Medicine (RMH) - Theses
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ItemPersonalised medicine for epilepsy: long-term outcome of antiepileptic drug therapy and pharmacogenetics testing( 2016)Epilepsy is a common neurological disorder that generally requires long-term antiepileptic drug (AED) therapy and poses a substantial public health burden. This thesis reports the studies carried out in three main themes. The first theme quantifies the burden of mortality and morbidity in people living with epilepsy. Screening for HLA-B*15:02 is recommended prior to commencing carbamazepine in Han Chinese and South-East Asians because the allele is strongly predictive of carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). The second theme sheds light on cost-effectiveness of pharmacogenetics in real-world clinical practice. The last theme aims to provide information on long-term response to AED therapy by analysing newly diagnosed and treated patients followed for up to three decades and to assess potential factors associated with treatment outcomes. By using population-based data from Hong Kong’s public hospitals in the six-year study period (16 September 2005 to 15 September 2011), the first theme demonstrated that newly treated epilepsy patients bear excess mortality and hospitalization risks. The standardized mortality ratio was 5.09 (95% confidence interval [CI]: 4.88-5.31) Patients treated with cytochrome P450 enzyme inducing AEDs (EIAEDs) bore a higher risk of being subsequently recorded with new physical comorbidities than those with non-EIAEDs (relative risk [RR]=1.48; 95% CI: 1.19-1.85), especially for cerebrovascular disease (RR=1.78; 95% CI: 1.14-2.77). In Theme 2, the three sub-studies used the same Hong Kong data as in Theme 1. The first sub-study evaluated the cost and efficiency of routine HLA-B*15:02 screening to prevent CBZ-SJS/TEN. It showed that up to 8,840 persons are need to be screened for HLA-B*15:02 to prevent one death from CBZ-SJS/TEN. The HLA-B*15:02 screening policy is as efficient as other broadly practiced and recommended screening programs, such as mammography and Pap smears for breast and cervical cancer, respectively. The second sub-study evaluated the impact of the HLA-B*15:02 screening policy using data from observed practice in Hong Kong. It reported the CBZ prescription declined from 16.2% (10,077/62,056) in the pre-policy period to 2.6% (1,910/74,606) in the post-policy period (p<0.001). CBZ-SJS/TEN was prevented in the post-policy period, but SJS/TEN induced by phenytoin increased (0.15% [18/11,839] vs. 0.26% [33/12,618], p=0.058) and the overall incidence of AED-induced SJS/TEN remained unchanged (0.09% [42/45,832] vs. 0.07% [39/55,326], p=0.238). Test-prescription practice was adherent to the policy in only 26.4% (1,302/4,929) of relevant patients. By incorporating the findings from the first two sub-studies, the last sub-study estimated the cost-effectiveness of the HLA-B*15:02 screening policy. The current screening policy was associated with an incremental cost-effectiveness ratio (ICER) of US$85,697 per quality adjusted life year (QALY) saved and hence it was not cost-effective. Its cost-effectiveness may be improved by enhancing policy adherence and by low cost point-of-care genotyping. By extending and expanding the newly diagnosed and treated epilepsy patient cohort recruited by the Epilepsy Unit at Western Infirmary in Glasgow since 1982, Theme 3 assessed the long-term outcome of AED therapy. It estimated the probability of achieving seizure freedom for various AED schedules. Despite available of new AEDs with differing mechanisms of action over the last decade, outcomes in newly diagnosed epilepsy have not improved substantially (63.7%) compared to 16 years ago (64.0%). The probability of achieving seizure-free diminishes for each unsuccessful AED schedule.