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

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

 HLA-B*35:05 was observed in 17.5% of patients with rash vs. 1.1% of NVP-tolerant patients  OR (95% CI , P= )  Sensitivity 17.5%  Specificity 98.9% Chantarangsu S et al. Pharmacogenet Genomics 2009;19:

Chantarangsu S et al. Clin Infect Dis 2011;53:341–8.  ∼ 550,000 markers  CCHCR1 significantly associated with rash  OR 2.59 (95% CI , 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 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 group N=549 Prospective-screening group N= 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 CharacteristicsProspective- 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, years38 (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 ( )55 (48-62) History of drug allergy, n (%) 78 (14.1)76 (13.8)154 (14.0)

Baseline Characteristics (continued) CharacteristicsProspective- screening group (N= 554) Control group (N=549) All participants (N=1,103) Median (IQR) baseline CD4 count, cells/mm (35-220)121 (40-229)116 (37-225) Median (IQR) plasma HIV RNA, copies/mL 44,400 (12, ,300) 57,390 (14, ,800) 50,580 (13, ,000) HIV subtype, n (%) AE515 (93.8)493 (89.0)1,008 (91.4) B32 (5.8)58 (10.4)90 (8.1) Others2 (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 Control group Prospective-screening group

Results CharacteristicsProspective- 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 GroupRelative risk 95% confidence interval P-value Overall Sex Male Female CD4 cell count, cells/mm 3 < >

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 CharacteristicsHLA-B*35:05CCHCR1Combined Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Relative risk % confidence interval P-value6.02 x

Sensitivity and Specificity of the Tests CharacteristicsCarbamazepineAllopurinolAbacavirNevirapine SJS/TENS/ DRESS SJS/TENS/ DRESS Clinical hyper- sensitivity CARs/ DRESS Sensitivity (%) Specificity (%) Positive predictive value (%) Negative predictive value (%) Positive likelihood ratio5.37N/A 7.39 (HLA-B*35:05) 1.89 (CCHCR1) Negative likelihood ratio0.07N/A 0.86 (HLA-B*35:05) 0.88 (CCHCR1) Relative risk2.27 (overall) 95% confidence interval P-value0.0021

Incidence of NVP-CAR

Results of Genetic Testing

Incidence of NVP-CAR

Standard of careGenetic testing Comparisons of strata by arms

Study Team Sasisopin 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, PhD 12 Yusuke Nakamura, MD, PhD, 13 Taisei Mushiroda, PhD, 13 Wasun Chantratita, PhD, 14 Somnuek Sungkanuparph, MD 1 1 Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand 2 Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand 3 Thailand Center of Excellence for Life Sciences, Mahidol University, Bangkok, Thailand 4 Department of Internal Medicine, Sawanpracharak Hospital, Nakornsawan, Thailand 5 Department of Internal Medicine, BamrasnaraduraInfectious Disease Institute, Nonthaburi, Thailand 6 Department of Internal Medicine, Chiang Rai Prachanukroh Hospital, Chiang Rai, Thailand 7 Department of Medicine, Faculty of Medicine, Thammasat University, Pratumthani, Thailand 8 Department of Internal Medicine, Maharaj Nakornratchasima Hospital, Nakornratchasima, Thailand 9 Department of Medicine, Buriram Hospital, Buriram, Thailand 10 Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand 11 Department of Preventive Medicine and Social Medicine, Faculty of Medicine, Srinakharinwirot University, Nakhon Nayok, Thailand 12 Laboratory for Genotyping Development, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan 13 Laboratory for Pharmacogenomic, RIKEN Center for Integrative Medicine Sciences, Yokohama, Japan 14 Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand