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Simplification of Successful Simplification of Successful Antiretroviral Therapy with Antiretroviral Therapy with Nucleoside Analogues: Nucleoside Analogues: Studies and Clinical Practice Studies and Clinical Practice Milos Opravil Opravil

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Simplification of Successful Simplification of Successful Antiretroviral Therapy with Antiretroviral Therapy with Nucleoside Analogues: Nucleoside Analogues: Studies and Clinical Practice Studies and Clinical Practice

Milos Milos Opravil Opravil Division of Infectious Diseases Division of Infectious Diseases University Hospital University Hospital Zurich, Switzerland Zurich, Switzerland

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SLIDE 2

Rationale Rationale for for simplification simplification of PI

  • f PI-
  • HAART with

HAART with NRTI NRTI or

  • r NNRTI

NNRTI

Equal Equal efficacy efficacy and and durability as PI continuation ? durability as PI continuation ? virological virological, also in , also in lymphoid lymphoid tissue tissue immunological immunological Other Other / / new new toxicity ? toxicity ? mitochondrial mitochondrial toxicity toxicity, , lipoatrophy (NRTI) lipoatrophy (NRTI) rash rash (ABC, NNRTI) (ABC, NNRTI) CNS CNS ( (EFV) EFV) liver (NNRTI) liver (NNRTI) Supporting adherence Supporting adherence less pill burden less pill burden no dietary restriction no dietary restriction reduction in adverse events (GIT) reduction in adverse events (GIT) Preventing or reversing metabolic complications Preventing or reversing metabolic complications hyperlipidemia hyperlipidemia fat accumulation fat accumulation Avoiding CYP interactions (NRTI) Avoiding CYP interactions (NRTI)

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SLIDE 3

ACTG5095: ACTG5095: randomized randomized, double , double-

  • blind

blind study study of 3

  • f 3 regimens

regimens for for the the initial initial treatment treatment of HIV:

  • f HIV: zidovudine

zidovudine– –lamivudine lamivudine– –abacavir abacavir, , zidovudine zidovudine– – lamivudine lamivudine plus plus efavirenz efavirenz, and , and zidovudine zidovudine– –lamivudine lamivudine– –abacavir abacavir plus plus efavirenz efavirenz

Gulick Gulick et al., NEJM 2004;350:1850 et al., NEJM 2004;350:1850

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SLIDE 4

ACTG5095: ACTG5095: Virologic Virologic failure failure in in pts pts with with at least at least once

  • nce

HIV RNA <200 c HIV RNA <200 c./ml ./ml – – Less durable effect of triple NRTI Less durable effect of triple NRTI

Gulick Gulick et al., NEJM 2004;350:1850 et al., NEJM 2004;350:1850

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SLIDE 5

Meta Meta-

  • analysis of 9 randomized controlled trials of simplified

analysis of 9 randomized controlled trials of simplified versus continued PI versus continued PI-

  • based HAART:

based HAART: virologic virologic failure failure

Bucher et al., AIDS 2003;17:2451 Bucher et al., AIDS 2003;17:2451-

  • 2459

2459 ABC / ABC / Trizivir Trizivir NNRTI NNRTI

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SLIDE 6

Bucher et al., AIDS 2003;17:2451 Bucher et al., AIDS 2003;17:2451-

  • 2459

2459

Meta Meta-

  • analysis of 3 randomized controlled trials of

analysis of 3 randomized controlled trials of simplification to ABC / simplification to ABC / Trizivir Trizivir: : virologic virologic failure failure

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SLIDE 7

Bucher et al., AIDS 2003;17:2451 Bucher et al., AIDS 2003;17:2451-

  • 2459

2459

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SLIDE 8

S Studies tudies in which some patients in which some patients received sub received sub-

  • optimal regimens
  • ptimal regimens

prior to HAART prior to HAART

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SLIDE 9

N pa N pat tients ients

Suboptimal Suboptimal Rx+ HAART Rx+ HAART (n= 237) (n= 237) Only HAART Only HAART (n= 223) (n= 223) Total Total VF VF

N NEV/ EV/ EF EFA/ A/ A ABA Trial BA Trial

V Virol irolo

  • gic

gical f ailure (VF) by previous therapy al f ailure (VF) by previous therapy

NEV NEV

N = 15 N = 155 5

EF EFA A

N = 156 N = 156

AB ABA A

N = 1 N = 149 49 5 5 3 3 8 8 4 4 1 1 5 5 1 14 4 2 2 16 16

Martinez et al., NEJM Martinez et al., NEJM 2003;349:1036 2003;349:1036-

  • 46

46

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SLIDE 10

SMT Study Design SMT Study Design PI-containing HAART Switch to ABC + COM

(Trizivir >Mar 2000)

Continue HIV HIV-

  • 1 RNA undetectable

1 RNA undetectable ≥ ≥ ≥ ≥ ≥ ≥ ≥ ≥ 6 6 months months induced induced by by PI PI-

  • containing

containing HAART HAART Randomize Randomize At At screening: screening:

  • negative for 215 ZDV

negative for 215 ZDV resistance mutation resistance mutation (PBMC DNA) (PBMC DNA)

  • <50 HIV

<50 HIV-

  • 1 RNA copies/ml

1 RNA copies/ml Initial mono/dual NRTI (46%)

Opravil et al., JID 2002;185:1251 Opravil et al., JID 2002;185:1251-

  • 60

60

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SLIDE 11

SMT: Time to SMT: Time to virologic virologic failure failure (ITT (ITT analysis analysis) )

Opravil et al., JID 2002;185:1251 Opravil et al., JID 2002;185:1251-

  • 60

60

P P = 0.061 = 0.061 logrank logrank test test

N ( N (cont cont.): .): 79 79 79 79 77 77 73 73 68 68 45 45 34 34 25 25 22 22 10 10 3 3 N ( N (simpl simpl.): .): 84 84 80 80 75 75 74 74 71 71 53 53 38 38 24 24 16 16 8 8 3 3

12 24 36 48 60 72 84 96 108 120 132 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

cont simpl

Weeks Proportion not failing

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SLIDE 12

Treatment Treatment failure failure vs.

  • vs. virologic

virologic failure failure

Change of Change of treatment treatment due due to AE to AE or

  • r preference

preference

  • Today

Today many many options

  • ptions
  • May

May even even be be desirable desirable if if it it improves improves adherence adherence Virologic Virologic failure failure

  • More

More severe severe because because resistance resistance possible possible: : decreases decreases future future treatment treatment options

  • ptions
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SLIDE 13

SMT: Time to SMT: Time to virologic virologic failure failure (ITT (ITT analysis analysis) )

Pre Pre-

  • treatment

treatment with with ZDV ZDV before before HAART HAART predicts predicts virologic virologic failure failure

Opravil et al., JID 2002;185:1251 Opravil et al., JID 2002;185:1251-

  • 60

60

12 24 36 48 60 72 84 96 108 120 132 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

cont: prior ZDV cont:no prior ZDV simp: prior ZDV simp: no prior ZDV

Proportion without virologic failure Weeks

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SLIDE 14

PI-containing HAART Switch to ABC + COM

(Trizivir >M ar 2000)

Continue HIV HIV-

  • 1 RNA undetectable

1 RNA undetectable ≥ ≥ ≥ ≥ ≥ ≥ ≥ ≥ 6 6 m

  • nths

m

  • nths induced

inducedby by PI PI-

  • containing

containingHAART HAART Random ize Random ize At At screening: screening:

  • negative for 215 ZDV

negative for 215 ZDV resistance m utation resistance m utation (PBMC DNA) (PBM C DNA)

  • <50 HIV

<50 HIV-

  • 1 RNA copies/m

l 1 RNA copies/m l Initial m

  • no/dual

NRTI (46% )

Trizivir Extended Follow-up End of randomized comparison

SMT: original study + extended follow SMT: original study + extended follow-

  • up

up

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SLIDE 15

SMT SMT study study: long : long-

  • term

term efficacy efficacy

# at risk: 51 44 44 24 24 25 14 14 10 10

1 2 3 4 5 6 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 ZDV prior to HAART No ZDV prior to HAART

Time after switch (years) Proportion of patients without virologic failure

Opravil et al., AIDS 2004 in Opravil et al., AIDS 2004 in print print

incidence of incidence of virologic virologic failure: failure: 3.4/100 PY 3.4/100 PY (N = 53) (N = 53) 13.5/100 PY 13.5/100 PY (N = 31) (N = 31) ( (P P = 0.008) = 0.008)

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SLIDE 16

PI-containing HAART Switch to ABC + COM

(Trizivir >M ar 2000)

Continue HIV HIV-

  • 1 RNA undetectable

1 RNA undetectable ≥ ≥ ≥ ≥ ≥ ≥ ≥ ≥ 6 6 m

  • nths

m

  • nths induced

inducedby by PI PI-

  • containing

containingHAART HAART Random ize Random ize At At screening: screening:

  • negative for 215 ZDV

negative for 215 ZDV resistance m utation resistance m utation (PBMC DNA) (PBM C DNA)

  • <50 HIV

<50 HIV-

  • 1 RNA copies/m

l 1 RNA copies/m l Initial m

  • no/dual

NRTI (46% )

Trizivir Extended Follow-up End of randomized comparison

SMT design: original study + extended follow SMT design: original study + extended follow-

  • up

up

Virologic Virologic failure among all 81 patients without prior ZDV mono/dual thera failure among all 81 patients without prior ZDV mono/dual therapy py who switched from PI who switched from PI-

  • regimens to

regimens to Trizivir Trizivir: : 2.45/100 PY (95% Poisson CI: 0.90 2.45/100 PY (95% Poisson CI: 0.90 – – 5.33/100 PY) 5.33/100 PY)

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SLIDE 17

Subjects with a history of mainly Subjects with a history of mainly HAART from initiation of therapy HAART from initiation of therapy

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SLIDE 18

TRIZAL: Proportion of TRIZAL: Proportion of Subjects Subjects with with Plasma HIV Plasma HIV-

  • 1 RNA

1 RNA < 50c/ml < 50c/ml at at Week Week 48 48

20 40 60 80 100 4 8 12 16 20 24 28 32 36 40 44 48 Study Week Percentage of Subjects Trizivir (AT) Continued HAART (AT) Trizivir (ITT) Continued HAART (ITT)

94% AT 90% AT 75 % ITT 69 % ITT Katlama Katlama C et al. HIV Medicine 2003;4:79 C et al. HIV Medicine 2003;4:79-

  • 86

86

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SLIDE 19

Switch Maintenance Therapy ( Switch Maintenance Therapy (Maggiolo Maggiolo) ) Virological Virological Failures over 104 Weeks Failures over 104 Weeks

No significant differences across the 3 study arms No significant differences across the 3 study arms

Maggiolo Maggiolo F et al. CID 2003;37:41 F et al. CID 2003;37:41-

  • 49

49

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SLIDE 20

Switch Switch studies studies (PI (PI → → → → → → → → ABC), ABC), compared compared to to continued continued PI PI Virologic Virologic failure failure "Optimal" "Optimal" patients patients PI arm PI arm ABC arm ABC arm Clumeck Clumeck (CNA30017) (CNA30017) 1.9% of 103 1.9% of 103 3.8% of 104 3.8% of 104 direct direct start of HAART start of HAART 2.9% 2.9% Katlama Katlama ( (Trizal Trizal) ) 1.0% of 103 1.0% of 103

  • 4. 7% of 106
  • 4. 7% of 106

direct direct start of HAART start of HAART 1.9% 1.9% Maggiolo Maggiolo 5.7% of 70 5.7% of 70 10.1% of 69 10.1% of 69 direct direct start of HAART start of HAART 0% 0% Pre Pre-

  • treated

treated patients patients Opravil (SMT) Opravil (SMT) 6.4% of 79 6.4% of 79 15.5% of 84 15.5% of 84 direct direct start of HAART start of HAART 8.2% 8.2% Martinez Martinez n.a. n.a. 10.7% of 149 10.7% of 149 direct direct start of HAART start of HAART 2.5% 2.5%

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SLIDE 21

Switch Switch PI to NRTI PI to NRTI or

  • r NNRTI:

NNRTI: Effect Effect on

  • n metabolic complications

metabolic complications in in randomized trials randomized trials

Trial Trial Switch Switch to to Chol Chol. . Triglyc Triglyc. . Lipodystrophy Lipodystrophy Opravil Opravil JID 02 JID 02 Trizivir Trizivir

  • no

no improvement improvement Clumeck Clumeck AIDS 01 AIDS 01 ABC ABC

  • na

na Katlama Katlama: : Trizal Trizal Trizivir Trizivir

  • improvement

improvement Maggiolo Maggiolo CID 03 CID 03 ABC ABC

  • na

na EFV EFV

  • na

na Ruiz JAIDS 01 Ruiz JAIDS 01 NVP NVP

  • no

no improvement improvement Barreiro Barreiro AIDS 00 AIDS 00 NVP NVP

  • improvement

improvement in 50% in 50% Negredo Negredo CID 02 CID 02 NVP NVP

  • no

no improvement improvement EFV EFV

  • no

no improvement improvement DMP266 DMP266-

  • 049

049 EFV EFV

  • no

no improvement improvement DMP266 DMP266-

  • 027

027 EFV EFV

  • less

less progression progression Martinez Martinez CROI 01 CROI 01 EFV EFV

  • no

no improvement improvement Martinez Martinez NEJM 03 NEJM 03 ABC ABC

  • no

no improvement improvement NVP NVP

  • no

no improvement improvement EFV EFV

  • no

no improvement improvement

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SLIDE 22

CNA30017: Adherence CNA30017: Adherence

A baseline, A baseline, une une grande grande proportion de patients proportion de patients affirme affirme prendre prendre toutes toutes les doses des les doses des molécules molécules de de l’étude l’étude ou

  • u oublie
  • ublie moins

moins de 1 dose par de 1 dose par semaine semaine. . ABC: 90/101 ABC: 90/101 (89%) (89%) ; PI: 77/93 ; PI: 77/93 (83%) (83%) A la A la semaine semaine 48, 48, cette cette proportion a proportion a augmenté augmenté dans dans le bras ABC et le bras ABC et diminué diminué dans dans le bras IP le bras IP ABC: 86/94 ABC: 86/94 (91%) (91%) ; PI: 72/95 ; PI: 72/95 (76%) (76%)

Clumeck Clumeck N et al. AIDS 2001;15:1517 N et al. AIDS 2001;15:1517-

  • 26

26

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SLIDE 23

Conclusions for s Conclusions for simplified therapy with ABC or NNRTI implified therapy with ABC or NNRTI Treatment efficacy against HIV infection: Treatment efficacy against HIV infection:

◆ ◆ documented for patients with

documented for patients with > >6 months of suppressed 6 months of suppressed VL on PI VL on PI-

  • based HAART

based HAART

◆ ◆ if treatment started as HAART and no

if treatment started as HAART and no virologic virologic failure: failure: switch to switch to Trizivir Trizivir (ABC) and NNRTI equally effective (ABC) and NNRTI equally effective

◆ ◆ if NRTI mono/dual therapy prior to HAART:

if NRTI mono/dual therapy prior to HAART: switch to NNRTI usually works switch to NNRTI usually works switch to switch to Trizivir Trizivir (ABC) has high (ABC) has high virological virological failure rate failure rate

◆ ◆ no

no ∆ ∆ ∆ ∆ ∆ ∆ ∆ ∆ in immunology between PI continuation and in immunology between PI continuation and simplification simplification

◆ ◆ no

no ∆ ∆ ∆ ∆ ∆ ∆ ∆ ∆ in VL in lymphoid tissue shown for both in VL in lymphoid tissue shown for both abacavir abacavir and and efavirenz efavirenz

◆ ◆ if

if virologic virologic failure: salvage therapy with PI still works failure: salvage therapy with PI still works

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SLIDE 24

Conclusions for s Conclusions for simplified therapy with ABC or NNRTI implified therapy with ABC or NNRTI Patients' benefit: Patients' benefit:

◆ ◆ less treatment changes due to AE / intolerance shown

less treatment changes due to AE / intolerance shown for most switch strategies in comparison to PI for most switch strategies in comparison to PI continuation continuation

◆ ◆ improved adherence and patient

improved adherence and patient safisfaction safisfaction shown shown for all switch strategies for all switch strategies

◆ ◆ effect on cholesterol and triglycerides

effect on cholesterol and triglycerides: : : : : : : :

◆ ◆ consistently

consistently ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓

  • nly after switch to
  • nly after switch to abacavir

abacavir

◆ ◆ variable after switch to

variable after switch to nevirapine nevirapine

◆ ◆ not significantly lower after switch to

not significantly lower after switch to efavirenz efavirenz

◆ ◆ effect on

effect on lipodystrophy lipodystrophy not finally resolved: not finally resolved: both fat accumulation and both fat accumulation and lipoatrophy lipoatrophy may reverse, may reverse, but effects variable between patients and studies but effects variable between patients and studies

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SLIDE 25

Who Who may may simplify simplify their their HAART to HAART to Trizivir Trizivir? ? Simplification to Simplification to Trizivir Trizivir: :

◆ ◆ Well documented regimen, but not for everybody

Well documented regimen, but not for everybody

◆ ◆ Effective in absence of archived NRTI resistance

Effective in absence of archived NRTI resistance mutations (in pts. who started directly with HAART) mutations (in pts. who started directly with HAART)

◆ ◆ Spares all other classes for the future

Spares all other classes for the future

◆ ◆ Best of all simplification strategies for blood lipids

Best of all simplification strategies for blood lipids

◆ ◆ No CYP interactions

No CYP interactions Data not applicable to other triple NRTI regimens Data not applicable to other triple NRTI regimens → → → → → → → → individualized assessment in treatment simplification: individualized assessment in treatment simplification: consider treatment history, cardiovascular risk, and consider treatment history, cardiovascular risk, and CYP ! CYP ! → → → → → → → → good adherence always important ! good adherence always important !

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SLIDE 26

Triple Triple NRTI NRTI regimens that don't work regimens that don't work

Simplification Simplification Retrospective analysis Retrospective analysis of 8

  • f 8 pts

pts

  • RNA <50 c./ml

RNA <50 c./ml during during median 8 median 8 months months (7.5 (7.5 -

  • 18)

18)

  • all

all had started with mainly had started with mainly PI PI-

  • containing

containing HAART HAART after switch after switch to ABC + 3TC + TDF: to ABC + 3TC + TDF: 63% (5/8) 63% (5/8) failed virologically failed virologically, , emergence emergence of 184V and 65R

  • f 184V and 65R mutations

mutations

  • if simplification to ABC:

if simplification to ABC: inclusion of ZDV or d4T seems important inclusion of ZDV or d4T seems important

Hoogewerf Hoogewerf et al., et al., Lancet Lancet 2003;362:1979 2003;362:1979

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SLIDE 27

Triple Triple NRTI NRTI regimens that don't work regimens that don't work

Start of Start of therapy in naive patients therapy in naive patients d4T + d4T + ddI ddI + ABC + ABC [

[Gerstoft Gerstoft AIDS 03 AIDS 03] ]

d4T + d4T + ddI ddI + 3TC + 3TC [CLASS, ATLANTIC]

[CLASS, ATLANTIC]

TDF + 3TC + ABC TDF + 3TC + ABC [

[Gallant Gallant ICAAC 03, ICAAC 03, COL40263, COL40263, TONUS TONUS Landman Landman CROI 04] CROI 04]

TDF + 3TC + TDF + 3TC + ddI ddI [

[Jemsek Jemsek CROI 04] CROI 04]

  • in all of

in all of them them, , higher rates higher rates of

  • f virological failure

virological failure than than in in Trizivir Trizivir studies studies

  • caution if used for simplification

caution if used for simplification

  • emergence

emergence of 184V and/

  • f 184V and/or
  • r 65R

65R mutations mutations Trizivir Trizivir [ACTG5095]

[ACTG5095] –

– differentiate between treatment differentiate between treatment start and simplification start and simplification