Genetic Susceptibility to Carbamazepine Induced Cutaneous Adverse Drug Reactions

Asia is a large region with 60% of world population. The region is the home of many national groups with different culture and ethnicity. Data from the WHO Uppsala Monitoring Center (WHO-UMC) and Novartis CBZ-SJS/TEN reports 2000-2006 showed that the incidence of ACDR induced by CBZ was high among some Asian countries. The incidence is not known in many geographical regions and ethnic groups. Therefore it is important to document the incidence of ACDR induced by CBZ in these areas. The importance of HLA-B*1502 as marker of CBZ-induced SJS/TEN is being established particularly among Han Chinese, and the prevalence of HLA-B*1502 in various ethnic groups are being determined, there are still large parts of Asia where the prevalence of HLA-B*1502 is not known. This is for example, the Han and non-Han Chinese from different parts of China, Filipinos, various ethnic groups in Indonesia, Pakistan, Bangladesh, Myanmar, Cambodia and Lao PDR. The determination of the prevalence of HLA-B*1502 in these ethnic groups is thus of high priority. The significance of HLA-B*1502 as a marker for CBZ-induced SJS/TEN is only established among the Han Chinese, less so among the Malays and Thais. As HLA-B*1502 as a marker of CBZ-induced SJS/TEN is ethnicity specific, the present study enlightens our knowledge about the relationship between HLA-B*1502 and CBZ-induced SJS/TEN in South India. There are many unanswered questions in CBZ induced ACDR and HLA-B*1502 waiting to be explored like the role of other HLA-B subtypes in CBZ induced SJS/TEN, significance of HLA-B*1502 and other HLA subtypes in ACDR induced by other antiepileptic drugs, e.g. phenytoin and lamotrigine. CONCLUSIONS: There is a high prevalence HLA-B*1502 allele in South Indian epileptic population on Carbamazepine (18.20%) when compared to the non-epileptic population (7%). This is being reported for the first time in the world literature and further studies have to be done in other centers in India and in other countries in different races to look for this difference. The mechanisms underlying this difference have to be elucidated. In our study, the presence of the HLA-B*1502 allele was strongly correlated to the development of SJS/TEN. The Positive Predictive Value for development of SJS/TEN on exposure to CBZ was 81.82 % with a very high Negative Predictive Value of 99.30%. The Sensitivity of HLA-B*1502 Test was 96.43% with a Specificity of 95.95%. There is a strong association (100%) of HLA–B*1502 allele and the development of SJS in South Asians. This observation is similar to that reported in Chinese, Malay and Thai populations in South East Asia. In conclusion, HLA-B*1502 has recently been linked to CBZ-induced SJS/TEN in some Asian groups. Screening of HLA-B*1502 in these ethnic groups before use of CBZ is recommended. Determination of prevalence of HLA-B*1502 allele and its association with CBZ-induced SJS/TEN in the different ethnic groups is thus of high priority for epilepsy care in India and South East Asia. IMPACT OF THE STUDY: The present study is the largest study reported from India. • The study clearly establishes a firm link between the presence of HLA-B*1502 allele and Carbamazepine induced SJS/TEN with high Positive and Negative Predictive Values. • It is imperative to test for HLA-B*1502 allele, prior to starting Carbamazepine and the drug should not started for patients testing positive for HLA-B*1502 allele. • Once a patient has developed SJS/TEN on exposure to CBZ, he should not be rechallenged with CBZ since this would trigger SJS/TEN with increased severity. • Patients testing Positive for HLA-B*1502 allele, should not only avoid CBZ, but also Oxcarbamazepine, Phenytoin, Phosphenytoin, Phenobarbitone, Sodium Valproate and Lamotrigine. • This thesis will change the way antiepileptic medications are prescribed in India. Ideally prescription for AED should be started only after testing for HLAB*1502 allele. • If HLA-B*1502 allele is detected in an epileptic patient, only AEDs like Gabapentin, Pregabalin, Zonisamide, Lacosamide and Clonazepam should be initiated. • During serial seizures or status epilepticus, Midazolam or Propofol should be initiated and Phosphenytoin should be started only if the HLA-B*1502 allele is not detected. The time for performing the test in emergency situations should take less than 6 hours. • The HLA-B*1502 allele is well standardized and easy to perform. The cost of the test, around Rupees fifteen hundred is affordable. This test should be performed in all clinical settings, prior to the initiation of AED therapy. • Failure to test HLA-B*1502 allele, prior to starting one of the offending AED may lead to SJS/TEN which are associated with high mortality rates of 5- 30 % and severe mobididity and sequelae affecting the skin and mucous membranes. RECOMMENDATION FOR USE OF CARBAMAZEPINE: As CBZ is an effective, safe and cost effective antiepileptic drug, the recent finding of HLAB* 1502 as marker of CBZ-induced SJS/TEN indicates that it is of high priority to develop facilities for testing of HLA-B*1502 in clinical practice involving Indians, Han Chinese, Malays and Thai patients. Patients of these ethnic groups should be screened for the HLA-B*1502 allele before starting treatment with CBZ. If tested positive, CBZ should be avoided. However, it should be noted that patients who are tested positive for HLA-B*1502 may be at increased risk of SJS/TEN from other antiepileptic drugs e.g. lamotrigine, phenytoin and phenobarbital. It is probably advisable to avoid other antiepileptic drugs also known to cause SJS/TEN, namely lamotrigine, phenytoin and phenobarbital289. The median duration of developing CBZ-induced SJS/TEN is 25 to 90 days290. Patients who have been taking CBZ for more than 3 months without developing skin reactions are at low risk of CBZ-induced ACDR. Therefore, use of CBZ can be continued without screening