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Late Breaker Track B WELBB04 HLA-B*35:05 and CCHCR1 Screening Reduces Nevirapine -associated Cutaneous Adverse Reactions in Thailand: A Prospective Multicenter Randomized Controlled Trial (NCT 00986063). Sasisopin Kiertiburanakul , MD, MHS , Surakameth Mahasirimongkol , MD, MSc, PhD,

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Sasisopin Kiertiburanakul , MD, MHS , Surakameth Mahasirimongkol , MD, MSc, PhD,

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Sasisopin kiertiburanakul md mhs surakameth mahasirimongkol md msc phd

Late Breaker Track BWELBB04HLA-B*35:05 and CCHCR1 Screening Reduces Nevirapine-associated Cutaneous Adverse Reactions in Thailand: A Prospective Multicenter Randomized Controlled Trial(NCT 00986063)

Sasisopin Kiertiburanakul, MD, MHS,SurakamethMahasirimongkol, MD, MSc, PhD,

Natta Rajatanavin, MD,AngkanaCharoenyingwattana, BSc (Pharm), MSc,

ArchawinRojanawiwat, MD, PhD,WittayaWangsomboonsiri, MD,WeerawatManosuthi, MD,PachareeKantipong, MD,AnuchaApisarnthanarak, MD,WilawanSangsirinakakul, MD,PawineeWongprasit, MD,RomaneeChaiwarith, MD, MHS,WoraphotTantisiriwat, MD, MPH,

Michiaki Kubo, MD, PhD, Yusuke Nakamura, MD, PhD,

Taisei Mushiroda, PhD,WasunChantratita, PhD,

SomnuekSungkanuparph, MD

7th IAS, Kuala Lumpur (July 3, 2013)


Background

Background

  • Nevirapine (NVP) is the main component of the regimen for the treatment of HIV infection

    • NVP-based regimen is recommended by EACS and resource-limited settings guidelines including Thailand

  • NVP-associated cutaneous adverse reaction (NVP-CAR) is a major drug adverse reaction

    • Prevalence ~15-20%

  • The associations of NVP-CAR and variations in major histocompatibility complex (MHC) region class I have been reported in Thais

    • HLA-B*35:05

    • Single nucleotide polymorphisms (SNPs) in CCHCR1


Sasisopin kiertiburanakul md mhs surakameth mahasirimongkol md msc phd

HLA-B*35:05 was observed in 17.5% of patients with rash vs. 1.1% of NVP-tolerant patients

OR 49.15 (95% CI 6.45-374.41, P=0.00017)

Sensitivity 17.5%

Specificity 98.9%

Chantarangsu S et al. Pharmacogenet Genomics 2009;19:139-46.


Sasisopin kiertiburanakul md mhs surakameth mahasirimongkol md msc phd

  • ∼550,000 markers

  • CCHCR1 significantly associated with rash

  • OR 2.59 (95% CI 1.82-3.68, P=0.007)

  • Receiver operating characteristic curve showed an area under the curve of 76.4%

Chantarangsu S et al. Clin Infect Dis 2011;53:341–8.


Objective

Objective

  • This study was designed to determine the effectiveness of prospective genotypes-based screening to prevent NVP-CAR in HIV-infected Thai patients


Patients and methods

Patients and Methods


Study methods

Study Methods

  • Prospective multicenter randomized study

  • 9 hospitals in Thailand

  • Study period: April 2009-April 2012

  • We randomly assigned patients to undergo prospective HLA-B*35:05 and CCHCR1 SNPs genotyping group and control group (standard-of-care group)


Study methods1

Study Methods

Prospective-screening group

  • Exclusion of patients with HLA-B*35:05 and CCHCR1 carrier from using NVP and initiated efavirenz (EFV)-based regimen

    Control group

  • NVP usage without prospective genotypic screening

    End point committee

  • NVP-CAR was reviewed by central end point committees composed of a clinical immunologist, a dermatologist and an infectious disease specialist

    Patients were followed for 6 months after ART initiation


Patient selection criteria

Patient Selection Criteria

  • Age 18-70 years old

  • Confirmed to be infected with HIV-1

  • Naïve to ART

  • Eligible for ART according to Thai national guidelines

  • Agreed to withholding other drugs and other medications which do not prescribed by the investigators 14 days prior to ART initiation and during the study

  • Not a pregnant woman or in a lactation period

  • AST/ALT <5 ULN


Results

Results


Study flow chart

Study Flow Chart

  • 1,137 patients were enrolled

34 patients did not receive randomization

10 patients withdrew consent

4 patients had a protocol violation

10 patients were lost to follow-up

10 patients were not treated owing to investigator’s

decision

  • Randomized by gender and CD4 strata N=1,103

  • Prospective-screening group

  • N=554

Control group

N=549


Baseline characteristics

Baseline Characteristics


Baseline characteristics continued

Baseline Characteristics (continued)


Antiretroviral regimens

Antiretroviral Regimens

Prospective-screening

group

Control group


Results1

Results

*Division of AIDS table for grading the severity of adult and pediatric adverse events


Relative risk overall and by subgroup

Relative Risk: Overall and By Subgroup


Strength of the study

Strength of the Study

  • First randomized trial regarding personalized prescription of NVP

  • Point of care genotypic testing is effective preventive intervention for NVP-CAR

  • NVP can be initiated safely for those who less likely to develop NVP-CAR from the result of genetic testing


Limitations

Limitations

  • HLA-B genotype testing may be limited by facility and resource

  • HLA-B*35:05 is not common in other populations except Southeast Asian and Southern Americans

  • Additional genetic risks remained to be discovered


Conclusion

Conclusion

  • HLA-B*35:05 and CCHCR1 SNPs genotypic screening reduced the risk of NVP-CAR

  • Our results support the use of genotypes-based screening in a clinical setting to prevent NVP-CAR among naïve HIV-infected Thai patients


Acknowledgement

Acknowledgement

  • Research grant from Pharmacogenomics Projects, the collaboration between Ramathibodi Hospital, Mahidol University and Thailand Center of Excellence of Life Sciences (TCELS)

  • All study patients


Sensitivity and specificity of the tests

Sensitivity and Specificity of the Tests


Sensitivity and specificity of the tests1

Sensitivity and Specificity of the Tests


Incidence of nvp car

Incidence of NVP-CAR


Results of genetic testing

Results of Genetic Testing


Incidence of nvp car1

Incidence of NVP-CAR


Comparisons of strata by arms

Comparisons of strata by arms

Standard of care

Genetic testing


Study team

Study Team

Sasisopin Kiertiburanakul, MD, MHS,1 SurakamethMahasirimongkol, MD, MSc, PhD,2

Natta Rajatanavin, MD,1 AngkanaCharoenyingwattana, BSc (Pharm), MSc,3

ArchawinRojanawiwat, MD, PhD,2 WittayaWangsomboonsiri, MD,4

WeerawatManosuthi, MD,5PachareeKantipong, MD,6

AnuchaApisarnthanarak, MD,7 WilawanSangsirinakakul, MD,8

PawineeWongprasit, MD,9 RomaneeChaiwarith, MD, MHS,10

WoraphotTantisiriwat, MD, MPH,11 Michiaki Kubo, MD, PhD12

Yusuke Nakamura, MD, PhD,13Taisei Mushiroda, PhD,13

WasunChantratita, PhD,14SomnuekSungkanuparph, MD1 

1Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand

2Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand

3Thailand Center of Excellence for Life Sciences, Mahidol University, Bangkok, Thailand

4Department of Internal Medicine, Sawanpracharak Hospital, Nakornsawan, Thailand

5Department of Internal Medicine, BamrasnaraduraInfectious Disease Institute, Nonthaburi, Thailand

6Department of Internal Medicine, Chiang RaiPrachanukroh Hospital, Chiang Rai, Thailand

7Department of Medicine, Faculty of Medicine, Thammasat University, Pratumthani, Thailand

8Department of Internal Medicine, MaharajNakornratchasima Hospital, Nakornratchasima, Thailand

9Department of Medicine, Buriram Hospital, Buriram, Thailand

10Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

11Department of Preventive Medicine and Social Medicine, Faculty of Medicine, Srinakharinwirot University, NakhonNayok, Thailand

12Laboratory for Genotyping Development, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan

13Laboratory for Pharmacogenomic, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan

14Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand


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