HIV Therapy Failure

Pr Christine KatlamaHopital Pitié Salpérière

EACS Advanced

CourseSept 2010

SOLTHIS

• Stop HIV disease evolution

• Restore immunity

• Stop HIV immune activation

• Control HIV replication in compartments and reservoirs

• Reduce risk of resistance emergence

• Reduce transmission

This can only be obtained with maximal viral suppression

Antiretroviral Therapy Objectives

Antiretroviral Therapy Objectives

Control of viral replication has to be maximal

Individual level Health

– Stop disease progression

– Optimize immune restoration

– Prevent resistance– Optimize survival Daily normal life - to have children - Maximal reduction of

sexual transmission risk

Population level - Reduced transmission progressive control and decrease of epidemics - Decrease in tuberculosis - Longer durability of efficacy of first lines ART -Decrease of global cost of HIV

Viral replication has to maximally suppressed

Maximal suppression of HIV required to – Prevent disease progresion– Decrease immune activation– Prevent resistance

Which level of viral suppression ?

1000 cp/ml : clinical benefit 200 cp/ml : clinical and

immunological 50 cp/ml : resistance• Tomorrow : 1 cp ?

Which benefits

on reservoirs and activation ?

Epidemiology of ART failure

Overall ART failure in developping countries has decreased over time !!

• Better understanding of reasons for failure• Use of virological monitoring • More effective and better tolerated drugs• Greater number of drug classes

Lack of report of treatment failure in RSL may be only due to lack of access to viral load or drugs …

Second line failure in MSF programmes

• Cross-sectional study in 27 ART sites in RLC• Routine CD4 monitoring• VL for second line only in 4 sites• First line: > 95% D4T; < 15% EFV• Second line: > 70% LPV/r; 30% TDF; 28% DDI• Inclusion criteria:

– Adults who were ART naive when starting 1st line– Switch from NNRTI-based FL to PI-based SL– At least 6 months on SL

Pujades et al. CROI. 2010.

– 16.1 % Clinical symptoms : new stage 3 or 4 event after 6 months of ART

– 4.1% Immunological parameters : • decline of CD4 to or below baseline value, or • decline of ≥50% from on treatment peak value after

6 months of ART; or• CD4 <100 cells/µl after 1 year of ART; with

measurement confirmed within 3 months– 1.7% Virological failure : HIV RNA >10,000

copies/ml; with confirmed within 3 months

Any criteria of failure: 18.8% after a median of 22 months

Pujades et al. CROI. 2010.

Diagnosis of 2nd line failure in MSF 2

0.0

00

.25

0.5

00

.75

1.0

0

198 72(27) 39(3) 19(1) Number at risk

0 1 2 3analysis time

Kaplan-Meier failure estimate

Time in years to next confirmed failure after switch (2 x >=5000 copies/mL)

Second line failure in Khayelitsha MSF

25% virological failure at 2 years on 2nd line

Boulle et al. (unpublished)

C

N (events)153 (3) 65 (3) 37 (1) 17Patients

0.0

00

.05

0.1

00

.15

0.2

00

.25

0.3

00

.35

Cu

mu

lative

mo

rta

lity

- a

dju

ste

d

0 1 2 3Duration on secondline in years

Adjusted mortality

10% on 2nd line had died within 2 years

Mortality on second line in Khayelitsha

Boulle et al. (unpublished)

Ressource Limited countries : Risk factors for treatment failure

• First line failure : – concurrent TB treatment, – self reported poor adherence during the previous week

• Second line failure: – Changing 1 NRTI instead of 2– Other PI than LPV/r– attending a public clinic – not having a refrigerator at home– TB treatment

• No association with sex, type of clinic, duration of treatment, age, educational level, being unemployed, income level.

El Khatib. AIDS. 2010; Pujades et al. CROI. 2010.

Diagnosis of ART failure

viral load

BQL

50cp/ml

Consider absolute viral load :

duration of virologic failure

42

1

3

- low < 10 00 copies/ml- moderate 1000- 50 000 copies/ml- high > 50 000 copies/ml

Mechanisms for Virological Failure

Low plasma drug concentrations insufficient to control viral replication

Inadequate ARV potency/resistance Poor compliance

Drug- drug interactions

Development of viral resistance

Reasons for treatment failure

• Resistant Viruses• Inadequate treatment/prescriptions : dosage, drug

interactions , • Patients :

- poor adherence

- toxicity

- self treatment interruptions

- transient lost to follow up

Long life therapy is an individual challenge !!

Prevention of adherence problems

• Education to long life treatment

• Patient should be THE actor of his therapy

- provide their results regularly

• Provide long enough prescription

• Consider minor intolerance..

• Social reasons

• Psychological distress

Consequences of persistent replicative

viremia

• Accumulation and archive of resistance • Immune activation induced by HIV replication• Decrease of CD4• HIV disease progression• Increased risk of HIV transmission • Resistant virus transmission

Cross-sectional study of patients >12 m. on ART in

Soweto.

First Line RX L1 Second line Rx L2

Viraemia 12% 33%

R to NRTI 64% 29%

R to NNRTI 81% 54%

R to PI 2% 6%

El Khatib. AIDS. 2010

International recommendations : When to switch:

Consider any viral load above < 50 as to be investigated

• Viral load > 400 cp/ml / tretment failure • VL > 50 cp/ml repeatedly• VL>50 cp/ml : Blip ..try to understand why

Current drugs allow full viral suppression .So always try to understand why a VL is not <

20 cp/ml

New WHO 2009 recommendations: When to

switch:• Where available, use viral load (VL) to confirm

treatment failure.

• Where routinely available, use VL every 6 months to detect viral replication.

• A persistent VL above 5 000 copies/ml confirms treatment failure.

• When VL is not available, use immunological criteria to confirm clinical failure.

Step 1 : To diagnose a situation of virological failure

• 1 Confirm viral replication

- Blips is defined as VL between 50 and 200 cp/ml

- Isolated blip should not be considered as failure

• 2 Evaluate adherence :

- the main reason for early failure or rebound after VL< 50cp/ml is

discontinuation of therapy

- many situations in life where a » compliant « patients will stop

transitorily treatment

- Monitoring plasma drug concentration at time of virological failure

may help to understand certain situations

Step 2 : To analyse a situation of virological failure 2

• Evaluate type and duration of virogical failure :

- rebound after undetectability

- persistant replication /intermittent replication - level of viral replication ? Higher is VL …more antiviral

potency needed

• Number of CD4 cells : clinical risk of progression?

• Patient:

- commitment to Rx, socio-psychological context ..

Step 3: To evaluate what sensitive drugs are left (2 )

• PAST : what resistance has been accumulated ?

- Prior History of ARV , CD4 and VL

- Resistance testing : current /pastLonger the virus has replicated ..greater is the risk

for resistanceHigher the viral load has been ..higher may be the

level of resistance

• NOW: What really active drugs left ?

New WHO recommendations 2009:Second line ART

• 1. 1. A boosted protease inhibitor (PI/r) plus two nucleosideA boosted protease inhibitor (PI/r) plus two nucleosideanalogues (NRTIs) are recommended for second-line ART.analogues (NRTIs) are recommended for second-line ART.

• 2. ATV/r and LPV/r are the preferred boosted PI’s for 2. ATV/r and LPV/r are the preferred boosted PI’s for secondlinesecondlineART.ART.

• 3. Simplification of second NRTI options is recommended.3. Simplification of second NRTI options is recommended.• • If d4T or AZT has been used in first-line, use TDF + 3TCIf d4T or AZT has been used in first-line, use TDF + 3TC or FTC as the NRTI backbone in second-line.or FTC as the NRTI backbone in second-line.• • If TDF has been used in first-line, use AZT + 3TC as theIf TDF has been used in first-line, use AZT + 3TC as the NRTI backbone in second-line.NRTI backbone in second-line.

Combination of active drugs :

the only way to success

Recently Approved New or Novel Antiretroviral Agents

Maturevirus

CCR5 inhibitorsMaravirocVicr

iviroc

Entryinhibitors

Reverse transcriptase

inhibitors

EtravirineIntegraseinhibitors

RaltegravirElvitegravir

PIsDarunavir Tipranavir

Raltegravir is highly and fastly effective

86%

Weeks P

erc

en

t o

f P

ati

en

ts w

ith

HIV

RN

A <

50

Co

pie

s/m

L

0 2 4 8 12 16 24 32 40 480

20

40

60

80

100

82%

Non-inferiority

p-Value<0.001

STARTMRK – Percent of Patients With HIV RNA <50 copies/mL (95% CI)

(Non-Completer = Failure)

281 279 281 279 281 279 278 280 280

282 282 282 282 281 282 280 281 281

Raltegravir 400 mg b.i.d.*

Efavirenz 600 mg q.h.s.*

p<0.001

62%

33%

0 2 4 8 12 16 24 32 40 48Weeks

0

20

40

60

80

100

Per

cent

of P

atie

nts

with

HIV

RN

A <

50 C

opie

s/m

L

BENCHMRK - Percent of Patients With HIV RNA <50 copies/mL (95% CI)

232 231 231 230 229 232 229 230 231

118 118 118 118 117 118 118 118 118

Raltegravir*

Placebo*

BENCHMRK-1 & -2: Raltegravir in Treatment-Experienced Patients

HIV-infected patients with triple-class resistance and HIV-1 RNA

> 1000 copies/mL

(BENCHMRK-1: N = 352;BENCHMRK-2: N = 351) Placebo + OBR*

(BENCHMRK-1: n = 118;BENCHMRK-2: n = 119)

Raltegravir 400 mg BID + OBR*(BENCHMRK-1: n = 232;BENCHMRK-2: n = 230)

Planned follow-up:Week 156

*Investigator-selected OBR based on baseline resistance data and history; inclusion of darunavir and tipranavir permitted.

Current Analysis:Week 48

1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789.

BENCHMRK-1: HIV-1 RNA < 50 c/mL at Week 48

0 2

Pat

ien

ts (

%)

60

40

0

Weeks

Raltegravir* n =Placebo* n =

100

80

20

8 12 16 24 32 40 484

118 118 118 118 117 118 118232 231 231 230 229 232 229

118230

118231

33%

P < .001

62%

31%

P < .001

65%

Cooper DA, et al. CROI 2008. Abstract 788. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright © 2008 Merck & Co., Inc., All Rights Reserved.

* Each + OBT; P-value was derived from a logistic regression model adjusted for BL HIV-1 RNA level (log10), first ENF use in OBT, first DRV use in OBT, active PI in OBT.

BENCHMRK-1 & -2: HIV-1 RNA < 50 c/mL at Week 48, Overall and by

GSS

0

GSS:

65166

68

Raltegravir 443

112

158

20

40

60

80

100

0

1

≥ 2

n

Percent of Patients

228

92

6434

453

3767

5975

PlaceboTotal

1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789.

Subgroup

Raltegravir ResistanceThree pathways defined by primary

mutations at 143, 148, and 155

Replicative capacity decreased with 155

Secondary mutations lead to higher resistance

Q148 pathway is preferred Q148 + 2ndary mutations higher levels of resistance less impact on RC (replication

capacity) Mixed populations generally

resolve to Q148 Virus population can switch from

N155 to Q148

Low genetic barrier to resistance -Cumulative mutations-Cross resistance with EVG

Hazuda et al ICAAC 2008

Raltegravir : summary

Disadvantages

Low genetic barrier to resistance : rapid emergence of R

Need active companion drugs

BID regimen

Advantages High Potency Fast antiviral effect Excellent tolerance Few drug drug interactions No metabolic effects

mutation frequency

Darunavir : a new PI generation

• A drug potent at all stages of HIV disease

• Virologic robustness

• Good tolerability

• Potential for QD if no resistance to DRV

A key drug in the context of RSL countries

DRV/RTV 600/100 mg BID*P < .001 vs comparator PI/RTV.

45*

12

46*

10

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48

Weeks1 2

Control

Pat

ien

ts W

ith

VL

< 5

0 c/

mL

(%

)

Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit.

Lazzarin A, et al. IAC 2006. Abstract TUAB0104.

POWER 1 and 2: CV VL < 50 copies/mL at

Week 48 (ITT-TLOVR)

Darunavir TITAN: Study design• Treatment-experienced, lopinavir (LPV)-naïve, HIV-1-infected patients were randomised (1:1) to DRV/r 600/100mg

bid, or LPV/r 400/100mg bid, plus optimised background therapy (2 NRTIs/NNRTIs) for 96 weeks.

785 screened, 595 patientsrandomised and treated

Screening phase (4 weeks)Treatment phase (96 weeks)

• Treatment-experienced, LPV-naïve

• VL ≥1,000 copies/mL• Stable HAART (≥12 wks) or

STI (≥ 4 wks)

DRV/r 600/100mg bid + OBR

LPV/r* 400/100mg bid + OBR

Rollover or follow-up

phase after 1 and 4 weeks

Primary endpoint: HIV-1 RNA <400 copies/ml

TITAN: confirmed virological response (<400 copies/mL) up to Wk 48 (PP-TLOVR)

PP – per protocol

100

90

80

70

60

50

40

30

20

10

0Pat

ient

s w

ith V

L <

400

copi

es/m

L (%

[95%

CI])

77%*

68%

BAS 4 8 12 24 36 48Time (weeks)

DRV/r (n=286)LPV/r (n=293)

16

*Estimated least square mean difference in response vs LPV/r = 9% (95% CI 2;16); p<0.001

TITAN: Less virological failures with DRV/r than with LPV/r – Week 96

14%41/298

26%76/297

0

10

20

30

DRV/r LPV/r

VF

s (%

)

Never suppressed

Rebounders

• Week 48 analysis: 31 VFs in the DRV/r arm and 65 VFs in the LPV/r arm

n=28p0.001*

*Exact Chi-Squared Test

Effect of Baseline Resistance on Response to DRV*

• BL mutations associated with diminished response

– V11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89V

– Presence associated with a higher number of PI mutations

– DRV response remained higher than that of CPI

De Meyer S, et al. CROI 2006. Abstract 157.

*Analysis excludes ENF-treated patients

% W

ith

HIV

-1 R

NA

<

50

cop

ies/

mL

0

1020

3040

5060

CPI Darunavir

Number of BL PI Resistance-Associated Mutations

≤ 5 6 7 8 9 10 11 ≥ 12

Correlates to FC > 10< 40

POWER0

20

40

60

80

100

45 %

Darunavir : Virologic efficacy % HIV RNA < 50 copies/ml à S48

% P

atie

nts

ave

c C

V <

50 c

op

ies/

mL

)

ARTEMISTITAN

DRV 600/100 b.i.d

DRV800/100 q.d

71 %

84 %

11 %

60 %

78 %

DeJesus E et al, 47th ICAAC chicago 2007Valdez-Madruga J, et Al. Lancet 2007; 370: 49-58

Clotet B. et al. The Lancet 2007, 369 : 1169-78

Etravirine DUET study : Efficacy

Response (<50 copies/mL) at Week 48 (ITT-TLOVR)

CV < 50 c/ml at W48 according to active molecules in OBT (PSS)

61%

40%

Pa

tien

ts w

ith v

iral l

oa

d <

50

co

pie

s/m

L

at

We

ek

48

(%

) (±

95

% C

Is)

Time (weeks)

Placebo + BR (n=604)ETR + BR (n=599)

10

20

30

40

50

60

70

80

90

100

0 2 4 8 12 16 20 24 32 40 480

p<0.0001

DUET-1 and -2: Predictors of response and resistance at

failure• 13 mutations associated with

ETR resistance

- V90I

- L100I

- V106I

- Y181C/I/V

• ≥ 3 ETR mutations impacts ETV sensitivity ; uncommon 14% of patients at baseline

• Most common ETR RAM at failure :V179F/I and Y181C/I

Patients (%)

Cahn P, et al. ICAAC 2007. Abstract H-717. Intelence [package insert]. Raritan, NJ: Tibotec Therapeutics; 2008.

Placebo + OBR

- V179D/F

- G190A/S

- A98G

- K101E/P

1725

0 1 2 3

< 5

0 co

pie

s/m

L (

%)

0

10

20

30

40

50

60

70

80

90

100

≥ 4No. of Baseline ETR Mutations

40 30 16 8 6

75

60 58

41

25

ETR + OBR

4438

25

12

1/1

61

64

/14

7

73

/12

1

59

/15

7

37

/64

17

/68

13

/32

6/2

4

7/2

8

3/1

8

MOTIVATE 1 and 2: MVC in Treatment-Experienced Patients With R5 Virus

Randomized, double-blind, placebo-controlled, phase IIb/III study

Placebo + OBR(n = 209)

MVC* 150 mg or 300 mg QD + OBR(n = 414)

MVC* 150 mg or 300 mg BID + OBR(n = 426)

2:2:1 randomization;stratified by ENF use and

HIV-1 RNA < or 100,000 c/mLWeek 24

planned endpoint analysis Week 48

*Patients receiving PI (except TPV) or delavirdine received 150 mg; all others received 300 mg.

• Patients infected with R5; • HIV-1 RNA ≥ 5000 copies/mL; • stable ART or no ART for ≥ 4 weeks; previous ART experience with ≥ 1 agent (≥ 2 for PIs) from 3 of the 4 antiretroviral drug classes for ≥ 6 months or documented resistance to members of 3 of 4 classes

•(N = 1049)

Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1 and 2: Combined Virologic Efficacy at Week 48

0 4 20 28

Pat

ien

ts W

ith

HIV

-1 R

NA

< 5

0 c/

mL

(%

)

40

30

20

0

Time (Weeks)

Placebo + OBT (n = 209)

MVC BID + OBT (n = 426)MVC QD + OBT (n = 414)

16.7%

43.2%*45.5%*

100

90

80

70

60

50

10

8 12 16 24 32 36 40 44 48

*P < .0001 vs placebo

Hardy D, et al. CROI 2008. Abstract 792.

MOTIVATE 1&2 Change in HIV-1 RNA and CD4

Med

ian

chan

ge fr

om b

asel

ine

in

HIV

RN

A (l

og10

cop

ies/

ml)

Med

ian

chan

ge fr

om b

asel

ine

in

CD

4+ T

-Cel

l Cou

nt (c

ells

/mm

3 )Week

105

89

59

0

20

40

60

80

100

120

0 2 4 8 12 16 20 24 32 40 48

Week

-0.53

-2.30

-2.41

-3

-2.5

-2

-1.5

-1

-0.5

00 4 8 12 16 20 24 32 40 48

PBO (N=209)

MVC QD (N=414)

MVC BID (N=426)

Rapid decrease in HIV RNA > 2 log by W4Rate of < 50 cp/ml : 45% in MVC vs 17% in OBTRapid increase in CD4 > 60 cells by W4

Control of viral replication in treatment experienced patients

Lesson 1: Any new drug should be combined with active drugs… at least 2 active compounds

Lesson 2 : Earlier is better a failing strategy should be modified even in case of low VL and high CD4 -

Lesson 3 : Less access to new drugs you have more potent should be the regimen

Which treatment after 1st line treatment failure

2 NRTI

+ PI/r

2 NRTI

+NNRTI

AZT or D4T/3TCABC/3TCTDF/FTC

Lopi/rAtaza/r

AZTor D4T/3TCABC/3TCTDF/FTC

EFV

Adherence

= Principal raison d’échec

ABC/3TCTDF/FTC

+

PI/r QD• DRV/r• ATV/r• LPV/r

Ou NNRTI• EFV• ETV

+

+

Treatment adherence = main issue

Treatment adherence = main issue

A RV histoire IP

NRTI

2 new drugs /classes DRV/ETVPI/RAL

=AZT or D4T/3TCABC/3TCTENO/FTC

LPV/r – ATV/r =

= EFV /NVP

2 NRTI+ DRV/r

2 NRTI+ ETV

NNRTI

Other

Which treatment after 2nd line treatment failure

TRIO: DRV/r + ETR + RAL in highly-experienced viraemic patients (96 week study)

90% (95% CI; 85%–96%)

0

10

20

30

40

50

60

70

80

90

100

0 2 8 12 16 20 24

Time (weeks)

Pat

ien

ts w

ith

HIV

RN

A <

50

cop

ies/

mL

an

d 9

5% C

I (%

)

4

103 patients enrolled

Yazdanpanah Y, et al. 17th IAC. 2008 [Presentation THAB0406].

-2.4 log10copies/ml

(-1.9 to -2.9)

Time (weeks)Time (weeks)

HIV

RN

A d

elta

fro

m w

eek

0 (l

og

10

cop

ies/

mL

) m

edia

n a

nd

IQ

R

HIV

RN

A d

elta

fro

m w

eek

0 (l

og

10

cop

ies/

mL

) m

edia

n a

nd

IQ

R

00 22 44 88 1212 1616 2020 2424-3-3

-2-2

-1-1

00

11

Intent to treat analysisIntent to treat analysis

ETVPI

DRV

PI

How to combine new drugs in patients with resistant viruses ?

VL

and

resi

stan

ce

+

+ + ±ETV RAL

DRV RAL

+

or ? ETV

If no NRTIs RLow viral replication

+

Target Maximal viral suppression

Every patient should have access to viral load monitoring

Any detectable viral load means virological failure Any failure should be investigated - compliance - drug interactions or inadequate dosages - résistance Any virological failure should lead to intervention - compliance issues and reinforce education - change ARV therapy

Major role for HIV clinical team

Conclusion Art failure: not a

fatality

Access to viral load monitoring: mandatory tool for long term success

Training to management of ART failure

Potent and safe drugs needed to control and prevent ART failure.