5 ± 0.7

42%7%19%3%

Early cART0-3 weeks

N=16

Early cART0-3 weeks

N=16p-valuep-value

NSNS

<0.03<0.050.020.02

NSNS

<0.03<0.050.020.02

CROI-2009; Abs. # 36a

Abs. # 36a

CROI-2009; Abs. # 36a

Sept 2008: DSMB stopped sequential arm and recommended that all begin ART

CROI-2009; Abs. # 36a

Effect of Simultaneous Use of HAART on Survival of HIV Patients With Tuberculosis

Velasco M et al. J Acquir Immune Defic Syndr 2009; 50:148-52.

Effect of Simultaneous Use of HAART on Survival of HIV Patients With Tuberculosis

Velasco M et al. J Acquir Immune Defic Syndr 2009; 50:148-52.

Retrospective study performed in Spain (COMESEM)

313 pts with TB diagnosed in the HAART era (>1996). Extrapulmonary TB was diagnosed in 67% of pts.CD4 (median [IQR]) = 160 (69; 289) c/mm3. Plasma HIV-1 viral load = 5 (4; 5,7) log10/mL

140 pts started cART within 2 months(Simultaneous group) and 173 after 3 months of TB diagnosis (Delayed group).Mortality: 9% vs. 20% (P=0.01)

Retrospective study performed in Spain Retrospective study performed in Spain (COMESEM)(COMESEM)

313 pts with TB diagnosed in the HAART era 313 pts with TB diagnosed in the HAART era (>1996). (>1996). ExtrapulmonaryExtrapulmonary TB was diagnosed in 67% of TB was diagnosed in 67% of pts.pts.CD4 (median [IQR]) = 160 (69; 289) c/mm3. CD4 (median [IQR]) = 160 (69; 289) c/mm3. Plasma HIVPlasma HIV--1 viral load = 5 (4; 5,7) log1 viral load = 5 (4; 5,7) log1010/mL/mL

140 pts started 140 pts started cARTcART within 2 monthswithin 2 months(Simultaneous group) (Simultaneous group) and 173 after 3 and 173 after 3 months of TB diagnosismonths of TB diagnosis (Delayed (Delayed group).group).Mortality: 9% Mortality: 9% vs.vs. 20% (20% (PP=0.01)=0.01)

Survival of HIV-1 infected patients with TB

P = 0.003.

RCT of Immediate vs. Deferred Antiretroviral Therapyin HIV-Associated Tuberculous Meningitis

Torok ME et al. 49th ICAAC, San Francisco. 2009; Abs. H-1224.

RCT of Immediate vs. Deferred Antiretroviral Therapyin HIV-Associated Tuberculous Meningitis

Torok ME et al. 49th ICAAC, San Francisco. 2009; Abs. H-1224.

Randomized, double-blind, placebo-controlled, phase IV strategy trial ofimmediate vs. deferred cART in HIV patients with tuberculous meningitis, to determine whether immediatecART reduced the risk of death during9 months of follow-up. Antiretroviral drugs (zidovudine, lamivudine and efavirenz) werestarted either at study entry(Immediate arm) or two months post-randomization (Deferred arm).

RandomizedRandomized, , doubledouble--blindblind, placebo, placebo--controlledcontrolled, , phasephase IV IV strategystrategy trialtrial ofofimmediateimmediate vs. vs. deferreddeferred cARTcART in HIV in HIV patientspatients withwith tuberculoustuberculous meningitis, meningitis, toto determine determine whetherwhether immediateimmediatecARTcART reducedreduced thethe riskrisk ofof deathdeath duringduring9 9 monthsmonths ofof followfollow--up. up. AntiretroviralAntiretroviral drugsdrugs ((zidovudinezidovudine, , lamivudinelamivudine andand efavirenzefavirenz) ) werewerestartedstarted eithereither at at studystudy entryentry((ImmediateImmediate armarm) ) oror twotwo monthsmonths postpost--randomizationrandomization ((DeferredDeferred armarm)). .

ImmediatecARTN=127

DeferredcARTN=126

- AEs (grade3/4)- AEs (<2 months)

- Death

P

90%86%

60%

89%75%

56%

NS.04

NS

Immediate ART was not significantly associatedwith 9-month mortality (hazard ratio (HR) 1.12, 95%

confidence interval (CI) 0.81 to 1.55, p=0.50)

Early vs. delayed (10 weeks) cART in CryptococcalMeningitis (N=54)

Tx: Fluconazole 800 mg daily and d4T/3TC/NVPNo use of amphotericin or management of raised intracranial pressure

Mortality: 87% immediate vs. 37% delayed (P=0.002)

Most deaths in immediate ART group occurred within the first month, possibly due to IRISFluconazole-NVP drug interaction postulated

Early Early vs.vs. delayed delayed (10 weeks) (10 weeks) cARTcART in in CryptococcalCryptococcalMeningitis (N=54)Meningitis (N=54)

TxTx: : FluconazoleFluconazole 800 mg daily and 800 mg daily and d4T/3TC/NVPd4T/3TC/NVPNo use of No use of amphotericinamphotericin or management of or management of raised intracranial pressureraised intracranial pressure

Mortality: 87% immediate Mortality: 87% immediate vs.vs. 37% 37% delayed (delayed (PP=0.002)=0.002)

Most deaths in immediate ART group Most deaths in immediate ART group occurred within the first month, possibly occurred within the first month, possibly due to IRISdue to IRISFluconazoleFluconazole--NVP drug interaction NVP drug interaction postulatedpostulated

cART and Cryptococcal Meningitis: Zimbabwe

Comparison of Kaplan-Meier Survival Estimatesby Treatment Group

1.00

0.75

0.00

0.25

0 200 400 600 800

Time to Death (in days)

0.50

Time to Death (days)

P=0.028Delayed

EarlySurv

ival

Makadzange A, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 36cLB.Makadzange A, et al. 16th CROI; Montreal, Canada; February 8-11, 2009. Abst. 36cLB.

HRZEHRZEHRZE0 +0.5 +1 +2 +6 months00 +0.5 +0.5 +1 +2 +1 +2 ++6 months6 months

CD4 < 100 CD4 < 100 CD4 < 100

Timing of HAART in HIV-infected patients with TB according to CD4 cell count

Timing of HAART in HIV-infected patients with TB according to CD4 cell count

HRHRHR

CD4 100-350CD4 100CD4 100--350350

CD4 >350CD4 >350CD4 >350

Int-TB RxIntInt--TB TB RxRx Con-TB RxConCon--TB TB RxRx HAARTHAARTHAART GESIDA/PNS Guidelines. EIMC. 2008.GESIDA/PNS Guidelines. EIMC. 2008.

• Introducción



• Conclusiones

• Introducción



• Conclusiones



NRTI*Zidovudine (AZT)Didanosine (ddI)Zalcitabine (ddC)Lamivudine (3TC)Stavudine (d4T)Abacavir (ABV)Emtricitavine (FTC)

NRTI*NRTI*ZidovudineZidovudine (AZT)(AZT)DidanosineDidanosine ((ddIddI))ZalcitabineZalcitabine ((ddCddC))LamivudineLamivudine (3TC)(3TC)StavudineStavudine ((d4Td4T))AbacavirAbacavir (ABV)(ABV)EmtricitavineEmtricitavine (FTC)(FTC) PROTEASE INHIBITORS (IP)

Saquinavir / Indinavir / NelfinavirRitonavir (rtv) Fosamprenavir/rtvLopinavir/rtv (Kaletra®)Atazanavir/rtvTipranavir/rtvDarunavir/rtv

PROTEASE INHIBITORS (IP)Saquinavir / Indinavir / NelfinavirRitonavir (rtv) Fosamprenavir/rtvLopinavir/rtv (Kaletra®)Atazanavir/rtvTipranavir/rtvDarunavir/rtv

NNRTI**EfavirenzNevirapineEtravirine

NNRTI**EfavirenzNevirapineEtravirine

NtRTI*Tenofovir (TDF)NtRTI*Tenofovir (TDF)

ENTRY INHIBITORS- Fusion inhibitors: Enfuvirtide (T-20)- CCR5 inh.: Maraviroc; Vicriviroc (viral phenotype)

ENTRY INHIBITORS- Fusion inhibitors: Enfuvirtide (T-20)- CCR5 inh.: Maraviroc; Vicriviroc (viral phenotype)

Approved antiretrovirals (2009)Approved antiretrovirals (2009)

INTEGRASE INHIBITORSRaltegravirElvitigravir/rtv

INTEGRASE INHIBITORSRaltegravirElvitigravir/rtv

*Combos: Combivir®; Kivexa®; Truvada®; Trizivir®; ** Atripla ®. *Combos: Combivir®; Kivexa®; Truvada®; Trizivir®; ** Atripla ®.

2010 Spanish Recommendations for cART in HIV-1-InfectedAntiretroviral Naïve PatientsFirst Line Regimens

NNRTI-based regimens:NNRTINNRTI--basedbased regimensregimens:: EFV + 2 NRTIs* QDEFV + 2 NRTIs* QDPI/r-based regimens:PI/rPI/r--basedbased regimensregimens:: LPV/r (Kaletra®)+ 2 NRTIs* BID/QD

FPV/r or SQV/r + 2 NRTIs* BIDATV/r or DRV/r + 2 NRTIs* QD

LPV/r (Kaletra®)+ 2 NRTIs* BID/QDFPV/r or SQV/r + 2 NRTIs* BIDATV/r or DRV/r + 2 NRTIs* QD

Triple NRTI RegimenTriple NRTI Triple NRTI RegimenRegimen Not recommended as first line Rx.Only alternative: Trizivir® ± TDF.Not recommended as first line Rx.Only alternative: Trizivir® ± TDF.

*NRTIs: Truvada® Atripla®; Kivexa® if HLA-B*5701 Neg.; Alternative: Combivir®; ddI+FTC/3TC.*NRTIs: Truvada® Atripla®; Kivexa® if HLA-B*5701 Neg.; Alternative: Combivir®; ddI+FTC/3TC.

GESIDA-PNS. Enferm Infecc Microbiol Clin. 2009;27:222–235.GESIDA-PNS. Enferm Infecc Microbiol Clin. 2009;27:222–235.

AlternativesAlternativesAlternatives Maraviroc (R5)+ 2 NRTIs*.Maraviroc (R5)+ 2 NRTIs*.

Raltegravir-based regimens:RaltegravirRaltegravir--basedbased regimensregimens:: RAL BID + 2 NRTIs* QDRAL BID + 2 NRTIs* QD

Antiretroviral Therapy

EfavirenzEfavirenzAt nightAt night

CombivirCombivir®®NNRTIsNNRTIsNRTIs/NtRTINRTIs/NtRTI

TTruvadaruvada®®

TrizivirTrizivir®®

KivexaKivexa®®

AtriplaAtripla®®

LopinavirLopinavir+ + RitonavirRitonavir ((KaletraKaletra®®))

RaltegravirRaltegravir

Boosted PIsBoosted PIs

IntegraseIntegrase InhibitorsInhibitorsNRTIs/NtRTI+NNRTINRTIs/NtRTI+NNRTI

PROPROExcellent efficacy with longest dataExcellent efficacy with longest dataHigh genetic barrierHigh genetic barrierLower pill burden with newer PILower pill burden with newer PI‘‘s and newer formulationss and newer formulationsOnce daily schedule is possibleOnce daily schedule is possibleNew PINew PI‘‘s with less side effectss with less side effectsMore data in advanced patients. Higher CD4 increaseMore data in advanced patients. Higher CD4 increase

Boosted PI first line

CONCONHigher pill burden than NNRTIHigher pill burden than NNRTIMetabolic adverse events (lipids, insulin resistance)Metabolic adverse events (lipids, insulin resistance)Strong PK interactions with rifampin/rifabutinStrong PK interactions with rifampin/rifabutin

Rifampin RifabutinIndinavir No 150 mg/day*Nelfinavir No 150 mg/day*Saquinavir Yes (SQV/rtv) 150 mg/TIW (SQV/rtv)

ToxicidadAtazanavir No 150 mg/TIWAmprenavir No 150 mg/dayDarunavir No 150 mg/TIWRitonavir Yes (full dose) 150 mg two times x weekKaletra® Yes (400/400 150 mg TIW

or 800/200)

RifampinRifampin RifabutinRifabutinIndinavirIndinavir NoNo 150 150 mgmg//dayday**NelfinavirNelfinavir NoNo 150 150 mgmg//dayday**SaquinavirSaquinavir YesYes (SQV/(SQV/rtvrtv)) 150 150 mgmg/TIW (SQV//TIW (SQV/rtvrtv))

ToxicidadToxicidadAtazanavirAtazanavir No No 150 150 mgmg/TIW/TIWAmprenavirAmprenavir NoNo 150 150 mgmg//daydayDarunavirDarunavir NoNo 150 150 mgmg/TIW/TIWRitonavirRitonavir YesYes (full (full dosedose) ) 150 150 mgmg twotwo times x times x weekweekKaletraKaletra®® YesYes (400/400(400/400 150 150 mgmg TIWTIW

oror 800/200)800/200)

Combination of PIs-Rifamycins2009 Guidelines

Combination of PIs-Rifamycins2009 Guidelines

Source: http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm; * Increase PI dose to 1,000 mg TID.

http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

PROPROExcellent efficacy with long term dataExcellent efficacy with long term dataVery low pill countVery low pill countOnce dailyOnce dailyWell toleratedWell toleratedLess metabolic Less metabolic adverse effectsadverse effects

NNRTI first line

CONCONLess experience in advanced patientsLess experience in advanced patientsLess PK interactions (rifampin/rifabutin)Less PK interactions (rifampin/rifabutin)Lower genetic barrierLower genetic barrierClass resistanceClass resistance

Combination NNRTI-Rifamycins2009 Guidelines

Rifampin Rifabutin

Nevirapine Yes YesEfavirenz Yes Rb 450-600 mg QD

EFV 600-800 mgDelavirdine No NoRilpivirina No No datos

RifampinRifampin RifabutinRifabutin

NevirapineNevirapine YesYes YesYesEfavirenzEfavirenz YesYes Rb 450Rb 450--600 600 mgmg QDQD

EFV 600EFV 600--800 800 mgmgDelavirdineDelavirdine No No NoNoRilpivirinaRilpivirina No No NoNo datosdatos

Source: http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm

No clinically significant interactions betweenrifampin/rifabutin and NRTIs & Fusion inhibitors

– Stavudine (d4T) - Enfuvirtide (T-20)– Didanosine (ddI)– Zidovudine (AZT)– Lamivudine (3tC)– Abacavir (ABC)– Zalcitabine (ddC)– Tenofovir (TFD)

No No clinicallyclinically significantsignificant interactionsinteractions betweenbetweenrifampinrifampin//rifabutinrifabutin andand NRTIsNRTIs & & FusionFusion inhibitorsinhibitors

– Stavudine (d4T) - Enfuvirtide (T-20)– Didanosine (ddI)– Zidovudine (AZT)– Lamivudine (3tC)– Abacavir (ABC)– Zalcitabine (ddC)– Tenofovir (TFD)

NRTIs & Entry Inhibitors- Rifamycins InteractionsNRTIs & Entry Inhibitors- Rifamycins Interactions

Few data on CCR5-inhibitors butthey are metabolized by

cytochrome P-450 isoenzyme 3A4.⇒ No clinical data in HIV-1

infected patients.

Few data on CCR5-inhibitors butthey are metabolized by

cytochrome P-450 isoenzyme 3A4.⇒ No clinical data in HIV-1

infected patients.

• Elvitigravir/rtv: Combination between vicriviroc and rifampin is notrecommended.

•• ElvitigravirElvitigravir//rtvrtv: : CombinationCombination betweenbetween vicrivirocvicriviroc andand rifampinrifampin isis notnotrecommendedrecommended..

Integrase Inhibitors - Rifamycins InteractionsIntegrase Inhibitors - Rifamycins Interactions

• Raltegravir is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin.• Doubling the raltegravir dose to 800 mg/12 h. when coadministered withrifampin compensates for the effect of rifampin on raltegravir exposure (AUC [0-12]) but does not overcome the effect of rifampin on raltegravir troughconcentrations (C[12])*. • Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used and TDM is recommended.

• Raltegravir is metabolized by glucuronidation via UGT1A1 and may be affected by inducers of UGT1A1, such as rifampin.• Doubling the raltegravir dose to 800 mg/12 h. when coadministered withrifampin compensates for the effect of rifampin on raltegravir exposure (AUC [0-12]) but does not overcome the effect of rifampin on raltegravir troughconcentrations (C[12])*. • Coadministration of rifampin and raltegravir is not contraindicated; however, caution should be used and TDM is recommended.

* Wenning LA al. Antimicrob Agents Chemother. 2009;53:2852-6. * Wenning LA al. Antimicrob Agents Chemother. 2009;53:2852-6.

D-DInteractions between second-line antituberculosis drugs and antiretroviral agents are unlikely

Koyne KM et al. AIDS 2009, 23:437–446

D-DInteractions between second-line antituberculosis drugs and antiretroviral agents are unlikely

Koyne KM et al. AIDS 2009, 23:437–446

Problems1) These are drugs approved nearly

40 years ago and their pathwaysof drug metabolism are not wellknown.

2) There are no published studies ofpossible D-D interactions betweensecond-line antituberculosis drugsand antiretroviral drugs.

3) Only ethionamide & macrolideshave a potential interaction withantiretroviral drugs (NNRTIs/PIs).

4) Rifabutin << Rifampin.

Problems1) These are drugs approved nearly

40 years ago and their pathwaysof drug metabolism are not wellknown.

2) There are no published studies ofpossible D-D interactions betweensecond-line antituberculosis drugsand antiretroviral drugs.

3) Only ethionamide & macrolideshave a potential interaction withantiretroviral drugs (NNRTIs/PIs).

4) Rifabutin << Rifampin.

CROI 2009 Abs. # 35CROI 2009 Abs. # 35

• Rifampicina se puede utilizar con un TARGA basado en un ITINN, preferentemente efavirenz (EFV), aumentando la dosis de EFV a 800 mg/día en pacientes de > 60 kg (o monitorizar niveles); o,

• Se debe utilizar rifabutina en lugar de rifampicina para poder usar IP/r. El uso de rifabutina presenta varios problemas: a) requiere ajuste de dosis del fármaco, y la dosis de rifabutina es de 150 mg 3 días por semana con la mayoría de IP/r; b) en algunos IP hay que aumentar la dosis o están contraindicados (LPV/r); c) incluso en los IP que se pueden utilizar, sus niveles son muy “sensibles” a si el paciente no toma rifabutina, por lo que se requiere TDO y TDM.

• Rifampicina se puede utilizar con un TARGA basado en un ITINN, preferentemente efavirenz (EFV), aumentando la dosis de EFV a 800 mg/día en pacientes de > 60 kg (o monitorizar niveles); o,

• Se debe utilizar rifabutina en lugar de rifampicina para poder usar IP/r. El uso de rifabutina presenta varios problemas: a) requiere ajuste de dosis del fármaco, y la dosis de rifabutina es de 150 mg 3 días por semana con la mayoría de IP/r; b) en algunos IP hay que aumentar la dosis o están contraindicados (LPV/r); c) incluso en los IP que se pueden utilizar, sus niveles son muy “sensibles” a si el paciente no toma rifabutina, por lo que se requiere TDO y TDM.

Cual es la mejor pauta de TARGA en pacientes con TBGESIDA/PNS Guidelines. Enferm Infecc Microbiol Clin. 2008;26:356-79


• No hay suficiente experiencia para recomendar una pauta de TARGA con raltegravir en pacientes con TB tratados con una pauta que incluya rifampicina.

• En los pacientes con CD4 < 100 cél/mm3, se ha descrito desarrollo de resistencias en pacientes tratados con rifamicinas en pautas intermitentes, por lo que no están recomendadas.

• En casos de tuberculosis multirresistente (MDR-TB; XDR-TB) en que sea preciso utilizar otros fármacos de primera o segunda línea, pueden utilizarse tanto IP/r como ITINN o raltegravir, dado que no se han descrito interacciones relevantes con fármacos antituberculosos de segunda línea.

• No hay suficiente experiencia para recomendar una pauta de TARGA con raltegravir en pacientes con TB tratados con una pauta que incluya rifampicina.

• En los pacientes con CD4 < 100 cél/mm3, se ha descrito desarrollo de resistencias en pacientes tratados con rifamicinas en pautas intermitentes, por lo que no están recomendadas.

• En casos de tuberculosis multirresistente (MDR-TB; XDR-TB) en que sea preciso utilizar otros fármacos de primera o segunda línea, pueden utilizarse tanto IP/r como ITINN o raltegravir, dado que no se han descrito interacciones relevantes con fármacos antituberculosos de segunda línea.



• Introducción



• Conclusiones

• Introducción



• Conclusiones



• In TB patients, efavirenz-based HAART has severaladvantages over PI-based HAART (low pill burden, less PK interactions), thus allowing rifampin-based TB therapy.

• In TB In TB patientspatients, , efavirenzefavirenz--basedbased HAART has HAART has severalseveraladvantagesadvantages overover PIPI--basedbased HAART (HAART (lowlow pillpill burdenburden, , lessless PK PK interactionsinteractions), ), thusthus allowingallowing rifampinrifampin--basedbased TB TB therapytherapy..

ConclusionsConclusions• In TB patients, cART must be started before TB Rx isfinished. However, it is not known when it should be startedduring TB Rx. While waiting for RCT results, it isrecommended to start cART after 2 weeks of Rx for TB in patients with <100 CD4+ T cells/mm3.

• In TB patients, cART must be started before TB Rx isfinished. However, it is not known when it should be startedduring TB Rx. While waiting for RCT results, it isrecommended to start cART after 2 weeks of Rx for TB in patients with <100 CD4+ T cells/mm3.

• In MDR- or XDR-TB patients, any cART regimen can be given because there are not PK interactions.• In MDRIn MDR-- oror XDRXDR--TB TB patientspatients, , anyany cARTcART regimenregimen can be can be givengiven becausebecause therethere are are notnot PK PK interactionsinteractions..

Taller UiTB – 2009 Barcelona, a 30 de Noviembre del 2009 ... · Tuberculosis extrapulmonar 80...

Documents

Transcript of Taller UiTB – 2009 Barcelona, a 30 de Noviembre del 2009 ... · Tuberculosis extrapulmonar 80...