Impact of first line ART resistance in resource limited settings-Implications for future treatment options

Dr. N. Kumarasamy
Chief Medical Officer
YRGCARE Medical Centre

VHS, Chennai, India

Chief- Chennai International Clinical Trials Unit

Goal of antiretroviral therapy

Viral Load

LLD

10

Time (years)

Ideal combination
Potent Available Convenient dosing (qd, FDC) Less toxic, comorbid(TB,Cardiac,Renal,Liver),Pregnancy

Antiretroviral Agents Approved by US FDA

NRTIs NNRTIs
nevirapine (NVP), efavirenz (EFV) Rilvipirine (RLP) etravirine (ETV)

PIs
saquinavir (SQV) indinavir (IDV) ritonavir (RTV) nelfinavir (NFV) lopinavir/ritonavir (LPV/r) atazanavir (ATV) fosamprenavir (FPV) tipranavir (TPV) Darunavir(DRV)

zidovudine (AZT)

didanosine (ddI)

zalcitabine (ddC)

stavudine (d4T)

Nucleotide RTIs
tenofovir DF (TDF)

lamivudine (3TC)

abacavir (ABC)

Entry Inhibitors
enfuvirtide (ENF, T20) Maraviroc (CCR5)

emtricitabine (FTC)

Integrase Inhibitors
Raltegravir (RAL) Elvitegravir(ELV),Dolutegravir( DLG)

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

2 NRTIs + 1 NNRTI 2 NRTIs + 1 PI/RTV 1 PI/RTV + Integrase/CCR5 inhibitor NRTIs 2nd Gen NNRTI + ENF + other CCR5 inhibitor PI/RTV Maturation inhibitor + other entry inhibitor(s) + ?

st 1

line HAART

AZT/d4T + 3TC + NVP/EFV TDF + FTC/3TC + EFV

Switching to Second-Line Treatment

WHO Guidelines 2010
Clinical Failure Immunological Failure New or recurrent WHO stage 4 condition Fall of CD4 to pre-therapy baseline or below 50% fall from the ontreatment peak value Persistent CD4 levels below 100 Plasma Viral Load above 5000 copies/ml

Virological Failure

Treatment Failure and Drug Resistance: Virologic, Immunologic, and Clinical Definitions
CD4 Count Virologic failure
Immunologic failure
Drug Resistance

Clinical failure

Viral Load

Resistance Patterns After Initial Failure of Common NRTI Backbones ZDV/3TC d4T/3TC ABC/3TC

M184V

TAMs L74V, K65R

M184V

TDF/3TC

M184V

K65R

Failure of first line regimen

d4T/ZDV + 3TC/FTC + NVP/EFV
M184V K103N V106M G190A TAMs

Failure of first line regimen

TDF/ABC/d dI + 3TC/FTC + NVP/EFV
M184V K103N V106M G190A K65R L74V

Second-line Treatment Regimens

d4T or ZDV + 3TC + NVP or EFZ + ATV/r or DRV/r or LPV/r TDF + 3TC or FTC

Treatment Failure and Drug Resistance: Virologic, Immunologic, and Clinical Definitions
CD4 Count Virologic failure
Immunologic failure
Drug Resistance

Clinical failure

Viral Load

Severe mutations following WHO immunologic 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, 71 % had NNRTI mutations, (K103N,Y181C,G190A) 60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q) 11% had Q151M 5% had K65R and 5% had L74V. 26% had 3 or more NNRTI mutations This data clearly warns that patients with immunological failure with standard WHO criteria have severe mutations and which can jeopardize future 2nd line NRTI options and newer drugs.

DART Study: Evolution of resistance on therapy

100 80 Percent 60 42 40 20 0 Week 24 Week 48 27 4 54 TAMs 0 TAMs 13 TAMs 46 44 39

DART virology substudy from Uganda and Zimbabwe (n=377) ZDV/3TC + TDF for 48 weeks with limited prospective laboratory monitoring

Plasma HIV RNA <1000 c/mL in 63% of patients at weeks 24 and 48 Baseline resistance in 10% of those analyzed NRTI, 6% NNRTI, 4%

Persistent viremia resulted in increasing TAMs between Weeks 24 and 48

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

High-level NRTI resistance among Malawians 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

Treatment Failure and Drug Resistance: Virologic, Immunologic, and Clinical Definitions
CD4 Count Virologic failure
Immunologic failure
Drug Resistance

Clinical failure

Viral Load

K103N/Y181C

M184V

TAMS/K65R

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 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

A Phase-3, Randomized, open-label evaluation of the efficacy of once daily protease inhibitor and once daily NNRTI containing combinations for initial treatment of HIV-1 infected subjects from diverse areas of the world

Co-Chairs: Thomas Campbel,N.Kumarasamy,Timothy Flanigan ,James Hakim

Study regimens:
Arm 1A: Arm 1B: Arm 1C: ZDV + 3TC + EFV- (Bid) ddI+ FTC + ATZ- (Qd) TDF + FTC + EFV-(Qd)
What Antiretrovirals to with start?

PEARLS Study Sites

UNAIDS 2001

F a v o rs A rm 1 B ddI + FTC + ATV

F a v o rs A rm 1 A Z D V /3 T C + E F V

P r im a r y E n d p o in t
V ir o lo g i c F a ilu r e A ID S P r o g r e s s io n D e a th

0 .0 1

0 .1

10

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

Hazard Ratio (95% CI) Total Prim ary Endpoints All Death All AIDS Progression All Confirm ed irological Failure 20
18 20 11 12 78 78 0.89 (0.39, 2.01) 0.77 95 98

100

0.95 (0.72, 1.27) 0.74

Cumulative Probability of Regimen Failure (%)

80 60 40 20

0.99 (0.48, 1.70) 0.74

3TC/ZDV+EFV FTC/TDF+EFV

0.99 (0.72, 1.36)

0.95

40 60 80 100 Num ber of Events

3TC/ZDV + EFV FTC/TDF + EFV

24

48

96

144

192

W eek

No differences in risk of regimen failure or any of the primary efficacy endpoint components between arms Similar low cumulative probabilities of regimen failure over time No significant statistical interactions between treatment effect and gender, race and ethnicity, country or viral load stratum

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)
Hazard Ratio (95% CI) Total Safety Endpoints All Initial ARV Dose M odification All Initial Grade 3 / 4 Signs and Sxs All Initial Grade 3 / 4 Lab Abnorm alites
140 222 115 116 98 154 0.55 (0.43, 0.71) 243 313

0.64 (0.54, 0.76) < 0.0001

0.54 (0.44, 0.67) < 0.0001

0.96 (0.74, 1.24)

0.73

< 0.000

50 100 150 200 250 300 Num ber of Events

100

3TC/ZDV + EFV FTC/TDF + EFV

Cumulative Probability of Safety Event (%)

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)

80 60 40 20

3TC/ZDV + EFV FTC/TDF + EFV

No significant interaction with race and ethnicity, country or viral load stratum Difference in probabilities of safety events similar over time

24

48

96

144

192

W eek

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 geography Supports current WHO recommendations

Significant safety advantage to EFV + FTC/TDF

Lower risk of potentially serious or life-threatening laboratory abnormalities 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 treatment of patients at high risk of adverse events, particularly HIVinfected women IAS 2011; Plos Medicine 2012

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 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 Trial- Univ New South Wales Multicenter Study of Options for SEcond-Line Effective Combination Therapy (SELECT)- ACTG 5273 EARNEST Phase IIIb/IV, international, randomised, open label study comparing two regimens .The study will run for 96weeks ritonavir boosted lopinavir (LPV/r) + 2N(t)RTIs vs II. ritonavir boosted lopinavir (LPV/r) + raltegravir

Status of 2nd and 3rd Line ART in RLS

~8.4M persons on ART at the end of 2012; 6.6% (468,000) on 2nd 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

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs

Treatment Outcomes of 2nd Line ART in RLS

19 studies reporting data from 2,035 pts receiving 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 Line ART 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

Darunavir is a good third-line ARV for HIV-1 infected failing 2nd line PI based regimen in South India
87 HIV-1-infected patients experiencing virologic failure to second-line regimens containing protease inhibitors boosted with ritonavir Major DRV RAMs were L76V (9%) and I84V (8%) followed by I54L (1%) and I50L (1%). Among minor DRV RAMs, L33F (9%), T74P (9%), L89V (2%), V11I (2%) and V32I (1%) . Overall, 29 patients (33%) had anyDRV RAM, of which 24 had one DRV RAM, two patients had two DRV RAMs and one patient had 3 DRV RAMs low prevalence (3%) of 3 darunavir resistance associated mutations
Saravanan S, Madhavan V, Pachamuthu B, Smith DM, Solomon SS, Sivamalar S, Poongulali S, Kumarasamy N, Schooley R M D, Solomon S, Kantor R. 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 2nd line HAART- 918 patients Median followup- 24 months Virologic failure- 145 (16%) Genotyping 32 ( 22%)- ATV mutations: 3(9%) I50L,I84V,N88S LPV mutations: 2 (6%) V82A,V32I Major DRV RAMS: 2(6%) I54L, I84V Minor DRV RAMS : 1 (3%) V32I Kumarasamy N, et al. CART study cohort (WHO-ARV Guidelines meeting,Geneva-Dec 2012)

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs

Treatment Failure and Drug Resistance: Virologic, Immunologic, and Clinical Definitions
CD4 Count Virologic failure
Immunologic failure
Drug Resistance

Clinical failure

Viral Load

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

Pts With VL <50 c/mL (%)

Lazzarin A, et al. IAC 2006. Abstract TUAB0104

Effect of Baseline Resistance on Response to DRV

11 mutations associated with reduced response
100 Patients With HIV RNA < 50 c/mL at Wk 24 (%) 80 60 40 20 0
n= 67 94 113 58

V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V and L89V Patients With HIV RNA < 50 c/mL at Wk 24 (%) 64 50 42 22 10
41

Baseline fold-change strongest predictor of Week 24 response

100 80 60 40 20 0
n= 255 65

50 25 13
48

3 0 1 2 4 Number of Primary PI Baseline Mutations

FC 10

FC 11-40

FC > 40

Baseline DRV FC

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

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 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

Third line regimen: Principles

Three(atleast 2) active drugs (triple therapy) One from a new class (e.g.IntegraseRAL,EVG,DLG) A newer PI ( Darunavir/RTV) CCR5 inhibitor(Maraviroc) based on Tropism testing (Genotyping-ENV sequence-V3 loop) Or NRTIs selected on basis of resistance Genotypic resistance testing Anticipate patterns (speculative?)

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs 2nd Gen NNRTI (ETV)+ ENF + other CCR5 inhibitor PI/RTV

79% of them had M184V, 71 % had NNRTI mutations, (K103N,Y181C,G190A) 60% had TAMS, (M41L,T215Y/F,K70R,L210W,K219E/Q) 11% had Q151M 5% had K65R and 5% had L74V. 26% had 3 or more NNRTI mutations This data clearly warns that patients with immunological failure with standard WHO criteria have severe mutations and which can jeopardize future 2nd line NRTI options and newer drugs.

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs 2nd Gen NNRTI(ETV) + ENF + other CCR5 inhibitor PI/RTV

Response to HAART

Ideal Response
RNA

Common Response
RNA

Sequencing Therapy in 2012 and Beyond: How Many Tries Do You Get?

2 NRTIs(AZT or d4T) + 1 NNRTI 2 NRTIs(TDF/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs 2nd Gen NNRTI(ETV) + ENF + other CCR5 inhibitor PI/RTV

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 assuming availability of PI/r therapy in 2nd line regimens Assumes genotype costs $300; delay to change in ART of 3 mos 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

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

2 NRTIs(TDF/FTC or3TC) + 1 NNRTI(EFV) 2 NRTIs(AZT/3TC) + 1 PI/RTV(ATVr or LPVr) 1 PI/RTV(DRVr) + Integrase/CCR5 inhibitor NRTIs 2nd Gen NNRTI + ENF + other CCR5 inhibitor PI/RTV

Summary
Response to 2nd line ART can be excellent if:
Virologic failure detected early and ART switches are made before accumulation of complex patterns of resistance mutations

Approach to 3rd line ART will require judicious use of drug resistance testing and characterization of resistance patterns in diverse RLS related to drugs used in 1st and 2nd line regimens Support for adherence and accelerated strategies for access to new drugs will be critical

A5288:Management Using the Latest Technologies in Resource-Limited Settings

to Optimize Combination Therapy After Viral Failure

(MULTI-OCTAVE)

Hypothesis
The availability of novel ART and use of contemporary management tools for selection and monitoring of 3rd-line treatment will enable a 65% rate of successful virologic control at 48 weeks of follow-up. ACTG/NIH YRGCARE,NARI,BJMC

Screening Process up to 120 days-genotyping

Allocation to Cohort Based on ARV History and Genotype; Initiation of Study Regimen

Cohort A
No resistance to NRTIs, PIs, or NNRTIs Continue 2nd line regimen; NRTIs can be modified

Cohort B Susceptible to DRV/RTV and ETR resistance to NRTIs Randomized 1:1 to cohort B1 or B2

Cohort C
Resistance to ETR resistance to NRTIs
Best available NRTIs, RAL and DRV/RTV

Cohort D
Multiple NRTI resistance and/or DRV/RTV resistance Best available regimen, includes study-provided and any locallyavailable drugs

Cohort B1 Best available NRTIs, RAL and DRV/RTV

Cohort B2
ETR, RAL and DRV/RTV

Cohort B3
HBV positive Best available NRTIs, RAL and DRV/RTV

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

Collaborators
Brown University Kenneth Mayer Timothy Flanigan Charles Carpenter Kartik Venkatesh Susan Cu Uvin Bharat Ramratnam Rami Kantor Karen Tashima UCSD Constance Benson Robert Schooley Davey Smith Scot Letendre Ajay Bharati Susan Little T.Patterson,Stefanie Harvard University Kenneth Freedberg Rochele Walensky Kenneth Mayer Fenway Health Center Steve Safren Marcy, Rodney Stanford University David Katzenstein UCSF Joel Palefsky Maria Ekstrand Kirby Inst-UNSW David Cooper Mathew Law Mark Boyd Sean Emery Tufts University Christine Wanke Rush University Alan Landay Emory Univ Amara Rao Carlos Del Rio Univ of W. Australia Martyn French McFarlane,Melbourne Suzzane Crowe Johns Hopkins Univ David Celentano Shruti Mehtha Univ.of Miami Savita Pawha Karolinska Inst,Sweden

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