Winai Ratanasuwan, MD, MPH

Dept. Preventive and Social Medicine

Faculty of Medicine, Siriraj Hospital

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

The Current Role of Integrase Inhibitors in Clinical Practice

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

Clinical Role of Integrase Inhibitors in Treatment-Naive

Patients

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. .

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

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].

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

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.

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.

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.

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?

Clinical Role of Integrase Inhibitors as Switch Strategy in

Virologically Suppressed Patients

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?

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

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

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.

Clinical Role of Integrase Inhibitors in Treatment-

Experienced Patients

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

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

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

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.

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

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

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

Summary: Potential Uses of Integrase Inhibitors in Clinical Practice

Treatment naive

Switch

Treatment experienced

–

First failure

–

After multiple failures

Etravirine possible use

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

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

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

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

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

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

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

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

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

•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)

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

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

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

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

•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