Virological predictors of clinical outcome Anna Maria Geretti Royal Free Hampstead NHS Trust & UCL...

Virological predictors of clinical outcome

Anna Maria Geretti

Royal Free Hampstead NHS Trust & UCL Medical School

London

0

0.05

0.1

0.15

0.2

0.25

Mortality risk with detectable viraemia during HAART

Cu

mu

lati

ve m

ort

alit

y

Months after starting HAART0 18 36 54 72

Lohse et al, Clin Infect Dis 2006

Cumulative mortality stratified by % VL ≥400 cps/ml recorded during 18 months after HAART initiation

100%

51%-75%

76%-99%

26%-50%1%-25%

0%

n=2046 patients who started HAART before 2002Follow-up: 8898 patient-years after 18 months on HAART

Determinants of HAART outcomes

Drug exposure• Adherence• PK• Compartments

Host-related factors• Immune status• Genetics• Tolerability

Virological factors• Viral load• Sequence variability• Drug-resistance

Drug potency• IC50 value• Genetic barrier to resistance

First-line HAART in the UK

Drug-naïve cohort (n= 1175)

Started HAART in 1996-2006

82% achieved a VL<50 cps/ml

At median 3.5 months

IQR 2.4, 5.5 months

Geretti et al, EHDRW 2008

3.6

21.5

1.7

73.2

01020304050607080

2 NRTIs+ NNRTI

2 NRTIs+ PI

2 NRTIs+ PI/r

3 NRTIs%

of

pat

ien

ts

HAART regimen started

Independent predictors of achieving a VL <50

HR 95% CI P

Year of starting HAART

1999-2001 0.61 0.46, 0.79 0.0002

2002-2003 0.78 0.67, 0.93 0.004

2004-2006 1 - -

Age Per 10 yrs older 1.17 1.06, 1.28 0.001

Baseline VL Per 1 log 0.63 0.56, 0.70 <0.0001

Baseline CD4 Per 50 cells 0.97 0.94, 1.00 0.02

GSS Per 1 unit 1.50 1.19, 1.89 0.001

Regimen NNRTI 1 - -

PI/r 0.86 0.70, 1.05 0.13

PI 0.39 0.22, 0.71 0.002

Triple NRTI 0.51 0.35, 0.76 0.001

No effect of gender, risk group, ethnicity, or B vs non-B subtype

Geretti et al, EHDRW 2008

Impact of low-level viraemia

Impact of HIV-1 subtype

Impact of transmitted drug resistance

Exploring the determinants of HAART failure

Investigate the long-term virological outcomes of a large cohort initially showing good responses to first-line HAART

Explore the occurrence and impact of low-level viraemia between 50 and 400 cps/ml

Study objectives

Geretti et al, Antiviral Therapy 2008

Study population

129

24

16

39

0

5

10

15

20

25

30

35

40

45

2 NRTIs+ NNRTI

2 NRTIs+ PI

2 NRTIs+ PI/r

3 NRTIs Other

% o

f p

atie

nts

Drug-naïve cohort (n= 1386)


Achieved a VL <50 cps/ml

In the following year:

• In follow-up

• On HAART

• No VL >400 cps/mL


Note: 320 (23.1%) changed the initial regimen before achieving <50 cps/ml due to toxicity (allowed)

HAART regimen at first VL <50 cps/ml

Virological status in the first year after achieving a VL <50 cps/m

74.5

19.4

6.1

0102030405060708090

100

Consistentsuppression

Transient low-level rebound

Persistent low-level rebound

% o

f p

atie

nts

Low-level rebound = 50-400 cps/ml


Virological status in the first year after achieving a VL <50 cps/m

74.5

19.4

6.1

0102030405060708090

100

Consistentsuppression

Transient low-level rebound

Persistent low-level rebound

% o

f p

atie

nts

269 patientsBlips per person 1 84.8% 2 13.4% 3 1.5% 4 0.4%

85 patients Consecutive VL >50

2 in 54.1% 3 in 28.2% ≥4 in 17.6%

Low-level rebound = 50-400 copies/ml



Predictors of low-level rebound

Multivariate model Factors analysed: age, gender, risk group, ethnicity/country of

birth, baseline CD4 and VL, CD4 at first VL <50 cps/ml, time from start of HAART to first VL <50 cps/ml, HAART regimen, year when first achieved a VL <50 cps/ml, HAART changes for toxicity prior to first VL <50 cps/ml

OR 95% CI P

2 NRTIs + 1 NNRTI 1.00 - 0.01

2 NRTIs + 1 PI/r 1.39 1.00, 1.94

2 NRTIs + 1 PI 1.48 0.96, 2.26

Triple NRTIs/Other 1.73 1.23, 2.42


Virological outcomes

Follow-up started 1 year after 1st VL <50 cps/m

Lasted for median 2.2 years (range 0.0–7.4)

Failure = VL >400 cps/ml

Failure rate = 86 patients (6.2%)

• Consistent undetectability 5.0%

• Transient low-level rebound 8.2%

• Persistent low-level rebound 14.1%



Predictors of virological failure Multivariate model Factors analysed: As in previous analysis + VL status in the first year

after achieving a VL <50 cps/m

Predictors RR 95% CI P

Virological status in 1st yr after achieving <50 cps/ml

Consistent <50 1.00 – 0.02

Transient rebound 1.41 0.86, 2.34

Persistent rebound 2.18 1.15, 4.10

Gender Male 1.00 – 0.02

Female 1.79 1.12, 2.85

HAART regimen 2 NRTIs + 1 NNRTI

1.00 – 0.09

2 NRTIs + 1 PI/r 1.88 1.02, 3.46

2 NRTIs + 1PI 1.23 0.66, 2.31

3 NRTIs/Other 1.87 1.04, 3.36


Effect of VL on the detection of resistance(multivariate analysis)

VL N %

RAMsRR (95% CI)

<300 449 60 0.94 (0.87-1.01)300-1000 552 72 0.99 (0.94-1.04)

1000-3000 1120 76 13000-10000 1312 77 1.01 (0.97-1.05)

10000-30000 1326 67 0.91 (0.87-0.95)30000-100000 1438 60 0.84 (0.80-0.88)

≥100000 1682 49 0.70 (0.66-0.74)

RAMs: resistance-associated mutationsRR: Relative risk

Geretti et al, IHDRW 2009

Number of mutations detected by VL strata*

3 3 3 3

4

3 3

0

1

2

3

4

5

6

7

<300 300-1000 1000-3000

3000-10000

10000-30000

30000-100000

>100000

Med

ian

nu

mb

er (

IQR

)

*in patients with ≥1 mutation

N= 270 399 850 1014 888 858 809

Geretti et al, IHDRW 2009

Study population

Drug-naïve cohort (n=2116)


• Most commonly 2 NRTIs + 1 NNRTI

≥12 months of follow-up Excluded patients with TDR

Outcomes measured: Time to VL suppression <50 cps/ml For those who achieved <50, time to rebound >1000 cps/ml Median follow-up of 39 months (IQR 23, 67)

Geretti et al, Clin Infect Dis 2009

D, 2%

AG, 3%

B, 73%Other,

6%

C, 13%

A, 3%

Subtype

Ethnicity and risk group strongly associated with subtype (P<0.001)

Responses to first-line HAART by subtype

0

20

40

60

80

100

120

A B C D AG Other

%

VL suppression VL rebound

N = 64 1381 255 37 51 118N = 13 238 51 7 7 19

1906/2116 (90%) achieved VL suppression <50 cps/ml 335/1906 (18%) rebounded >1000 cps/ml


VL suppression

0.00

0

0.20

0.40

0.60

0.80

1.00

3 6 9 12

Pro

bab

ility

of

ach

ievi

ng

<50

cp

s/m

l

Analysis time (months)

Log-rankp<0.0005

ABC

Number at riskA 66 23 9 5 2B 1550 785 332 218 169C 272 10 41 23 17

Median time to VL suppression Subtype A 2.6 monthsSubtype C 2.8 monthsSubtype B 3.1 months

Multivariate analysis* Time to VL suppression shorter for A (HR 1.35 [1.04,1.74] P=0.02) and C (HR 1.16 [1.01,1.33] P=0.04) vs B

*adjusted for age, centre, HAART regimen, calendar year, baseline CD4 and VL


VL rebound

*adjusted for age, centre, HAART regimen, calendar yr, baseline CD4 and VL, and time to VL suppressionNumber at risk

A 64 49 34 22 17 15B 1381 1167 830 630 454 317C 255 197 116 74 48 30

0.00

0

0.20

0.40

0.60

0.80

1.00

12 24 36 48

Pro

bab

ility

of

rem

ain

ing

<50

cp

s/m

l

Analysis time (months)

Log-rankp=0.09

ABC

60

Multivariate analysis*Time to VL rebound shorter for C vs B (HR 1.40 [1.00, 1.95] P=0.05) 143 rebounds: virological failure192 rebounds: non-adherence or treatment discontinuation

Time to virological failure similar for C vs B


CD4 recovery over time


100

0

200

300

400

500

6 12 18

CD

4 co

un

t (c

ells

/mm

3 )

Time since ART initiation (months)

ABC

Number in analysisA 66 50 57 42 38 28 20B 1550 1253 1174 970 796 668 552C 272 225 201 167 121 93 63

3024 36

Detection of TDR

0.001

0.01

0.1

1

10

100

Detected by ultrasensitive methods

Mu

tatio

n F

requ

enc

y

Detected by routine methods

Natural background

6-13% of naïve patients in Europe & N America1-9

1. Masquelier JAIDS 2005; 2. Wensing JID 2005; 3. Booth JAC 2007; 4. Geretti COID 2007; 5. SPREAD AIDS 2008; 6. Vercauteren AIDS RHR 2008; 7. Peuchant AIDS 2008; 8. Bannister JAIDS 2008; 9. Weinstock JID

2004; 10. Peuchant AIDS 2008; 11. Metzner AIDS 2005; 12. Johnson PLoS ONE 2007; 13. Johnson PLOS Med 2008; 14. Siemen JID 2009; 15. Geretti JAIDS 2009; 16. Goodman IHDRW 2009

Rates doubled10-16

The clinical significance of low-frequency TDR

Different methods, interpretative cut-offs, populations, HAART regimens

Metzner, Antivir Ther 2007

Peuchant, AIDS 2008

Geretti, JAIDS 2009

Johnson, PLOS Med 2008

Siemens, JID 2009

Goodman IHDRW 2009

Impact on virological responses

No

Yes

The FIRST study

Mutations Method P

Bulk UDS

NNRTI 6.6% 15.1% <0.001

NRTI 6.2% 14.0% <0.001

PI 2.3% 4.7% 0.03

Any 13.6% 28.3% <0.001

N=258

HR for failure in patients with NNRTI resistance

Bulk : 12.4 [3.41-45.1]

UDS: 2.50 [1.17-5.36]

Siemen et al, JID 2009USD = Ultra deep sequencing

Impact of NNRTI TDR on responses to first-line NNRTI-based HAART

Case control study

Patients with virological failure (n=18) vs those who achieved and maintained VL suppression <50 for ≥24 weeks (n=75)

Pre-HAART sample tested by sensitive PCR

Targets: K65R, K103N, G190A, Y181C, M184V

Interpretative cut-off of 0.5-0.9%

Geretti et al, JAIDS 2009

NNRTI TDR reduces responses to first-line NNRTI-based HAART

Resistance at baseline

7/18 cases vs 0/75 controls

2 K103NHIGH 1 G190AHIGH 4 K103NLOW

Odds of virological failure

Bulk resistance p=0.006

4 K103NLOW p=0.001

Combined p <0.0001

Geretti et al, JAIDS 2009

HIGH= detected also by bulk genotyping; LOW= detected only by PCR (>0.9%)

K103N >2% or >2000 cps/ml predicts failure of first-line NNRTI-based HAART

Goodman et al, IHDRW 2009

Fit plot for VF (>400 c/mL)

0 1 2 3 4

Log copies of RNA with K103N mutation

-1

Clin

ical

viro

logy

VF

(>40

0 c/

mL)

-0.5

0

0.5 VF

Non-VF

Fit 99% confidence band

103.3 = 1995 c/mL

0 2.5 5 12.5 15

Percent of RNA with K103N mutation

-1Clin

ical

viro

logy

VF

(>40

0 c/

mL)

-0.5

0

0.5 VF

Non-VF

Fit 99% confidence band1

7.5 10

GS-01-934 (n=487)

TDF/FTC/EFV

ZDV/3TC/EFV

K103NLOW in 16/476 (3.4%) patients

6/16 (38%) of patients with K103NLOW had VF

VF = virological failure

Conclusions-1

Low risk of virological failure once suppression is achieved and maintained for 1 year

Consistent suppression <50 the optimal target

NNRTI-based HAART least likely to result in low-level viraemia and virological failure

Women at increased risk of virological failure

Problems with long-term adherence

Cultural and social-economic factors

Resistance testing at low VL yields clinically useful information

Conclusions-2

Predominantly NNRTI-based HAART achieves excellent outcomes regardless of the infecting subtype

Subtype C patients show an increased risk of rebound possibly related to non-adherence

Conclusions-3

Low-frequency K103N mutants as prevalent as bulk-detectable resistant variants

Significantly associated with virological failure

Patients infected with single NNRTI mutants

? Impact on second generation NNRTIs

Etravirine

Nevirapine Efavirenz

Thank [email protected]

Virological predictors of clinical outcome Anna Maria Geretti Royal Free Hampstead NHS Trust & UCL...

Documents

Transcript of Virological predictors of clinical outcome Anna Maria Geretti Royal Free Hampstead NHS Trust & UCL...