late breaker track b welbb04 hla-b*35:05 and cchcr1 screening reduces nevirapine-associated...

Late Breaker Track BWELBB04

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,

Natta Rajatanavin, MD, Angkana Charoenyingwattana, BSc (Pharm), MSc,

Archawin Rojanawiwat, MD, PhD, Wittaya Wangsomboonsiri, MD, Weerawat Manosuthi, MD,

Pacharee Kantipong, MD, Anucha Apisarnthanarak, MD, Wilawan Sangsirinakakul, MD,

Pawinee Wongprasit, MD, Romanee Chaiwarith, MD, MHS, Woraphot Tantisiriwat, MD, MPH,

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

Taisei Mushiroda, PhD, Wasun Chantratita, PhD,

Somnuek Sungkanuparph, MD

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

Background

Nevirapine (NVP) is the main component of the regimen for the treatment of HIV infectionNVP-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 reactionPrevalence ~15-20%

The associations of NVP-CAR and variations in major histocompatibility complex (MHC) region class I have been reported in ThaisHLA-B*35:05 Single nucleotide polymorphisms (SNPs) in CCHCR1

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.

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

∼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%

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

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 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

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

Study Flow Chart

1,137 patients were enrolled

Control groupN=549

Prospective-screening groupN=554

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

Baseline Characteristics

Characteristics Prospective-screening

group(N= 554)

Control group(N=549)

All participants

(N=1,103)

Male sex, n (%) 328 (59.2) 338 (61) 661 (59.9)

Median (IQR) age, years 38 (31-45) 36.5 (31-43) 37 (31-44)

HIV exposure, n (%)

Heterosexual 420 (75.8) 424 (77.2) 844 (76.5)

Homosexual 102 (18.4) 96 (17.5) 198 (18.0)

Injecting drug use 18 (3.2) 13 (2.4) 31 (2.8)

Blood transfusion 7 (1.3) 6 (1.1) 13 (1.2)

Other/unknown 13 (2.3) 15 (2.7) 28 (2.5)

Median (IQR) body weight, kg 54.7 (48.9-62) 55 (48-62) 55 (48-62)

History of drug allergy, n (%) 78 (14.1) 76 (13.8) 154 (14.0)

Baseline Characteristics (continued)

Characteristics Prospective-screening

group(N= 554)

Control group(N=549)

All participants

(N=1,103)

Median (IQR) baseline CD4 count, cells/mm3 114 (35-220) 121 (40-229) 116 (37-225)

Median (IQR) plasma HIV RNA, copies/mL

44,400 (12,760-151,300)

57,390(14,990-164,800)

50,580(13,620-156,000)

HIV subtype, n (%)

AE 515 (93.8) 493 (89.0) 1,008 (91.4)

B 32 (5.8) 58 (10.4) 90 (8.1)

Others 2 (0.4) 3 (0.6) 5 (0.5)

Positive HLA-B*35:05, n (%) 19 (3.4) - -

Positive CCHCR1, n (%) 78 (14.1) - -

Positive both HLA-B*35:05 and CCHCR1, n (%) 17 (3.1) - -

Antiretroviral Regimens

1%

46%

1%

47%

0%5%

6%

40%

8%

41%

2%3%

Prospective genetic screening

AZT+3TC+EFV

AZT+3TC+NVP

d4T+3TC+EFV

d4T+3TC+NVP

TDF+3TC+EFV

TDF+3TC+NVP

Control groupProspective-screeninggroup

Results

Characteristics Prospective-screening

group(N= 554)

Control group

(N=549)

All participants

(N=1,103)

NVP-CAR*, n (%) 73 (13.2) 99 (18.0) 172 (15.6)

Grade 1 and 2 29 (5.2) 39 (7.1) 68 (6.2)

Grade 3 and 4 44 (7.9) 60 (10.9) 104 (9.4)

Hepatitis*, n (%) 44 (7.9) 47 (8.6) 91 (8.3)

Grade 1 and 2 23 (4.2) 28 (5.1) 51 (4.6)

Grade 3 and 4 21 (3.8) 19 (3.5) 40 (3.6)

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

Relative Risk: Overall and By Subgroup

Group Relative risk

95% confidence

interval

P-value

Overall 0.68 0.49-0.94 0.020

Sex

Male 0.84 0.52-1.35 0.491

Female 0.55 0.32-0.91 0.016

CD4 cell count, cells/mm3

<250 0.64 0.43-0.96 0.027

>250 0.88 0.43-1.77 0.740

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

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

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

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

Characteristics HLA-B*35:05 CCHCR1 Combined

Sensitivity (%) 13.3 25.2 26.3

Specificity (%) 98.2 86.7 86.4

Positive predictive value (%) 61.9 29.4 29.9

Negative predictive value (%) 83.9 84.0 84.0

Relative risk 8.35 2.20 2.27

95% confidence interval 3.36-20.76 1.29-3.73 1.35-3.83

P-value 6.02 x10-6 0.0035 0.0021

Sensitivity and Specificity of the Tests

Characteristics Carbamazepine Allopurinol Abacavir Nevirapine

SJS/TENS/DRESS

SJS/TENS/DRESS

Clinical hyper-

sensitivity

CARs/DRESS

Sensitivity (%) 94.1 100 45.5 26.3

Specificity (%) 82.5 87 97.6 86.4

Positive predictive value (%) 1.43 1.52 61.2 29.9

Negative predictive value (%) 99.98 100 95.5 84.0

Positive likelihood ratio 5.37 N/A 7.39 (HLA-B*35:05)1.89 (CCHCR1)

Negative likelihood ratio 0.07 N/A 0.86 (HLA-B*35:05) 0.88 (CCHCR1)

Relative risk 2.27 (overall)

95% confidence interval 1.35-3.83

P-value 0.0021

Incidence of NVP-CAR

Total patients N=1,103

Prospective-screening group

N=554

Positive

N=80

Rash

N=3

Grade 1-2

N=1

Grade 3-4

N=2

Negative

N=474

Rash

N=70

Grade 1-2

N=28

Grade 3-4

N=42

Control group

N=549

Positive

N=87

Rash

N=26

Grade 1-2

N=5

Grade 3-4

N=21

Negative

N=462

Rash

N=73

Grade 1-2

N=34

Grade 3-4

N=39

Results of Genetic Testing

Total patients N=1,103

Prospective-screening group

N=554

Positive

N=80

HLA-B*35:05

N=2

CCHCR1

N=61

Both

N=17

Negative

N=474

Control group

N=549

Positive

N=87

HLA-B*35:05

N=2

CCHCR1

N=66

Both

N=19

Negative

N=462

Incidence of NVP-CAR

Total patients N=1,103

Prospective-screening group

N=554

Rash

N=73

Grade 1-2

N=29

Grade 3-4

N=44

No rash

N=481

Control group

N=549

Rash

N=99

Grade 1-2

N=39

Grade 3-4

N=60

No rash

N=450

Standard of care Genetic testing

Comparisons of strata by arms

Study TeamSasisopin Kiertiburanakul, MD, MHS,1 Surakameth Mahasirimongkol, MD, MSc, PhD,2

Natta Rajatanavin, MD,1 Angkana Charoenyingwattana, BSc (Pharm), MSc,3

Archawin Rojanawiwat, MD, PhD,2 Wittaya Wangsomboonsiri, MD,4

Weerawat Manosuthi, MD,5 Pacharee Kantipong, MD,6

Anucha Apisarnthanarak, MD,7 Wilawan Sangsirinakakul, MD,8

Pawinee Wongprasit, MD,9 Romanee Chaiwarith, MD, MHS,10

Woraphot Tantisiriwat, MD, MPH,11 Michiaki Kubo, MD, PhD12

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

Wasun Chantratita, PhD,14 Somnuek Sungkanuparph, MD1 

1Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand2Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand3Thailand Center of Excellence for Life Sciences, Mahidol University, Bangkok, Thailand4Department of Internal Medicine, Sawanpracharak Hospital, Nakornsawan, Thailand5Department of Internal Medicine, BamrasnaraduraInfectious Disease Institute, Nonthaburi, Thailand6Department of Internal Medicine, Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand7Department of Medicine, Faculty of Medicine, Thammasat University, Pratumthani, Thailand8Department of Internal Medicine, Maharaj Nakornratchasima Hospital, Nakornratchasima, Thailand9Department of Medicine, Buriram Hospital, Buriram, Thailand10Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand

11Department of Preventive Medicine and Social Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand 12Laboratory for Genotyping Development, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan

13Laboratory for Pharmacogenomic, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan14Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand