Professor Anna Maria Geretti - Mediscript · 16th Annual Resistance and Antiviral Therapy Meeting...

16th Annual Resistance and Antiviral

Therapy Meeting

Professor Anna Maria Geretti 1

Thursday 20 September 2012, Wellcome Collection Conference Centre, London

Professor Anna Maria GerettiInstitute of Infection and Global Health

University of Liverpool

16161616 thththth Annual Resistance Annual Resistance Annual Resistance Annual Resistance andandandandAntiviral Therapy MeetingAntiviral Therapy MeetingAntiviral Therapy MeetingAntiviral Therapy Meeting

Changing ART in patients

with low-level viraemia:

Reviewing the evidence base

Anna Maria Geretti

Institute of Infection &

Global Health

University of Liverpool


Therapy Meeting


HIV-1 genome

sequenced

1982 1985 1991 1995 1996 2009 2010 ��

The HIV Virology Timeline

HIV replicates at

high levels

throughout

the infection

Virus

replication

causes

immunological

compromise

Viral load testing

HAART

Viral replication

drives disease

pathogenesis

through immune

activation &

inflammation

HIV-1 isolated

Is HIV

eradication

possible?

Plasma HIV-1 RNA levels predict

CD4 count decline and risk of disease & death

-80

-60

-40

-20

0

20

40

CD

4 ce

ll ch

ang

e p

er y

ear

<500 501- 3000

3001-10000

10001-30000

>30000

Viral load

01020304050607080

Ris

k (%

) o

ver

6 yr

s

<500 501- 3000

3001-10000

10001-30000

>30000

Viral load

Progression Death

-80

-60

-40

-20

0

20

40

Dec

reas

e in

ris

k o

f p

rog

ress

ion

an

d d

eath

(%

)

0.3 0.6 1

Viral load reduction with ART (log10) Mellors, Science 1996


Therapy Meeting


0

0.05

0.1

0.15

0.2

0.25

Risk of mortality according to frequency of viral load

measurements >400 cps/ml during first-line ARTC

um

ula

tiv

e m

ort

ali

ty

Months after starting ART

0 18 36 54 72

Lohse, Clin Infect Dis 2006

Cumulative mortality stratified by % of VL measurements ≥400 over 18 months after ART initiation

100%

51-75%

76-99%

26-50%1-25%

0%

N=2046

Started ART before 2002

Follow-up: 8898 patient-yrs

clinicaloptions.com/hivNorton, IHDRW 2006

MONARK: Emergence of resistance during LPV/r

monotherapy in a patients with viral load persistently

between 50 and 400 cps/ml

0

1

2

3

4

5

6

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Week

Pla

sma

HIV

-1 R

NA

lo

g1

0c/

mL

LPV/r

PRO: L10F/L L63P V82A/V

RT: none

PRO: L10F/L L63P V82A/V

RT: none

LPV IC 50 1.13 fold

PRO: L10I/L L63P A71A/T

RT: none

LPV IC 50 1.49 fold

Screen

(50 c/mL)

(400 c/mL)


Therapy Meeting


The goal of ART according to guidelines

� To achieve viral load suppression in both ART-naive

and ART-experienced patients

� EACS 2011: <50 cps/ml

� DHHS 2011: <assay detection limits

� BHIVA 2012: <50 cps/ml

� IAS-USA 2012 : <50 cps/ml

Defining viral load rebound during ART

10

1000

100000

Dec-04 Jun-05 Dec-05 Jun-06 Dec-06 Jun-07 Dec-07 Jun-08 Dec-08 Jun-09 Dec-09 Jun-10

ART

VL

<50

Blip Bump

Failure?


Therapy Meeting


DHHS 2011

The inability to achieve or maintain a VL <200 cps/ml

BHIVA 2012

Failure to achieve a VL <50 cps/ml 6 months after

commencing ART or following suppression to <50 cps/ml

a VL rebound to >400 cps/ml on two consecutive occasions

IAS-USA 2012

Sustained VL elevation between 50 and 200 cps/ml should

prompt evaluation of factors leading to failure and

consideration of switching ART

Defining virological failure

What is the acceptable outcome of ART?

1. Viral load suppression <1000 cps/ml?






7. Undetectable RNA by ultrasensitive assay?


Therapy Meeting


�The recommended target for defining treatment success

has traditionally been dictated by the technical properties

of the VL assay

�First-generation assays <400 copies/ml

�Second-generation assays <50 copies/ml

�These cut-offs were not selected a priory based upon

clinical or biological significance

�Patients who achieve and maintain a VL <50 cps/ml have a

small risk of showing a VL rebound above this level during

follow-up, and the risk declines further the longer the VL

stays below that level

Defining viral load cut-offs

Viral load monitoring during first-line ART

• Started ART in 1996-2005

• n=1386

• Achieved <50 cps/ml

• In the following 12 months all

VLs <400 cps/ml

� Over median 2 yrs (0-7.4 yrs) of follow-up rebound rates were 5% for

consistent suppression vs. 22% for low-level rebound

� In adjusted analyses, persistent low-level rebound in the first year after

achieving <50 cps/ml doubled the risk of VL rebound >400 cps/ml during

subsequent follow-up compared with consistent suppression

Geretti, Antiv Ther 2008


Therapy Meeting


Last news on blips: Big blips predict rebound!*

*Rebound = VL ≥50 cps/ml x 2 or VL >1000 cps/ml

� Blips 500-1000 cps/ml more than double the risk of rebound

� Data obtained with second-generation VL assaysGrennan, JID 2012

Implications for clinical care

• Importance of regular VL monitoring in the first year after

achieving a VL <50 cps/ml. Patients who show a VL

persistently <50 cps/ml during this period have a very

small risk (5%) of experiencing subsequent rebound

• Importance of confirming VL detection >50 cps/ml in a

subsequent sample. Persistent VL rebound >50 cps/ml

carries greater significance than isolated blips

• Large blips or frequent blips predict rebound

• Due to assay variation around the LLQ repeat testing of

the same sample may not be as useful as obtaining a

further sample


Therapy Meeting


Third-generation VL assays

� Real-time PCR technology

� LLQ 40 cps/ml (e.g., Abbott RealTime; Roche Taqman v1) or

20 cps/ml (e.g., Roche Taqman v2)

� Report qualitative RNA detection below the LLQ as

“target detected”

� Patients on ART can now show one of three results:

• VL quantified above the LLQ

• RNA detected below the LLQ

• RNA not detected

� Abbott RealTime detection rates below the LLQ are

96% for 30 cps/ml, 88% for 20 cps/ml and 68% for 10 cps/ml

Are current viral load assays interchangeable?

aMedian VL 104 [51-814] cps/ml

Geretti, EACS 2009

RealTime vs TaqMan-v2

r = 0.96

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0

RealTime

B

B

CRF_AE

A A

A

A

Taq

Ma

n-v

2

Analysis of treated patients (n=130)

TaqMan-v2

<20 ≥20 <50 ≥50

Real

Time

<40 49% 21% 56% 13%

≥40 1% 29% 6% 25%

<50 49% 25% 59% 15%a

≥50 <1% 25% 3%b 22%

LLQ

Abbott RealTime = 40 cps/ml

Roche TaqMan-v1 = 40 cps/ml

Roche TaqMan-v2 = 20 cps/ml

bMedian VL 69 [51-97] cps/ml

1

10

100

1,000

10,000

100,000

Dilution

log

sca

le

Median difference (log10 cps/ml):

RealTime 0.0 (-0.1, 0.1)

TaqMan-v1 0.2 (0.1, 0.5)

TaqMan-v2 0.7 (0.4, 0.7)

2nd RNA Standard

Taqman 1

Taqman 2

RealTime


Therapy Meeting


Implications for clinical care

• interpretation of VL results appears to have become

assay-dependent

• Caution is required when extrapolating findings obtained

with older VL assay to populations monitored with current

assays

What are the causes of low-level

HIV-1 RNA detection in plasma during ART?

Virus-related?

Drug-related?

Patient-related?

Technique-related?


Therapy Meeting


Rong, PLoS Comp Biol 2009

ART intensification* does not affect residual viraemia

*with EFV, ATV/r, LPVr, RAL (x4), MVC (x2), or T20

Patients with low-level HIV-1 RNA during ART

� With the Abbott RealTime assay, patients who have a target not detected result (RNA-) differ from those with VL 40-50 cps/ml or RNA+ <40 cps/ml:

� Treated for longer, longer VL <50 cps/ml (P<0.0001)

� Lower pre-ART VL (p=0.04)

� Higher CD4 count (p<0.0001)

� Older (p<0.0001)

� White MSM (P=0.006)

� On NNRTI-based ART (P<0.0001)

� Greater adherence (P<0.0001)

Doyle, Clin Infect Dis 2012


Therapy Meeting


0

0.5

1

1.5

2

2.5

3

Baseline Week48 Week96 Week144

HIV

-1D

NA

log1

0c

op

ies/

10

6P

BM

C

Studyweek

DRV/r DRV/r+2NRTIs

Change -0.10 -0.08 -0.05

Change +0.01 -0.09 +0.03

N 71 12 10 50

N 59 5 10 44

MONET: Mean HIV-1 DNA levels over 144 weeks

Geretti, in press

Baseline HIV-1 DNA:

2.4 with VL consistently <50

cps/ml vs. 2.8 for at least one

VL>50 cps/ml during 144 wks

(p<0.05)

2.6 with nadir CD4 counts <200

vs. 2.5 with nadir CD4 counts

>200 (p=0.03)

HIV persistence during ART

� Pre-ART cellular HIV-1 DNA levels predict the detection of

residual viraemia during suppressive ART

� Pre-ART cellular HIV-1 DNA load and residual HIV-1 RNA

levels also predict episodes of HIV-1 RNA elevation >50

cps/ml during ART

� Cellular HIV-1 DNA levels in turn are predicted by the

nadir CD4 cell count


Therapy Meeting


Shen, J Allergy Clin Immunol 2008

Ongoing virus replication

in sanctuary

cellular or body

compartments due to

poor drug penetration or

activity

Virus reactivation in

latently infected cells in

response to antigenic

stimulation, with presence

of ART ensuring that new

cells cannot be

productively infected

The other view: Residual viraemia during ART reflects ongoing virus replication

� Adding ABC to EFV+IDV in patients

with a VL <50 but >2.5 cps/ml lowers

the VL <2.5 cps/ml

� RNA levels increase gradually before

rebounding >50 cps/ml after

simplifying triple ART to ATV/r

monotherapy

� HIV-1 genetic evolution occurs at RNA

levels >6.5 cps/ml

� The 3rd drug in triple ART is associated

with residual RNA levels in patients

with VL <50 cps/ml

� IVIG transiently decrease residual

viraemia

Reviewed in Doyle & Geretti 2012

Median values (IQR)4


Therapy Meeting


Exploring the clinical significance

of plasma RNA detection <50 cps/ml

Background

� Abbott RealTime VL assay introduced at RFH in 2005

� Range of quantification 40-10,000,000 cps/ml

� Reports qualitative RNA detection <40 cps/ml as yes / no signal

� Ability to detect RNA below 40 cps/ml:

� 30 cps/ml 96%; 20 cps/ml 88%; 10 cps/ml 68%

� All results 40-49 and RNA detected <40 cps/ml issued as

<50 cps/ml in 2005-2009

Aim

� Determine the virological outcomes over 12 months of 1247 treated

patients with VL <50 cps/ml at an arbitrarily selected time point during

ART (= T0) according to whether the (unreported) T0VL was 40-49 cps/ml

(n=240); RNA detected <40 cps/ml (n=507); or RNA not detected (n=500)


34.2%

11.3%

4%

13%

3.8%1.2%

0

5

10

15

20

25

30

35

40

T0 VL 40-49 cps/ml T0 RNA+ T0 RNA-

Po

rpo

rtio

nsh

ow

ing

vir

al

loa

d

reb

ou

nd

du

rin

g

12

mo

nth

s

HIV-1 RNA detection at T0

Rebound >50 cps/ml

Rebound >400 cps/ml

Percentage with viral load rebound above 50 cps/ml

and 400 cps/ml during 12 months of follow-up



Therapy Meeting


Factors associated with viral load rebound

Multivariate model VL >50 cps/ml VL >400 cps/mlAll patients HR 95% CI P HR 95% CI P

T0 VL 40-49 cps/ml 4.67 2.91,7.47 <0.0001 6.91 2.90, 16.47 <0.0001

RNA detected 1.97 1.25, 3.11 2.88 1.24, 6.69

RNA not detected 1.00 - 1.00 -Length VL <50 cps/ml Per yr longer 0.74 0.65, 0.83 <0.0001 0.82 0.69, 0.97 0.02

RFH patients

T0 VL 40-49 cps/ml 4.68 2.40, 9.12 <0.0001 10.71 3.30, 34.81 <0.0001

RNA detected 2.33 1.26, 4.31 3.78 1.23, 11.59

RNA not detected 1.00 - 1.00 -Length VL<50 cps/ml Per yr longer 0.79 0.69, 0.91 0.0005 0.88 0.72, 1.06 0.15

HAART duration Per yr longer 1.06 0.99, 1.15 0.10 1.14 1.02, 1.27 0.03

Gender Male 0.81 0.45, 1.45 0.47 1.49 0.65, 3.38 0.35

Female 1.00 - 1.00 -

Age Per 10 yrs older 0.80 0.61, 1.04 0.09 1.07 0.71, 1.62 0.74

Ethnicity White 1.00 - 0.11 1.00 - 0.17

Black 1.91 1.00, 3.63 2.40 0.91, 6.36

Other 1.50 0.75, 2.98 1.85 0.59, 5.83

Risk group Homosexual 1.00 - 0.36 1.00 - 0.63

Heterosexual 0.83 0.41, 1.70 1.36 0.48, 3.85

Other 1.70 0.63, 4.64 2.07 0.50, 8.60

HAART regimen NNRTI based 0.40 0.21, 0.77 0.002 0.46 0.17, 1.23 0.23

Other/Unknown 1.40 0.79, 2.48 0.99 0.40, 2.46

PI based 1.00 - 1.00 -

Adherence Not available 0.59 0.32, 1.10 0.23 0.99 0.39, 2.47 0.99

<95% 1.00 - 1.00 -

>95% 0.87 0.54, 1.39 0.96 0.45, 2.07

CD4 count Per 100 cells higher 0.92 0.84, 1.00 0.06 1.00 0.87, 1.15 0.97

Pre-HAART VL Per 1 log10 cps higher 1.04 0.80, 1.33 0.79 0.74 0.52, 1.05 0.10

What about Taqman assay?

� Taqman v1: T0 VL detectable <48 cps/ml predicts rebound

>50, >200 and >400 cps/ml

� Taqman v2: T0 VL detectable between 20 and 50 cps/ml

associated with rebound >50 cps/ml

Henrich, PLOS One, in press; Álvarez,10th European Meeting on HIV & Hepatitis Treatment Strategies & Antiviral Drug Resistance 2012


Therapy Meeting


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5 6

Pro

po

rtio

n o

f p

ati

en

ts w

ith

ta

rge

t

lev

el

of

sup

pre

ssio

n

Time since start of ART (months)

<50 copies/ml

<40 copies/ml

RNA-

Time to viral load “undetectability” (Abbott RealTime assay)


Conclusions: Viral load suppression

� Consistent suppression <50 cps/ml is the optimal target

� Some patients may not be able to achieve these levels due

to a high reservoir load or ongoing replication(e.g., in

sanctuary sites) – their optimal management remains

unclear

� Confirmed viraemia >50 cps/ml (>40 cps/ml with RealTime

assay and possibly >20 cps/ml with Taqman v2 assay)

should be managed:

• Review expected efficacy, adherence, tolerability

• Consider resistance test +/- TDM

• Urgency of intervention depends on regimen

(and other considerations)

• Cost-effectiveness of possible interventions?


Therapy Meeting


Thank you

Professor Anna Maria Geretti - Mediscript · 16th Annual Resistance and Antiviral Therapy Meeting...

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