late breaker track b welbb04 hla-b*35:05 and cchcr1 screening reduces nevirapine-associated...
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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)
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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
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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.
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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%
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Objective
This study was designed to determine the effectiveness of prospective genotypes-based screening to prevent NVP-CAR in HIV-infected Thai patients
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Patients and Methods
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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)
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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
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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
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Results
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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
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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)
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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) - -
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Standard of care Genetic testing
Comparisons of strata by arms
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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