Genetik og bivirkningertil

antiretroviral terapi

(HLA, HIV & abacavir hypersensitivity)

Thomas BenfieldOverlæge, dr.med.

Infektionsmedicinsk afdelingHvidovre Hospital

Antiretrovirale stoffer

Nucleo(t)side reverse transcriptase inhibitors (NRTI’s)

Non-nucleoside reverse transcriptase inhibitors (nNRTI’s)

Protease inhibitors (PI’s)

Zidovudine (AZT)(’87) Didanosine (ddI)(´91) Zalcitabine (ddC)(’92) Lamivudine (3TC)(’96) Stavudine (d4T) (’97) Abacavir (1592)(´98) Tenofovir (’02)

Nevirapin (´98) Efavirenz (´99)

Ritonavir (´96) Indinavir (´96) Saquinavir (´96) Nelfinavir (´97) Lopinavir (’00) Amprenavir (’01) Fos-amp. (´03) Atazanavir (’04)

T-20 (’04)Maraviroc (’06)

Tipranavir (’05)Darunavir (’06)

Etavicrine (’07)

Raltegravir (’07)

Emtricitabine

Entry inhibitors: Integration:

0

5

10

15

20

25

30

35

19951996

19971998

19992000

2001

Year

Inci

den

ce (

per

100

PY

FU

)

Deaths AIDS

EuroSIDA: Mocroft et al. Lancet 2003

Association between presence of HLA-B*5701, HLA-DR7, and

HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase

inhibitor abacavir

Mallal et al. Lancet 2002; 359: 727

185 patients with either reaction or > 6 weeks exposure

PPV 100%NPV 97%

Genetic variations in HLA-B region and hypersensitivity reactions to

abacavir

Hetherington et al. Lancet 2002; 359: 1121

Case-control study of 85 patients with ABC reaction and115 controls with > 6 weeks ABC exposure

Sensitivity 33-55%

Martin et al. PNAS2004

Predisposition to abacavir hypersensitivity conferred by HLA-B*5701

and a haplotypic Hsp70-Hom variant

Martin et al. PNAS2004

Martin et al. PNAS2004

Original Article HLA-B*5701 Screening for Hypersensitivity to

Abacavir

Simon Mallal, M.B., B.S., Elizabeth Phillips, M.D., Giampiero Carosi, M.D., Jean-Michel Molina, M.D., Cassy Workman, M.B., B.S., Janez Tomažič, M.D., Eva Jägel-

Guedes, M.D., Sorin Rugina, M.D., Oleg Kozyrev, M.D., Juan Flores Cid, M.D., Phillip Hay, M.B., B.S., David Nolan, M.B., B.S., Sara Hughes, M.Sc., Arlene Hughes, Ph.D., Susanna Ryan, Ph.D., Nicholas Fitch, Ph.D., Daren Thorborn, Ph.D., Alastair Benbow,

M.B., B.S., for the PREDICT-1 Study Team

N Engl J MedVolume 358(6):568-579

February 7, 2008

Eligibility Criteria

Key inclusion criteria:

– Naïve to ABC

– Pre-study need for ABC treatment

Key exclusion criteria:

– Contraindications to ABC

– Known HLA-B*5701 status

Double-Blind Study Design

• 6-Week Observation Period

ABC-naïve subjects ABC-containing regimen

HSR monitoring according toStandard of Care

plus HLA-B*5701 screening2

(screening arm)

ABC-containing regimen HSR monitoring according to

Standard of Care1

(control arm)

Randomise (1:1) HLA-B*5701 positive

subjects excluded

HLA-B*5701 negative subjects

continued

1. retrospective high resolution typing2. prospective high resolution typing

Blinded Independent Skin Patch Testing

Immune cell-mediated reaction

Research tool used to identify patients with immune-mediated abacavir HSR

Adhesive surface

Petrolatum control

Excipient control

1% abacavir

10% abacavir

Phillips et al. AIDS 2002 and 2005Phillips et al. IAS 2007 Abstract MOPEB001

24-hour reading (48 hour reading)

Analysis Populations

ITT (n=1956) – number of subjects randomised

ITT exposed (n=1772) – number of subjects with at least one dose of ABC-containing medication

Primary population for analysis

ITT evaluable (n=1650) – all randomised patients who started abacavir and either completed the six-week observation period or stopped ABC early due to HSR

0

1

2

3

4

5

6

7

8

9

Inci

denc

e (%

)

3.4%(27/803)

7.8%(66/847)

2.7%(23/842)

OR 0.40P < 0.0001

OR 0.03P < 0.0001

Control arm

Prospective HLA-B*5701 screening arm

Clinically SuspectedHSR

Immunologically ConfirmedHSR

Clinically Suspected and Immunologically Confirmed HSR

in ITT evaluable population

0.0%(0/802)

(0.25, 0.62)

(0, 0.18)

Multivariate Analysis of Covariates associated with HSR

(Odds Ratio)Covariates Clinically

suspectedImmunologically

-confirmed* Clinically

suspected but not immunologically-

confirmed†

Prospective HLA-B*5701 screening vs control

0.40P<0.0001

0.03P<0.000001

0.69P=0.1513

White vs non-white 2.19 P=0.0242

4.21P=0.1139

2.00P=0.0879

ART-naïve vs ART- experienced

1.37P=0.2611

1.20P=0.6637

1.49P=0.2213

Introduction of NNRTI: yes vs no

3.19P=0.0011

1.45P=0.5693

4.04P=0.0008

Concurrent PI use: yes vs no

1.86P=0.0094

1.05P=0.9123

2.38P=0.0031

* For the analysis of immunologically-confirmed HSR the same covariates were used as those found to beimportant for clinically diagnosed HSR.

† Clinically diagnosed cases with negative EPT results.

Performance Characteristics ofHLA-B*5701 Screening for HSR

HSR

No HSR

Pos Neg

Immunologically Confirmed HSR1

HLA-B*5701

23 0

25 794

Pos PV

48%

Neg PV

100%

Sens 100%

Spec 97%

Clinically Suspected HSR1

HLA-B*5701

Pos Neg

30 36

19 762

Pos PV Neg PV

62% 96%

Sens 46%

Spec 98%

1 Control Arm Data Only

Screening Implications

Test 100 subjects:

– Treat 94 subjects at low risk for ABC HSR

– Prevent 4 ABC HSR events

– Inappropriately exclude ABC in 2 subjects

– Open screening may also reduce clinical overdiagnosis of HSR

Do not treat with ABC

Appropriate totreat with ABC

Example shown is based upon PPV calculated from PREDICT-1

HLA-B*5701 test

94Negative

6Positive

PREDICT-1 Populationn = 100

Conclusion• HLA-B*5701 screening reduced the risk of hypersensitivity reaction to

abacavir

• In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir

• Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug

The prevalence of HLA-B*5701in different parts of the world

Phillips et al. CID2006Nolan et al. J HIV Ther 2003

Ingelman-Sundberg. NEJM 2008

Baggrund:Codon 244-252 præsenteres af HLA-B5701RT og pol sekventeres rutinemæssigt

Prevalence of HLA-B*5701 and substitutions at RT codon 245 at

baseline.

HLA-B5701 Non-B5701

RT 245V (wild type)

1/24 (4%) 278/368 (76%)

RT 245E/M/L 23/24 (96%) 90/368 (14%)

Sensitivity: 96%Specificity: 76%PPV: 20%NPV: 99%

P < 0.001

http://www.ebi.ac.uk/imgt/hla/http://www.allelefrequencies.net

HLA nomenclature