2013-02-12 Impact of First Line ART Resistance in Resource Limited Settings-Implications for Future Treatment Options

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Impact of first line ART resistance inresource limited settings-Implications

for future treatment options

Dr. N. KumarasamyDr. N. Kumarasamy

Chief Medical Officer Chief Medical Officer

YRGCARE Medical Centre YRGCARE Medical Centre

VHS, Chennai, IndiaVHS, Chennai, India

Chief Chief -- Chennai International Clinical Trials UnitChennai International Clinical Trials Unit



V i r a l L o a d

0 2 4 6 8 10

Time (years)

Goal of antiretroviral therapy

LLD



Ideal combination

•• PotentPotent

•• AvailableAvailable

•• Convenient dosing (qd, FDC)Convenient dosing (qd, FDC)

•• Less toxic,Less toxic,comorbid(TB,Cardiac,Renal,Liver),Pregnancycomorbid(TB,Cardiac,Renal,Liver),Pregnancy



Antiretroviral Agents Approved by US FDA

NRTIsNRTIs NNRTIsNNRTIs PIsPIs

idovudineidovudine (AZT)(AZT) nevirapinenevirapine (NVP),(NVP), efavirenzefavirenz

(EFV)(EFV)saquinavir saquinavir (SQV)(SQV)

idanosineidanosine (ddI)(ddI) Rilvipirine (RLP)Rilvipirine (RLP) indinavir indinavir (IDV)(IDV)

alcitabinealcitabine (ddC)(ddC) etravirine (ETV)etravirine (ETV) ritonavir ritonavir (RTV)(RTV)

tavudinetavudine (d4T)(d4T) Nucleotide RTIsNucleotide RTIs nelfinavir nelfinavir (NFV)(NFV)

lamivudineamivudine (3TC)(3TC) tenofovir DFtenofovir DF (TDF)(TDF) lopinavir/ritonavir lopinavir/ritonavir (LPV/r)(LPV/r)

bacavir bacavir (ABC)(ABC) Entry InhibitorsEntry Inhibitors atazanavir (ATV)atazanavir (ATV)

mtricitabinemtricitabine (FTC)(FTC) enfuvirtideenfuvirtide (ENF, T20)(ENF, T20)

Maraviroc (CCR5)Maraviroc (CCR5)

fosamprenavir (FPV)fosamprenavir (FPV)

Integrase InhibitorsIntegrase Inhibitors

Raltegravir (RAL)Raltegravir (RAL)

Elvitegravir(ELV),Elvitegravir(ELV),Dolutegravir(Dolutegravir(DLG)DLG)

tipranavir (TPV)tipranavir (TPV)

Darunavir(DRV)Darunavir(DRV)



Sequencing Therapy in 2013 and Beyond: HowMany Tries Do You Get?

2 NRTIs +2 NRTIs + 1 NNRTI1 NNRTI2 NRTIs +2 NRTIs + 1 PI/RTV1 PI/RTV

1 PI/RTV +1 PI/RTV + IntegraseIntegrase /CCR5 inhibitor /CCR5 inhibitor ±± NRTIsNRTIs

22ndnd Gen NNRTI + ENF + other CCR5 inhibitor Gen NNRTI + ENF + other CCR5 inhibitor

±± PI/RTVPI/RTV

Maturation inhibitor +Maturation inhibitor +other entry inhibitor(s) + ?other entry inhibitor(s) + ?



1st line HAART

• AZT/d4T + 3TC + NVP/EFV

• TDF + FTC/3TC + EFV



Clinical Failure New or recurrent WHO stage

4 conditionImmunological Failure •Fall of CD4 to pre-therapy

baseline or below

•50% fall from the on-

treatment peak value

•Persistent CD4 levels below

100

Virological Failure Plasma Viral Load above 5000

copies/ml

Switching to Second-Line TreatmentWHO Guidelines 2010



Treatment Failure and Drug Resistance:Virologic, Immunologic, and Clinical Definitions

CD4 Count

Viral Load

Virologic

failure

Immunologicfailure

Clinical

failureDrugResistance



Resistance Patterns After InitialFailure of Common NRTI Backbones

ZDV/3TC

d4T/3TC

ABC/3TC

TDF/3TC

M184V

M184V

M184V

TAMs

L74V,

K65R

K65R



Failure of first line regimen

d4T/ZDV

+

3TC/FTC

+

NVP/EFV

M184V

K103N

V106MG190A

TAMs



Failure of first line regimen

TDF/ABC/ddI

+3TC/FTC

+NVP/EFV

M184V

K103N

V106M

G190A

K65R

L74V



Second-line Treatment Regimens

d4T or ZDV

+

3TC

+

NVP or EFZ

TDF

+

3TC or FTC

+

ATV/r or DRV/r or

LPV/r




CD4 Count

Viral Load

Virologic

failure

Immunologicfailure

Clinical




Severe mutations following WHOimmunologic failure- Chennai HIV cohort study

Total no.of patients registered for care: 10127

No.pts initiated on 1st line HAART: 3739(AZT/d4T+3TC+NVP/EFV)

Median CD4 at HAART initiation: 69 IQ (40-125)

No.of pts switched to 2nd line: 336 (9%)

Median CD4 at switch : 144 (90-199)

Median duration on 1st line 3.7yrs ( 2.2-6.3)

Kumarasamy et al CID 2009; CROI 2008



79% of them had M184V,79% of them had M184V,71 % had NNRTI mutations, (K103N,Y181C,G190A)71 % had NNRTI mutations, (K103N,Y181C,G190A)

60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)

11% had Q151M11% had Q151M

5% had K65R and5% had K65R and

5% had L74V.5% had L74V.

26% had 3 or more NNRTI mutations26% had 3 or more NNRTI mutations

This data clearly warns that patients with immunological failureThis data clearly warns that patients with immunological failure with standardwith standardWHO criteria have severe mutations andWHO criteria have severe mutations and which can jeopardize future 2ndwhich can jeopardize future 2ndline NRTI options and newer drugs.line NRTI options and newer drugs.



DART Study:Evolution of resistance on therapy

DART virology substudy fromDART virology substudy fromUganda and Zimbabwe (n=377)Uganda and Zimbabwe (n=377)

ZDV/3TC + TDF for 48 weeks withZDV/3TC + TDF for 48 weeks with

limited prospective laboratorylimited prospective laboratorymonitoringmonitoring

Pillay D, et al. 14th CROI, Los Angeles 2007, #642

Plasma HIV RNA <1000 c/mL in 63% of patients at weeks 24 and 48Plasma HIV RNA <1000 c/mL in 63% of patients at weeks 24 and 48Baseline resistance in 10% of those analyzedBaseline resistance in 10% of those analyzed

NRTI, 6%NRTI, 6%

NNRTI, 4%NNRTI, 4%

Persistent viremia resulted in increasing TAMs between Weeks 24Persistent viremia resulted in increasing TAMs between Weeks 24 and 48and 48

42

27

54

44

4

39

0

20

40

60

80

100

Week 24 Week 48

P e r c e n t

TAMs 0

TAMs 1–3TAMs 4–6



High-level NRTI resistance amongMalawians failing 1st line HAART

d4T/AZT+3TC+NVP

CD4 and clinical monitoring

96 failed patients were genotyped

Median CD4: 68; PVL: 4.72log; Duration on ART: 36 months

93%- NNRTI mutations

81%- M184V

23%- K70E or K65R

Mina Hosseinipour, et al. IAC 2008; AIDS 2009



Impact of 1st line NRTI mutations on 2nd line

options




CD4 Count

Viral Load

Virologic

failure

Immunologic

failureClinical


K103N/Y181C M184V TAMS/K65R




2 NRTIs(AZT or d4T) + 1 NNRTI2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr)

1 PI/RTV(DRVr) + Integrase /CCR5 inhibitor ±

NRTIs

2nd Gen NNRTI + ENF + other CCR5 inhibitor ± PI/RTV



ACTG 5175

PhasePhase--3, Randomized, open3, Randomized, open--label evaluation of the efficacy of oncelabel evaluation of the efficacy of oncedaily protease inhibitor and once daily NNRTI containingdaily protease inhibitor and once daily NNRTI containingcombinations for initial treatment of HIVcombinations for initial treatment of HIV--1 infected subjects from1 infected subjects fromdiverse areas of the worlddiverse areas of the world

oo--Chairs:Chairs: Thomas Campbel,N.Kumarasamy,Timothy Flanigan ,JamesThomas Campbel,N.Kumarasamy,Timothy Flanigan ,James

HakimHakim

Study regimens:Study regimens:

Arm 1A: ZDV + 3TC + EFVArm 1A: ZDV + 3TC + EFV-- (Bid)(Bid)Arm 1B: ddI+ FTC + ATZArm 1B: ddI+ FTC + ATZ-- (Qd)(Qd)

Arm 1C: TDF + FTC + EFVArm 1C: TDF + FTC + EFV--(Qd)(Qd)

What Antiretrovirals to with start?What Antiretrovirals to with start?



PEARLS Study SitesPEARLS Study Sites

NAIDS 2001



H a z a r d R a t io ( + / - 9 9 .8 % C I )

0 .0 1 0 .1 1 1 0

P r im a r y E n d p o in t

V ir o lo g ic F a i lu r e

A ID S P r o g r e s s io n

D e a t h

F a v o rs A r m 1 A

Z D V / 3 T C + E F VF a v o r s A r m 1 B

d d I + F T C + A T V

IAC-2008, Mexico



Study Regimens

Arm 1A: ZDV + 3TC + EFV- (Bid)Arm 1B: ddI+ FTC + ATZ- (Qd)

Arm 1C: TDF + FTC + EFV-(Qd)



Primary Efficacy Findings

• No differences in risk of regimen failure or any of the primaryefficacy endpoint components between arms

• Similar low cumulative probabilities of regimen failure over time

• No significant statistical interactions between treatment effect andgender, race and ethnicity, country or viral load stratum

Number of Events

20 40 60 80 100 3TC/ZDV + EFV

FTC/TDF + EFV

Total PrimaryEndpoints

All Death

All AIDSProgression

All Confirmedirological Failure

Hazard Ratio

(95% CI) P

0.95 (0.72, 1.27) 0.74

0.99 (0.48, 1.70) 0.74

0.89 (0.39, 2.01) 0.77

0.99 (0.72, 1.36) 0.95

98

95

20

18

12

11

78

78

Week

24 48 96 144 192

C u m u l a t i v e P r o b a b i l i t y

o f R e g i m

e n F a i l u r e ( % )

20

40

60

80

100

3TC/ZDV+EFV

FTC/TDF+EFV



Primary Safety Findings• Lower risk of Safety Endpoints for

FTC/TDF vs 3TC/ZDV

– ARV dose modification difference driven

by neutropenia and anemia (0 vs 59

cases)

– Lab abnormalities difference driven by

neutropenia, anemia, AST/ALT (67 vs

135 cases)

– Grade 3/4 creatinine 5 vs 2 cases

– Fewer serious metabolic dx in FTC/TDF

arm (3 vs 19 cases; P < 0.001;lipodystrophy, pancreatitis, lactic

acidosis)

• Interaction between sex and treatment arm for primary

safety endpoint (P = 0.005):

– HR for Women 0.48 (0.37-0.63) – HR for Men 0.83 (0.64-1.08)

• No significant interaction with race and ethnicity, country or

viral load stratum

• Difference in probabilities of safety events similar over time

Number of Events50 100 150 200 250 300 3TC/ZDV + EFVFTC/TDF + EFV

Total SafetyEndpoints

All InitialARV Dose

Modification

All Initial Grade3 / 4 Signs

and Sxs

All Initial Grade3 / 4 Lab

Abnormalites

Hazard Ratio(95% CI) P

0.64 (0.54, 0.76) < 0.0001

0.54 (0.44, 0.67) < 0.0001

0.96 (0.74, 1.24) 0.73

0.55 (0.43, 0.71) < 0.000

243

313

140

222

115

116

98

154

Week

24 48 96 144 19

C u m u l a t i v e P r o b a b i l i t y

o f S a f e t y E v

e n t ( % )

20

40

60

80

100

3TC/ZDV + EFV

FTC/TDF + EFV



Conclusions-ACTG 5175

The regimens EFV with either FTC/TDF or 3TC/ZDV had similar high levels of efficacy

Treatment effect did not vary by QD vs BID co-formulated NRTI, race,

ethnicity, gender or geographySupports current WHO recommendations

Significant safety advantage to EFV + FTC/TDF

Lower risk of potentially serious or life-threatening laboratoryabnormalities and related dose modifications/substitutions

Lower risk of serious metabolic diagnoses

Overall safety benefit most pronounced in women

FTC/TDF should be preferred over 3TC/ZDV for initial treatmentof patients at high risk of adverse events, particularly HIV-infected women

IAS 2011; Plos Medicine 2012




2 NRTIs(AZT or d4T) + 1 NNRTI2 NRTIs(TDF/3TC)/Integrase + 1 PI/RTV

1 PI/RTV(DRVr) + 2nd Gen NNRTI/CCR5

inhibitor ± NRTIs

ENF + other CCR5 inhibitor ± PI/RTV



2nd line Trials

Secondline International TrialSecondline International Trial-- Univ New South WalesUniv New South Wales

Multicenter Study of Options for Multicenter Study of Options for SESEcondcond--LLineine EEffectiveffectiveCCombinationombination TTherapy (SELECT)herapy (SELECT)-- ACTG 5273ACTG 5273

EARNESTEARNEST

Phase IIIb/IV, international, randomised, open label studyPhase IIIb/IV, international, randomised, open label studycomparing two regimens .The study will run for 96comparing two regimens .The study will run for 96--weeksweeks

ritonavir boosted lopinavir (LPV/r) + 2N(t)RTIsritonavir boosted lopinavir (LPV/r) + 2N(t)RTIs

vsvs

II. ritonavir boosted lopinavir (LPV/r) +II. ritonavir boosted lopinavir (LPV/r) + raltegravir raltegravir



Status of 2nd

and 3rd

Line ART in RLS

• ~8.4M persons on ART at the end of 2012; 6.6% (468,000) on2nd line ART worldwide

• ARV resistance major threat to sustained effectiveness

• Number and pattern of resistance mutations depends on

drugs used in regimens, HIV-1 subtype, duration of VF,timing/criteria for ARV switch

• Current 2nd line regimen failure rates at > 10%; need for 3rd line

options – Based on characterizing populations of people failing 2nd

line ART in diverse RLS and their outcomes




2 NRTIs(AZT or d4T) + 1 NNRTI2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr)

1 PI/RTV(DRVr) + Integrase /CCR5 inhibitor ±

NRTIs



Treatment Outcomes of 2nd

Line ART inRLS

• 19 studies reporting data from 2,035 ptsreceiving 2nd line ART in RLS

– Cumulative proportion with virologic failure

(VF) at 12, 24, and 36 months was 23.1, 26.7,and 38%, respectively

– Rates of VF were associated with duration of

prior treatment and poor adherence

Ajose O, et al. AIDS 2012; 26:929



2nd Line ART Failure in RLS• 106 patients with 2nd

line ART failure (Mali)• Median of 4 yrs of

ART (median of 6

drugs)• Genotypic

resistance:

– LPV/RTV in 25% – Darunavir/RTV in 12%

– Etravirine in 38%

Duration of prior exposure to NRTIs

was associated with abacavir, tenofovir

resistance; 2% with K65R mutations

Maiga AI, et al. J Antimicrob

Chemother 2012; 67:2943



Treatment Outcomes with 2nd

LineART in RLS

• 33 pts with VF on 2nd

line ART in South Africa – Median duration of 1st line ART 23 months;

median duration of 2nd line ART 10 months

before detection of VF – 22 of 33 (67%) had wild-type virus

– No major PI resistance mutations observed

Levinson J, et al. PLoS One 2012; 7:e32144

D i i d thi d li ARV f HIV 1



Darunavir is a good third-line ARV for HIV-1infected failing 2nd line PI based regimen in

South India•• 87 HIV87 HIV--11--infected patients experiencing virologic failure toinfected patients experiencing virologic failure to

secondsecond--line regimens containing protease inhibitors boostedline regimens containing protease inhibitors boosted

with ritonavir with ritonavir •• Major DRV RAMs were L76V (9%) and I84V (8%) followed byMajor DRV RAMs were L76V (9%) and I84V (8%) followed by

I54L (1%) and I50L (1%).I54L (1%) and I50L (1%).

•• Among minor DRV RAMs, L33F (9%), T74P (9%), L89V (2%),Among minor DRV RAMs, L33F (9%), T74P (9%), L89V (2%),

V11I (2%) and V32I (1%) .V11I (2%) and V32I (1%) .

•• Overall, 29 patients (33%) had anyDRV RAM, of which 24 hadOverall, 29 patients (33%) had anyDRV RAM, of which 24 had

one DRV RAM, two patients had two DRV RAMs and oneone DRV RAM, two patients had two DRV RAMs and one

patient hadpatient had≥≥

3 DRV RAMs3 DRV RAMs•• low prevalence (3%) of low prevalence (3%) of ≥≥3 darunavir resistance associated3 darunavir resistance associated

mutationsmutations

Saravanan S, Madhavan V, Pachamuthu B, Smith DM, Solomon SS, SivSaravanan S, Madhavan V, Pachamuthu B, Smith DM, Solomon SS, Sivamalar amalar

S, Poongulali S, Kumarasamy N, Schooley R M D, Solomon S, Kantor S, Poongulali S, Kumarasamy N, Schooley R M D, Solomon S, Kantor

R.R.

AIDS Res Hum Retroviruses. 2012 Oct 9.AIDS Res Hum Retroviruses. 2012 Oct 9.



TDF/3TC+ATV/RTV Single strip



Pattern of mutations on ATVr

containing 2nd line HAART

ATV/r containing 2ATV/r containing 2ndnd line HAARTline HAART-- 918 patients918 patients

Median followupMedian followup-- 24 months24 months

Virologic failureVirologic failure-- 145 (16%)145 (16%)

Genotyping 32 ( 22%)Genotyping 32 ( 22%)-- ATV mutations: 3(9%) I50L,I84V,N88SATV mutations: 3(9%) I50L,I84V,N88S

LPV mutations: 2 (6%) V82A,V32ILPV mutations: 2 (6%) V82A,V32I

Major DRV RAMS: 2(6%) I54L, I84VMajor DRV RAMS: 2(6%) I54L, I84V

Minor DRV RAMS : 1 (3%) V32IMinor DRV RAMS : 1 (3%) V32I

Kumarasamy N, et al. CART study cohort (WHOKumarasamy N, et al. CART study cohort (WHO--ARV GuidelinesARV Guidelines

meeting,Genevameeting,Geneva--Dec 2012)Dec 2012)




2 NRTIs(AZT or d4T) +2 NRTIs(AZT or d4T) + 1 NNRTI1 NNRTI2 NRTIs(TDF/3TC) +2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)

1 PI/RTV(DRVr) +1 PI/RTV(DRVr) + IntegraseIntegrase /CCR5 inhibitor /CCR5 inhibitor ±±

NRTIsNRTIs




CD4 Count

Viral Load

Virologicfailure

Immunologicfailure

ClinicalfailureDrug

Resistance



POWER 1 and 2: VL < 50 c/mL at Week 48(ITT-TLOVR)

Lazzarin A, et al. IAC 2006. Abstract TUAB0104

P t s

W i t h V L < 5 0 c / m

L ( % )



50

1

42

2 ≥ 4

10

3

22

0

6450

FC ≤ 10

25

FC 11-40

13

FC > 40

Effect of Baseline Resistance onResponse to DRV

•• 11 mutations associated11 mutations associated

with reduced responsewith reduced response•• V11I, V32I, L33F, I47V,V11I, V32I, L33F, I47V,

I50V, I54L, I54M, G73S,I50V, I54L, I54M, G73S,

L76V, I84V and L89VL76V, I84V and L89V

•• Baseline foldBaseline fold--changechange

strongest predictor of strongest predictor of Week 24 responseWeek 24 response

80

0

20

40

P a t i e n t s W i t h H I V R

N A

< 5 0 c

/ m L a t W k 2 4 ( % )

60

100

80

0

20

40

60

100

DeMeyer S, et al. Resistance Workshop 2006. Abstract 73.

Baseline DRV FC

P a t i e

n t s W i t h H I V R

N A

< 5 0 c / m L a t W k 2 4

( % )

Number of Primary PI Baseline Mutations

n = 255 65 4894 113 4167 58n =





1 PI/RTV(DRVr)1 PI/RTV(DRVr) ++ IntegraseIntegrase /CCR5 inhibitor /CCR5 inhibitor ±±

NRTIsNRTIs22ndnd Gen NNRTI + ENF + other CCR5 inhibitor Gen NNRTI + ENF + other CCR5 inhibitor

±± PI/RTVPI/RTV

Third line regimen Principles



Third line regimen: Principles

•• Three(atleast 2) active drugs (triple therapy)Three(atleast 2) active drugs (triple therapy)

– – One from a new class (e.g.IntegraseOne from a new class (e.g.Integrase--

RAL,EVG,DLG)RAL,EVG,DLG)

– – A newer PI ( Darunavir/RTV)A newer PI ( Darunavir/RTV)

– – CCR5 inhibitor(Maraviroc) based on TropismCCR5 inhibitor(Maraviroc) based on Tropism

testing (Genotypingtesting (Genotyping--ENV sequenceENV sequence--V3 loop)V3 loop)Or NRTIs selected on basis of resistanceOr NRTIs selected on basis of resistance

•• Genotypic resistance testingGenotypic resistance testing

•• Anticipate patterns (speculative?)Anticipate patterns (speculative?)






NRTIsNRTIs22ndnd Gen NNRTI (ETV)Gen NNRTI (ETV)+ ENF + other CCR5+ ENF + other CCR5

inhibitor inhibitor ±± PI/RTVPI/RTV



79% of them had M184V,79% of them had M184V,

71 % had NNRTI mutations, (K103N,Y181C,G190A)71 % had NNRTI mutations, (K103N,Y181C,G190A)60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q)

11% had Q151M11% had Q151M

5% had K65R and5% had K65R and

5% had L74V.5% had L74V.

26% had 3 or more NNRTI mutations26% had 3 or more NNRTI mutations

This data clearly warns that patients with immunological failureThis data clearly warns that patients with immunological failure with standardwith standardWHO criteria have severe mutations andWHO criteria have severe mutations and which can jeopardize future 2ndwhich can jeopardize future 2nd

line NRTI options and newer drugs.line NRTI options and newer drugs.






NRTIsNRTIs22ndnd Gen NNRTI(ETV)Gen NNRTI(ETV) + ENF + other CCR5+ ENF + other CCR5




Response to HAART

RNA

RNA

Ideal Response

Common Response




2 NRTIs(AZT or d4T) +2 NRTIs(AZT or d4T) + 1 NNRTI1 NNRTI2 NRTIs(TDF/3TC)2 NRTIs(TDF/3TC) ++ 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)

1 PI/RTV(DRVr)1 PI/RTV(DRVr) ++ IntegraseIntegrase /CCR5 inhibitor /CCR5 inhibitor ±±

NRTIsNRTIs22ndnd Gen NNRTI(ETV)Gen NNRTI(ETV) + ENF + other CCR5+ ENF + other CCR5


Cli i l d E i I t f G t i



Clinical and Economic Impact of Genotypic

Resistance Testing at 1st Line ART Failure• CEPAC Model for genotype vs no genotype in selecting 2nd line

therapy

– Examined two strategies of no genotype vs genotype assumingavailability of PI/r therapy in 2nd line regimens

• Assumes genotype costs $300; delay to change in ART of 3mos

– Life expectancy increased by 2.2 mos with genotype

– Genotype “very cost effective” vs no genotype at $900 per year of life saved

• Sensitive to prevalence of wild type virus; cost effective if rate of WT virus > 12% at VF

Levinson JH, et al. Clin Infect Dis 2013; 56:587




2 NRTIs(TDF/FTC or3TC) +2 NRTIs(TDF/FTC or3TC) + 1 NNRTI(EFV)1 NNRTI(EFV)2 NRTIs(AZT/3TC) +2 NRTIs(AZT/3TC) + 1 PI/RTV(ATVr or LPVr)1 PI/RTV(ATVr or LPVr)


NRTIsNRTIs22ndnd Gen NNRTI + ENF + other CCR5 inhibitor Gen NNRTI + ENF + other CCR5 inhibitor

±± PI/RTVPI/RTV

S



Summary

•• Response to 2Response to 2ndnd line ART can be excellent if:line ART can be excellent if: – – Virologic failure detected early and ART switches are madeVirologic failure detected early and ART switches are made

before accumulation of complex patterns of resistancebefore accumulation of complex patterns of resistance

mutationsmutations

•• Approach to 3Approach to 3rdrd line ART will require judicious use of line ART will require judicious use of drug resistance testing and characterization of drug resistance testing and characterization of resistance patterns in diverse RLS related to drugs usedresistance patterns in diverse RLS related to drugs usedin 1in 1stst and 2and 2ndnd line regimensline regimens

•• Support for adherence and accelerated strategies for Support for adherence and accelerated strategies for access to new drugs will be criticalaccess to new drugs will be critical

A5288:Management Using the Latest



A5288:Management Using the Latest

Technologies in Resource-Limited Settingsto Optimize Combination Therapy After ViralFailure

(MULTI-OCTAVE)

HypothesisHypothesis

The availability of novel ART and use of The availability of novel ART and use of contemporary management tools for selectioncontemporary management tools for selectionand monitoring of 3and monitoring of 3rdrd--line treatment will enable aline treatment will enable a ≥≥

65% rate of successful virologic control at 4865% rate of successful virologic control at 48weeks of followweeks of follow--up.up.

ACTG/NIHACTG/NIH YRGCARE,NARI,BJMC YRGCARE,NARI,BJMC

Screening Process up to 120 days-genotyping



Cohort A

No resistance

to NRTIs, PIs,

or NNRTIs

Continue 2nd

line regimen;NRTIs can be

modified

Cohort B

Susceptible to DRV/RTV andETR ±resistance to NRTIs

Randomized 1:1 to cohort B1 or

B2

Cohort C

Resistance toETR ±

resistance to

NRTIs

Best availableNRTIs, RAL and

DRV/RTV

Cohort D

Multiple NRTIresistance and/or

DRV/RTV

resistance

Best availableregimen, includes

study-provided and

any locally-

available drugsCohort B1

Best availableNRTIs, RAL

and DRV/RTV

Cohort B2

ETR, RAL andDRV/RTV

Allocation to Cohort Based on ARV History

and Genotype; Initiation of Study Regimen

All Cohorts: At participating sites, randomize 1:1 to CPI+SOC orSOC

Cohort B3HBV positive

Best available

NRTIs, RAL and

DRV/RTV



Collaborators

Brown UniversityBrown University Harvard UniversityHarvard University Tufts UniversityTufts UniversityKenneth Mayer Kenneth Mayer Kenneth FreedbergKenneth Freedberg Christine WankeChristine Wanke

Timothy FlaniganTimothy Flanigan Rochele WalenskyRochele Walensky

Charles Carpenter Charles Carpenter Kenneth Mayer Kenneth Mayer Rush UniversityRush University

Kartik VenkateshKartik Venkatesh Alan LandayAlan Landay

Susan Cu UvinSusan Cu Uvin Fenway Health Center Fenway Health Center Emory UnivEmory Univ

Bharat RamratnamBharat Ramratnam Steve SafrenSteve Safren Amara RaoAmara RaoRami Kantor Rami Kantor Marcy, RodneyMarcy, Rodney Carlos Del RioCarlos Del RioKaren TashimaKaren Tashima Univ of W. AustraliaUniv of W. Australia

Stanford UniversityStanford University Martyn FrenchMartyn FrenchDavid KatzensteinDavid Katzenstein

UCSDUCSD UCSFUCSF McFarlane,MelbourneMcFarlane,Melbourne

Constance BensonConstance Benson Joel PalefskyJoel Palefsky Suzzane CroweSuzzane Crowe

Robert SchooleyRobert Schooley Maria EkstrandMaria EkstrandDavey SmithDavey Smith Kirby InstKirby Inst--UNSWUNSW Johns Hopkins UnivJohns Hopkins Univ

Scot LetendreScot Letendre David Cooper David Cooper David CelentanoDavid CelentanoAjay BharatiAjay Bharati Mathew LawMathew Law Shruti MehthaShruti Mehtha

Susan LittleSusan Little Mark BoydMark Boyd Univ.of MiamiUniv.of Miami

T.Patterson,StefanieT.Patterson,Stefanie Sean EmerySean Emery Savita PawhaSavita PawhaKarolinska Inst,SwedenKarolinska Inst,Sweden

NIH, ACTG, HPTN, EU, amfAR/TA, GFATM, USAID, Gates Foundation, INIH, ACTG, HPTN, EU, amfAR/TA, GFATM, USAID, Gates Foundation, ICMRCMR

Documents

2013-02-12 Impact of First Line ART Resistance in Resource Limited Settings-Implications for Future Treatment Options