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Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital New Antiretroviral Drugs: what we have and how to use ?

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Page 1: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Winai Ratanasuwan, MD, MPH

Dept. Preventive and Social Medicine

Faculty of Medicine, Siriraj Hospital

New Antiretroviral Drugs: what we have and how to use ?

Page 2: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

The Current Role of Integrase Inhibitors in Clinical Practice

Page 3: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Potential Uses of Integrase Inhibitors in Clinical Practice

Treatment-naive

Switch

To simplify or reduce toxicity to a given regimen after virologic suppression achieved

Treatment-experienced

First failure

After multiple failures

Page 4: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Clinical Role of Integrase Inhibitors in Treatment-Naive

Patients

Page 5: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

DHHS 2009: Recommended Regimens for Treatment-Naive PatientsDHHS Guidelines “Preferred”

Regimens, Decemember 2009[1]

NNRTI-based regimen EFV*

+ TDF/FTCPI-based regimen ATV/RTV QD

DRV/RTV QDRAL

1. DHHS guidelines. Available at: http://aidsinfo.nih.gov. .

Page 6: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Potential Uses of Integrase Inhibitors: Treatment-Naive Patients

Advantages

Novel mechanism of action

Efficacy data to 144 wks

Rapid HIV-1 RNA decay

Lack of transmitted drug resistance

Excellent safety and tolerability

Limited lipid effects

Limited drug interactions

Disadvantages

Twice-daily dosing

Cost

Some drug-drug interactions (varies by drug)

Fewer data than other agents

Low barrier to resistance

Lack of coformulation

Page 7: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Summary of RAL Treatment-Naive Data

Phase II (Protocol 004, N = 198): RAL comparable to EFV in virologic efficacy at 144 wks–

HIV-1 RNA < 50 copies/mL: 78% RAL vs 76% EFV

Fewer CNS adverse events with RAL vs EFV

RAL had less effect on serum lipids vs EFV

Phase III (STARTMRK, N = 563): noninferior virologic efficacy of RAL vs EFV at 96 wks–

HIV-1 RNA < 50 copies/mL: 81% RAL vs 79% EFV

Fewer CNS adverse events with RAL vs EFV

Lower cholesterol and triglyceride increases with RAL vs EFV1. Gotuzzo E, et al. IAS 2009. Abstract MOPEB030. 2. Lennox J, et al. Lancet. 2009;[Epub ahead of print].

Page 8: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

D:A:D: Recent and/or Cumulative PI/NNRTI Use and Risk of MI

Lundgren JD, et al. CROI 2009. Abstract 44LB. Graphics reproduced with permission.

*Approximate test for heterogeneity: P = .02

# PYFU: 68,469 56,529 37,136 44,657

61,855 58,946

# MI:

298

197

150

221 228 221

IDV NFV LPV/RTV SQV NVP EFV

PI* NNRTI1.2

1.13

1.00

1.10

0.90

Page 9: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

RAL Drug Interactions

Fewer due to alternative metabolism: glucuronidation (UGT1A1)

TDF ↑ RAL 49%

PI interactions

ATV

NNRTI Interactions

ETR and EFV (RAL AUC ↓

36%) acceptable

Rifampin

40% reduction in RAL AUC; RAL dose increased to 800 mg BID when administered with rifampin[1]

ANRS study (N = 150) of EFV vs RAL 400 mg vs RAL 800 mg for HIV/TB-

coinfected patients[2]

1. Raltegravir package insert. 2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00822315.

Page 10: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Can RAL Be Dosed Once Daily?

Study ongoing (QDMRK) to determine safety and efficacy of RAL once daily vs twice daily

Treatment-naive patients

RAL 400 mg BID vs RAL 800 mg QD, both plus TDF/FTC

Estimated enrollment: 750 patients

Primary outcome: HIV-1 RNA < 50 copies/mL at Wk 48

ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00745823.

Page 11: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Treatment-Naive Patients for Whom INSTIs May Be Considered

Currently, DHHS guidelines include INSTIs as preferred options for treatment-naive patients

Possible patients who might be considered

Patients unable to tolerate NNRTI (rash, CNS toxicity) or PI (any RTV dose)

High lipids or cardiovascular risk

Transmitted NNRTI resistance (care must be taken to ensure activity of other regimen components)

Women who may become pregnant

DHHS guidelines. Available at: http://aidsinfo.nih.gov.

Page 12: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Other First-line Considerations

Standard regimens

NNRTI + NRTIs

Boosted PI + NRTIs

Novel class-sparing regimens

ATV + RAL

LPV/RTV + RAL

DRV/RTV + RAL

MVC + RAL?

RIL + RAL?

Page 13: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Clinical Role of Integrase Inhibitors as Switch Strategy in

Virologically Suppressed Patients

Page 14: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Reasons to Switch Antiretrovirals in Patients on a Suppressive Regimen

Simplification/convenience

Reduce pill burden, dosing frequency, or avoid other specific dosing requirements

Tolerability/toxicity

Improve short-term tolerability, reduce risk of long-term complications

Drug-drug interactions

Lack of adequate CD4+ response?

Page 15: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Potential Uses of Integrase Inhibitors: Simplify or Reduce Toxicity

Disadvantages

Must be used with adequate support from other regimen components

Low barrier to resistance

Twice-daily dosing

Cost

Some drug interactions

Fewer data than other agents

Lack of coformulation

Advantages

Novel mechanism of action

Potent antiretroviral activity

Excellent safety and tolerability

Limited lipid effects

Limited drug interactions

Page 16: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Established Switch Regimens

Within-class substitutions

NRTI substitutions (eg, change d4T to TDF)

NNRTI substitution (eg, NVP to EFV)

PI substitutions (eg, add boosting, remove boosting, reduce toxicity)

Out-of-class substitution

PI to NNRTI

Reduce the number of active agents

Page 17: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

RAL Switch Regimens

RAL substituted for ENF in suppressed patients

Many studies, including 1 randomized,[1]

support this use

Rarely, unexpected adverse effects may occur (depression)[2]

SWITCHMRK[3]

Predefined criteria for virologic noninferiority not met

Demonstrated lipid benefits

When underlying resistance may be present (eg, experienced patients, transmitted resistance), careful patient selection needed

Lower barrier to resistance with RAL vs boosted PIs

1. De Castro N, et al. IAS 2009. Abstract MOPEB066. 2. Harris M,

et al. AIDS. 2009;22:1890-1892. 3. Eron J, et al. CROI 2009. Abstract 70aLB.

Page 18: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Clinical Role of Integrase Inhibitors in Treatment-

Experienced Patients

Page 19: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Potential Uses of Integrase Inhibitors: First Failure

Disadvantages

No data specific to first failures

What to combine (is a boosted PI required?)

Twice-daily dosing

Cost

Low barrier to resistance

Lack of coformulation

Advantages

Novel mechanism of action

Expectation that activity would be excellent

Excellent safety and tolerability

Limited lipid effects

Limited drug interactions

Page 20: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Principles Guiding Second-Line Integrase Inhibitor–Containing Regimens

Key strategy for success with integrase inhibitor–containing regimens is inclusion of ≥ 2 active agents

If resistance at VF with first-line NNRTI- or PI-based regimen involves NRTI-associated mutations, NRTIs in subsequent regimen cannot be considered fully active

Integrase inhibitor + 2 NRTIs may not be sufficient in these cases

In patients who discontinued first-line regimen, negative genotypic resistance test does not necessarily indicate absence of resistant viral population

Particularly for M184V

Use of RAL + boosted PI merits further study in 2 NRTI + NNRTI failure patients

Page 21: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Potential Uses of Integrase Inhibitors: Multiple Failures

Advantages

Novel mechanism of action

Well-established data

Excellent safety and tolerability

Limited lipid effects

Limited drug interactions

Disadvantages

Must be used with other active agents

Does a boosted PI always need to be included?

Low barrier to resistance

Cross resistance between RAL and ELV

Page 22: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Focus on Number of Active Agents

DHHS ARV guidelines: ≥ 2, preferably 3, fully active agents in new regimenHighest rate of virologic suppression in patients receiving investigational drug plus OBR containing ≥ 1 other active agent[1-4]

Trend toward greater benefit with 3 vs 2 fully active agents[1-4]

Not statistically significant–

Must also consider potential drug-drug interactions, adverse events, pill burden, absence of future options

Contribution of “partially active”

agents (eg, 3TC) difficult to calculate

No added benefit from using 4 vs 3 fully active agents1. Cooper DA, et al. N Engl J Med. 2008;359:355-365. 2. Haubrich R, et al. CROI 2008. Abstract 790. 3. Johnson M, et al. CROI 2008. Abstract 791. 4. Gulick RM, et al. N Engl J Med. 2008;359:1429-1441.

Page 23: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

BENCHMRK 1 & 2: HIV-1 RNA < 50 c/mL by New Agents in OBR, Wk 48

0

65

166

68

112

158

20 40 60 80 100

+

+

-

n Patients (%)

92

Enfuvirtide

166- 92

Darunavir

+

-

-

+

Cooper DA, et al. N Engl J Med. 2008;359:355-365.

8968

4769

60

5780

20

Page 24: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

RAL + MVC + ETR in Triple Class– Experienced Patients

Nonrandomized cohort study

0

100

200

300

Mea

n C

D4+

Cel

l Cou

nt

Incr

ease

(cel

ls/m

m3 )

Nozza S, et al. Glasgow 2008. Abstract P45. Reproduced with permission.

RAL + MVC + ETR (n = 28)RAL + MVC or ETR (n = 20)

RAL + MVC or ETR + PI (n = 28)RAL + PI (n = 19)

020406080

100

BL 4 12 24 36 48Wks

HIV

-1 R

NA

< 5

0 c/

mL,

%

Regimen

Page 25: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

BRAVO: Efficacy of RAL Without a PI?Retrospective cohort (chart review) of RAL with or without PI

PI cohort: 87% DRV, 36% ETR, 10% ENF (mean prior ARV: 4.1)

No PI cohort: 66% ETR, 17% ENF, 13% MVC (mean prior ARV: 3.8; P < .01 vs PI cohort)

Most pts received NRTI TDF + FTC

GSS (similar between groups) a significant predictor of Wk 12 response (P = .04)

Treatment group (PI vs non-PI) and number of ARVs not predictive of virologic success

Additional follow-up needed to evaluate RAL without PI n = 442 336 373 195

HIV

-1 R

NA

< 7

5 co

pies

/mL

(%)

Baseline Wk 4 Wk 12 Wk 240

20

40

60

80RAL + Pl (n = 332)No Pl (n = 110)

Skiest D, et al. IAS 2009. Abstract MOPE072. Reproduced with permission.

100

Page 26: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Summary: Potential Uses of Integrase Inhibitors in Clinical Practice

Treatment naive

Switch

Treatment experienced

First failure

After multiple failures

Page 27: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine possible use

Page 28: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Impact of NNRTI and NRTI resistance on the response to the regimen of Etravirine plus two NRTIs in study Etravirine-C227

Page 29: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine-C227: study design

PI naïve

NNRTI experienced, screening viral load >1,000 copies/mL

≥1 NNRTI resistance-associated mutation (historical or at screening)

Active control group: investigator-selected PI

95% used boosted PI (61% LPV/r, 32% ATV/r)

Both control and Etravirine groups: two investigator-selected NRTIs based on screening Virco®TYPE HIV-1 or treatment history

Etravirine arm discontinued after DSMB review

•Screening•Active control: 1 PI + 2 NRTIs n=57

•Etravirine 800mg bid + 2 NRTIs n=59

•48 weeks• Primary analysis 24 weeks

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

Page 30: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Region and country

RegionCountry, n (%)

All patients(n=116)

Asia and South AfricaSouth AfricaThailand

66 (56.9)48 (41.4)18 (15.5)

EuropeRussiaSpainUK

13 (11.2)5 (4.3)6 (5.2)2 (1.7)

Latin AmericaArgentinaBrazilMexico

37 (31.9)8 (6.9)

27 (23.3)2 (1.7)

•AE 13.8% •A1 2.6%•BF 2.6% •C 42.2%•F1 2.6% •B 36.2%

•Clade

•B

•AE

•C

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

Page 31: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine-C227: baseline detectable NRTI mutations A large number of NRTI

resistance-associated mutations were noted in this first-line failure population

Many NRTIs were recycled in this study*

Etravirine group

37% recycled one, 9% recycled two

control group

35% recycled one, 12% recycled two

•IAS-

USA

NR

TI re

sist

ance

-ass

ocia

ted

mut

atio

ns (%

)

•90

•80

•70

•60

•50

•40

•30

•20

•10

•0•Etravirine •Control

•100•0 •1 •2 •3 •4 •5 •6 •7

•Group

•16.9

•10.2

•15.3

•20.3

•28.8

•8.8

•10.5

•22.8

•38.6

•10.5

•6.8•1.7

•7.0

•1.8

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

•*Guided by resistance testing

Page 32: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine-C227: baseline detectable NNRTI mutations

Median fold change to:

EFV

129.8

NVP

88.0

Etravirine

2.0•Tibotec list of NNRTI mutations

•A98G -

L100I -

K101E/P/Q •K103H/N/S/T

•V106A/M -

V108I -

E138G/K/Q •V179D/E/F/G/I -

Y181C/I/V•Y188C/H/L -

G190A/C/E/Q/S•P225H -

F227C/L -

M230I/L -

P236L •K238N/T -

Y318F

•*All patients had NNRTI mutations at screening or from prior genotyping

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

•Tib

otec

NN

RTI

resi

stan

ce-a

ssoc

iate

dm

utat

ions

(%)

•100

•90

•80

•70

•60

•50

•40

•30

•20

•10

•0

•23.7

•40.7

•23.7

•19.3

•43.9

•22.8

•Etravirine •Control group

•0* •1 •2 •3 •4

•8.8•6.8

•5.3•5.1 A large number of NNRTI mutations* were noted in this first-line failure population

Page 33: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine-C227: change in viral load (observed)

•Etravirine•Control

•0

•−1

•−2

•−3

•Cha

nge

in lo

g vi

ral l

oad

(mea

n)

•Weeks

•0

•4 •8 •12 •16

•59 •56 •46 •36 •2 9

•59•n (Etravirine)=•57 •55 •49 •33 •29•57• n (control)=

•Initial 1.3 log decline in viral load was not sustained past 8 weeks, possibly affected by limited activity of the BR

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

Page 34: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine arm (C227): median viral load change at week 12, by baseline Etravirine fold change and number of TAMs + M184V

Use of recycled NRTIs in Etravirine group: 37% recycled one, 9% two

•Number of TAMs + M184V

•−2.5

•−2

•−1.5

•−1

•−0.5

•0

•1 •10 •100•Etravirine fold change

•Med

ian

chan

ge in

vira

l loa

d at

wee

k 12

•0

•2

•4 •3•5

•1

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

Page 35: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

C227 educational messagesWhile demonstrating a substantial decrease in viral load, use of Etravirine was associated with a lower virological response versus the control PI group

this is most likely due to high NRTI resistance and NRTI recycling

C227 study included a large proportion of patients from resource-limited settings. Baseline NRTI and NNRTI resistance was higher than is usual in countries where

monitoring of viral load is standard of care and virological failure is determined early

patients were PI-naïve, therefore, the PI group was not as affected by the compromised backbone and the pre-existing NNRTI resistance

Etravirine had a better tolerability profile than control PI treatment

compared with the PI regimen, Etravirine was better tolerated for gastrointestinal, lipid and liver-

related events

rash was higher in the Etravirine group, but this was generally mild and not associated with discontinuation

In contrast to the results of C227, the results of the large Phase III DUET trials showed that Etravirine provides substantial virological and immunological benefits in patients with NNRTI- and PI-resistant virus

The results of the C227 study demonstrate

the

need

to

switch

patients

who

experience

virological

failure,

to

minimise

the

accumulation

of

Page 36: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Etravirine-C227: conclusionsThe level of both NRTI and NNRTI resistance was higher than whatmight have been expected from a first-line failure population

many patients recycled previously used NRTIs, which was guided by resistance testing

Increasing numbers of TAMs and M184V were associated with increased NNRTI resistance

The combination of high-level NRTI and NNRTI resistance adversely impacted the Etravirine arm

less likely to have affected the PI arm in this PI-naïve population

Consistent with treatment guidelines, patients failing a first-generation NNRTI should immediately switch their regimen to avoid the accumulation of resistance-associated mutations and maximise future treatment options

Woodfall B, et al. HIV8, 2006. Abstract PL5.6

Page 37: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

•Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48

•24-week primary analysis

DUET study design and major inclusion criteria

DUET-1 and DUET-2 differed only in geographical location; pooled analysis was pre-specified

Major inclusion criteria

plasma VL >5,000 copies/mL and stable therapy for ≥8 weeks

≥1 NNRTI mutations,‡

at screening or in documented historical genotype

≥3 primary PI mutations at screening

Patients recruited from Thailand, Australia, Europe and the Americas

•Screening

•6 weeks

•600 patients target per trial

•48-week treatment period with optional 48-week extension

•*All patients received a BR

of DRV/r with optimised NRTIs and optional ENF

•Etravirine + BR*

•Placebo + BR*

•Follow-up

•4 weeks

‡From extended list of NNRTI mutations (Tambuyzer L et al. EHDRW 2007. Abstract 67)

Page 38: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

DUET trials: dosing

DRV/r dosed at 600/100mg bid

300mg tablets of DRV (i.e. two tablets bid)

Etravirine dosed at 200mg bid

100mg tablets (i.e. two tablets bid of Phase III formulation)

Etravirine matching placebo: two tablets bid

Both drugs were to be taken twice daily following a meal

less restrictive food requirements than Phase II trials

•Madruga JV et al. Lancet 2007;370:29–38; Lazzarin A et al. Lancet 2007;370:39–48

Page 39: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Week 96: patients with VL <50 copies/mL (ITT-TLOVR)

57% of patients in the Etravirine + BR group achieved confirmed undetectable VL (<50 copies/mL TLOVR) compared with 36% in the placebo group

This represents only a 3% drop from Week 48 for patients in each group

•*Logistic regression model controlling for baseline VL, ENF use and study number

•Trottier B et al. CAHR 2009. Abstract P148

•36%

•57%

•p<0.0001*

•60%

•39%

•100

• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72

84 96•Time (weeks)

•Pat

ient

s w

ith V

L <5

0 co

pies

/mL

at W

eek

96 (%

) •90

•80

•70

•60

•50

•40

•30

•20

•10

•0

•Etravirine + BR •Placebo + BR•Etravirine + BR •Placebo + BR

Page 40: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Week 96: change in CD4 cell count from baseline (ITT; imputed)

•*Analysis of covariance model;

•Trottier B et al. CAHR 2009. Abstract P148

•+86

•+128•+98

•+73

•Cha

nge

in C

D4

cell

coun

t (m

ean

±SE

), (c

ells

/mm

3 )

•250

•p<0.0001*

• Baseline 2 4 8 12 16 20 24 32 40 48 56 64 72

84 96

•Time (weeks)

•225•200•175•150•125•100•75•50•25

•0•–25

•Etravirine + BR •Placebo + BR

Page 41: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

Week 96: response (VL <50 copies/mL TLOVR) by PSS*

•*DRV considered sensitive if FC ≤10; ENF counted as sensitive if used de novo; Etravirine not included in the PSS calculation;

analysis excludes patients who discontinued except for VF

•Trottier B et al. CAHR 2009. Abstract P148

Patients in the Etravirine + BR group achieved consistently higher response rates than patients in the placebo + BR group, irrespective of number of active background agents; the difference was most apparent in patients with no active background agents

•Pat

ient

s w

ith V

L <5

0 co

pies

/mL

at W

eek

96 (%

)•Placebo + BR (n=477)•Etravirine + BR (n=497)

•Number of active background ARVs (PSS)•0 •1 •≥2

•46%

•6%

•61%

•29%

•76%

•59%

•39/84 •5/81 •117/191 •52/181 •168/222 •126/215

•p<0.0001

•p<0.0001

•p<0.0001

•10

0

•90

•80

•70

•60

•50

•40

•30

•20

•10

•0

Page 42: New Antiretroviral Drugs: what we have and how … AIDS Society/TAS1/25/New...Winai Ratanasuwan, MD, MPH Dept. Preventive and Social Medicine Faculty of Medicine, Siriraj Hospital

•Predicting response to Etravirine: weighted scores for each individual RAM combined to produce a total weighted score

•Weight for individual Etravirine

RAMs •Total weighted score

Vingerhoets

J et al. IHDRW 2008. Abstract 24