PPT Rusconi "Le multiresistenze dell'HIV/AIDS"

Le Multiresistenze dell’HIV/AIDS

Stefano Rusconi

Divisione Clinicizzata di Malattie Infettive DIBIC “Luigi Sacco”

Università degli Studi di Milano

Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.

Impossibile visualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se viene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.

Milano, Palazzo delle Stelline, 22 marzo 2014

Resistance to an8viral drugs

•  The (in)ability of the virus to replicate in the presence of an6retroviral drugs •  Caused by changes in relevant part of the virus genome (muta6ons)

2

The emergence of resistance is the inevitable consequence of incomplete suppression of HIV (HBV/HCV) replica8on by the current an8retroviral drugs,

and is a major limita8on of an8viral therapy

Viral escape

•  The ability of a virus to escape an6viral pressure depends also upon the

characteris6cs of drugs

•  Gene6c barrier: the number of muta6ons required by the virus to develop a fully

resistant virus

–  Low gene8c barrier: drugs whose efficacy is lost with a single muta6on

–  High gene8c barrier: drugs whose efficacy is lost only aAer the sequen6al

appearance and selec6on of a substan6al number of muta6ons

3

Dinamica virale e resistenza farmacologica

Pressione farmacologica

Tempo

Virus “selvaggio” (sensibile al farmaco) Virus “mutante” (resistente al farmaco)

viremia

Utilizzo (combinato) di antiretrovirali anti HIV-1

Pressione farmaco A

Tempo

Viremia Pressione farmaco B

Pressione farmaco C ...

“Functionally disabled HIV”

Selec8on -‐> Resistance A single muta8on preexis8ng therapy, selected under an8viral

pressure: an easy and rapid phenomenon

Inconsistent an8viral pressure Viral loa

d

Time

Wt Res. variant

For instance NNRTI (K103N) (gene6c barrier=1)

6

Selec8on + Genera8on -‐> Resistance A muta8on preexis8ng therapy, conferring only marginal

resistance, selected under an8viral pressure...

Selec8on

Viral loa

d/ freq

uency

Time

Wt

Single mut.

Double mut.

… a long-‐term phenomenon

For instance, ritonavir-‐boosted PIs 7

Selec8on

Viral loa

d/ freq

uency

Time

Wt

Single mut. Double mut.

Resist.mut.

For instance, ritonavir-‐boosted PIs

Evolu8on toward high resistance and high fitness

Selec8on + Evolu8on A muta8on preexis8ng therapy, conferring marginal resistance, selected under an8viral pressure, followed by the genera8on of

further muta8ons while con8nuing an8viral therapy

8

Selec8on

Viral loa

d/ freq

uency

Time

Wt

Single mut. Double mut.

Resist. mut.

For instance boosted PI

Evolu8on toward high resistance and high fitness

Events that require a long-‐term failing treatment to occur

Triple/quadruple mutant

Selec8on + Genera8on -‐> Resistance A muta8on preexis8ng therapy, conferring marginal resistance, selected under an8viral pressure, followed by the genera8on of

further muta8ons while con8nuing an8viral therapy

9

Drug Resistance in Europe during 1997-‐2012 (EuroSIDA)

A. Schultze et al., EACS 2013

The RAM prevalence significantly varied according to the viremia levels

P <0.001 (Chi-squared test for trend)

54

72 76 87

78 66

0

20

40

60

80

100

Pre

vale

nce

of s

ampl

es w

ith

at le

ast 1

MR

M (%

)

Viremia ranges (copies/mL)

N samples 3,726 374 270 227 1,060 1,173 622

Fabeni et al., V ICAR 2013

Viremia ranks (copies/mL)

Overview of 11,986 genotypic requests from clinical samples with different viremia ranks over the years.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall (N=11,986) Naive (N=4,711) Experienced (N=7,275)

>100,000 10,000-100,000 1,000-10,000 500-1,000 200-500 50-200

In experienced patients 1,115 (15.3%) samples had viremia values ≤500 copies/mL

Fabeni et al., 8° EHDRW 2013, V ICAR 2013

15

Methods

WHO – list 20091

Group 0

Patients with no detected

mutation (used as a reference group)

Patients having at least one mutation

Group 1

show no drug resistance to their

prescribed drug (classified as ‘susceptible’ or as

‘potential low level resistance’)

Group 2

resistant to at least one of their prescribed drugs

(classified as ‘Low-level resistance‘, ‘Intermediate' or as ‘High level resistance‘)

Stanford2 version 6.0.5

•  Virologic endpoint: –  time to first of two consecutive viral load>500 copies/mL

after six months of therapy •  Definition TDR (two steps):

1Bennett PlosOne 2009, 2Liu CID 2006 EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011

16

Virological failure according to TDR

In adjusted analysis*: Ø  Patients with resistance to ≥1 drug:

- significant higher risk of VF compared to patients without mutations - HR: 3.3 (2.5; 4.4) P<10-4

Ø  patients receiving a fully active cART and patients with no mutation:

- risk of VF was not significantly different - HR: 1.4 (0.9; 2.3) P=0.17 Time after start of therapy (month)

% VF

6 7 8 10 11 12 9 0

5

10

15

20

25

*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011

17

Impact of TDR according to treatment strata

0.1

1

10

No TDR TDR andfully-activecART

TDR andresistant


TDR andresistant


TDR andresistant

ALL 2NRTI+1NNRTI 2NRTI+1PI/rtv

HR*

TDR and fully

active

TDR and fully

active

TDR and fully

active

TDR and

resistant

TDR and

resistant

TDR and

resistant

No TDR

No TDR

No TDR

ALL

2NRTIs + 1NNRTI

2NRTIs + PI/rtv

*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV transmission risk group, origin

EuroCoord-CHAIN: L. Wittkop et al., Lancet Infect Dis. Feb 28, 2011

Impact of Minority Drug Resistant and X4 variants in Naive Pa6ents Star6ng ART with <100 CD4/mm3

M. Casadellà et al., CROI 2014, abs 602

Primary resistance to integrase inhibitors in Europe (Spread)

M. Casadellà et al., CROI 2014, abs 580

Impact of RAL/EVG selected muta6ons on DTG cross-‐resistance Pa6ent viruses containing Q148H/K/R muta8ons displayed reduced DTG suscep8bility with a median fold change in IC50 (FC)=4.6 (range 1.7 to 96.0). Q148K viruses that emerge less frequently than Q148H/R variants exhibited larger reduc6ons in DTG suscep6bility compared to Q148H/R viruses. All pa6ent viruses contained one or more addi6onal IN muta6ons with G140 subs6tu6ons occurring most frequently followed by E138 subs6tu6ons. Based on the analysis of a panel of SDMs, a single muta6on at posi6on 148 did not reduce DTG suscep6bility (DTG FC=0.5 to 0.7). However, the addi8on of a second muta8on at posi8on 140 conferred measurable reduc8ons in DTG suscep8bility (FC=2.2 to 58). The further introduc6on of addi6onal muta6ons at posi6ons 74, 92, 97 and 138 conferred incremental reduc6ons in DTG suscep6bility. Q148K SDMs containing addi8onal muta8ons displayed larger reduc8ons in DTG suscep8bility than corresponding Q148H/R SDMs.

W. Huang et al., CROI 2014, abs 595

Clin Microbiol Infect. 2013 Jan 4. doi: 10.1111/1469-‐0691.12100.

Weeks24201612840

One

min

us s

urvi

val

1,0

0,8

0,6

0,4

0,2

0,0

1.50+1-1.49<1

GSS

Figure 1a. Time to first undetectable HIV-‐RNA by GSS


Weeks24201612840

One

min

us s

urvi

val

1,0

0,8

0,6

0,4

0,2

0,0

1.50+1-1.49<1

Weighted GSS

Figure 1b. Time to first undetectable HIV-‐RNA by weighted GSS


0,1

1

10

100

GSS GSS 1-1.5 GSS >1.5 WeightedGSS

WeightedGSS 1-1.5

WeightedGSS >1.5

Log

Scal

e

Factors associated with virological response at six months according to mul8variate analysis (AOR)


Detec8on of NNRTI resistance muta8ons ager interrup8ng NNRTI-‐based regimens

V. Cambiano et al., CROI 2014, abs 593

•Among the 208 individuals with a resistance test performed aAer stopping suppressive NNRTI-‐based ART (see characteris6cs in table 1), 12% (n=25, 95% CI: 8%-‐17%) had ≥1 NNRTI resistance muta8on detected at the first resistance test following ART treatment interrup8on. •In those with at least 1 NNRTI resistance muta8on detected the median 8me between TI and the resistance test was 12 months (IQR: 3-‐20 months).



Decay Rate of Archived HIV-1 Drug Resistance Mutations

J. De La Cruz et al., CROI 2014, abs 604

Prevalence of Minority Resistant Variants to ETR, DRV and RAL at Baseline in the ANRS 139 TRIO

Trial

C. Charpen6er et al., CROI 2014, abs 605

P. Di Vincenzo, S. Rusconi et al., HIV Medicine (2010) 11, 530–534

Prevalence of muta8ons and determinants of genotypic resistance to etravirine (TMC125) in a large Italian resistance database (ARCA)

Determinants of genotypic resistance [Tibotec (TBT) score 0–2 or >2] to TMC125

< 0.001

0.015

0.005

< 0.001 0.964

0.004

< 0.001 < 0.001 0.002 0.665

< 0.001 0.369 0.207

Category TBT score 0-‐2 TBT score >2 AOR 95%CI p

This mul8variate analysis was conducted with the endpoint of having a TBT score 4 2. Values in the TBT score columns are n (%), with the excep8on of mean (median) for age. AOR for age is for each addi8onal 10 years. *Reference category. AOR, adjusted odds ra8o; CI, confidence interval; ND, not determined; EFV, efavirenz; NVP, nevirapine; PI, protease inhibitor; T20, enfuvir8de.

P. Di Vincenzo, S. Rusconi et al., HIV Medicine (2010) 11, 530–534

TMC125 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 29 59 n (TMC125) = 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 background regimen.

TMC125-C227: Change in viral load (observed)

B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6

l  A large number of NRTI resistance-associated mutations were noted in this first line failure population

l  Many NRTIs were recycled in this study l  TMC125 group

l  37% recycled one, 9% two

l  Control group l  35% recycled one,

12% two IAS-

USA

NR

TI re

sist

ance

ass

ocia

ted

mut

atio

ns

(%)

90

80

70

60

50

40

30

20

10

0 TMC125 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

Baseline NRTI mutations

B. Woodfall et al., HIV8, Glasgow Nov 12-16, 2008. Abstract PL5.6

1.8

Low-‐Frequency HIV-‐1 Drug Resistance Muta8ons and Risk of NNRTI-‐Based An8retroviral Treatment Failure

A Systema8c Review and Pooled Analysis Systema6c Review and Baseline Characteris6cs 10 studies with 985 pa6ents were iden6fied as mee6ng the inclusion and exclusion criteria. The median CD4 cell count was 229 cells/mm3 and mean plasma HIV-‐1 RNA level was 5.0 log10 copies/mL. All studies evaluated the presence of NNRTI muta6ons K103N, Y181C (N=435) and NRTI muta6ons M184V (N=228) and K65R (N=163).

Li et al JAMA 2011

•  Minority drug-‐resistant variants were found in 14% (117/808).

Baseline Parameter Odds Ratio (95% CI) P-Value Χ2 - test

K103N >= 2,000 copies/mL K103N detectable and < 2,000 copies/mL

47.4 (5.2, 429.2) 1.19 (0.15, 9.71)

0.0006 0.8703

BL HIV RNA >100,000 0.98 (0.51, 1.88) 0.9471

BL CD4 >=200 0.60 (0.31, 1,16) 0.1282

Treatment arm 0.75 (0.40, 1.41) 0.3695

•  Multivariate logistic regression to predict risk of VF with predictors treated as categorical variables

•  16 of 476 (3.4%) evaluable participants had low-level K103N at baseline by AS-PCR (0.8-15%).

•  K103N >2% was also predictive of VF with Odds Ratio = 25.5 and P = 0.0002

Svarovskaia et al XVIII Inter HIV Drug Resist 2009 Goodman et al AIDS 2011

The presence of K103N mutant virus in plasma above 2000 copies/ml prior to therapy in treatment-naive individuals

correlated with increased risk of virologic failure of efavirenz-containing triple-drug regimens

Prevalence of etravirine (ETR)-RAMs at NNRTI failure and predictors of resistance to ETR in a

large Italian resistance database (ARCA)

S. Rusconi et al., Clin Microbiol Infect 2013

Adjusted risk of triple class virologic failure after the

start of cART

Lodwick R, for COHERE, 16th CROI; Montreal (CA), 2009

Boosted-PIs are associated with lower risk of HIV resistance at any level of adherence

Lima VD et al, JID 2008

*Plasma viral load log

* *

Differential Presence of Selected Drug Resistance in Patient Populations

70.7 66.1

61.3

37.2

70

10.1

61.5

23.7

0 10 20 30 40 50 60 70 80

Long-term treated patients (n=380) PHI (Untreated n=59)

Prev

alen

ce (

%)

TAMs NNMs M184V PRAMs

D Turner et al, J AIDS 37, 1627ff, 2004

PPT Rusconi "Le multiresistenze dell'HIV/AIDS"

Health & Medicine

Transcript of PPT Rusconi "Le multiresistenze dell'HIV/AIDS"