Cost-Effectiveness Analysis of HLA-B*5801 Testing in Preventing Allopurinol-Induced SJS/TEN in Thai Population

Background

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), caused by allopurinol therapy, are strongly associated with the human leukocyte antigen (HLA), HLA-B*5801. Identification of HLA-B*5801 genotype before prescribing allopurinol offers the possibility of avoiding allopurinol-induced SJS/TEN. As there is a paucity of evidence about economic value of such testing, this study aims to determine the cost-effectiveness of HLA-B*5801 testing compared with usual care (no genetic testing) before allopurinol administration in Thailand.

Methods and Finding

A decision analytical and Markov model was used to estimate life time costs and outcomes represented as quality adjusted life years (QALYs) gained. The model was populated with relevant information of the association between gene and allopurinol-induced SJS/TEN, test characteristics, costs, and epidemiologic data for Thailand from a societal perspective. Input data were obtained from the literature and a retrospective database analysis. The results were expressed as incremental cost per QALY gained. A base-case analysis was performed for patients at age 30. A series of sensitivity analyses including scenario, one-way, and probabilistic sensitivity analyses were constructed to explore the robustness of the findings. Based on a hypothetical cohort of 1,000 patients, the incremental total cost was 923,919 THB (USD 29,804) and incremental QALY was 5.89 with an ICER of 156,937.04 THB (USD 5,062) per QALY gained. The cost of gout management, incidence of SJS/TEN, case fatality rate of SJS/TEN, and cost of genetic testing are considered very influential parameters on the cost-effectiveness value of HLA-B*5801 testing.

Conclusions

The genetic testing for HLA-B*5801 before allopurinol administration is considered a highly potential cost-effective intervention in Thailand. The findings are sensitive to a number of factors. In addition to cost-effectiveness findings, consideration of other factors including ethical, legal, and social implications is needed for an informed policy decision making.     

Hepatic cytochrome P450 2A6 and 2E1 status in peri-tumor tissues of patients with Opisthorchis viverrini-associated cholangiocarcinoma

Endogenous nitrosation due to chronic inflammation is enhanced in opisthorchiasis and plays a crucial role in the development of cholangiocarcinoma (CCA). Hepatic cytochrome P450 (CYP) family enzymes, especially CYP2A6 and CYP2E1, are involved in the metabolism of procarcinogens; these two enzymes metabolize endogenous nitrosamines to carcinogenic N-dimethylnitrosamine (NDMA). CYP2A6 activity is increased in patients infected with Opisthorchis viverrini. Our aim was to determine whether the expression and function of CYP2A6 and 2E1 in the livers of patients with O. viverrini-associated cholangiocarcinoma (CCA) was altered compared to livers without CCA. Livers of CCA patients (n = 13 cases) showed increased enzyme activities, protein and mRNA levels of CYP2A6 whereas the enzyme activity and protein levels of CYP2E1 were markedly decreased (P < 0.05). CYP2E1 mRNA levels were not altered. Large numbers of inflammatory cells and increased iNOS expression was found in areas adjacent to the tumor. The data provide evidence to support the concept that enhanced CYP2A6 activity and diminished CYP2E1 activity probably involve to the progression of CCA.     

Contamination of Aflatoxins in Herbal Medicinal Products in Thailand

Twenty-eight herbal medicinal products from Thailand were investigated for aflatoxin (AF) contaminations by employing a specific HPLC assay for the determination of AFB1, B2, G1 and G2. The samples were extracted with 80% (v/v) methanol in water before further cleaned up with an immunoaffinity column and followed by the detection of AFs by using an electrochemically post-column derivatization with iodine and fluorescence detector. The extraction procedure was optimized in order to obtain the best recovery. The method was successfully carried out with all the herbal products diversified as to compositions and dosage forms. The results revealed that five (18%) of herbal samples were contaminated with detectable amount of the total AFs ranging from 1.7 to 14.3 ng/g. The association between particular herbal/plant and the AF contaminated could not be determined due to the low frequency of positive samples. The contaminated products were those in tablet (4) and capsule (1) dosage forms. It was possible that the original fungal infection of these products may have been derived from either the crude herbal or other ingredients making these preparations, such as starch. In conclusion, none of the AF contaminated level found was above the current legislative level permissible in Thailand (20 ng/g). A word of caution, however, exporting some high AF-contaminated herbal products to countries where more stringent permissable level of aflatoxins exist could result in trade Barriers.     

Inhibition selectivity of grapefruit juice components on human cytochromes P450

Five compounds including furanocoumarin monomers (bergamottin, 6', 7'-dihydroxybergamottin (DHB)), furanocoumarin dimers (4-??6-hydroxy-71-?(1-hydroxy-1-methyl)ethyl-4-methyl-6-(7-oxo-7H- furo?3,2-g1benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl- 2-octenyl]oxy]-7H-furo[3,2-g]?1benzopyran-7-one (GF-I-1) and 4-??6-hydroxy-7??4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo?3, 2-g1benzopyran-4-yl)-4-hexenyl?xy-3, 7-dimethyl-2-octenyl?xy-7H-furo?3,2-g1benzopyran-7-one (GF-I-4)), and a sesquiterpene nootkatone have been isolated from grapefruit juice and screened for their inhibitory effects toward human cytochrome P450 (P450) forms using selective substrate probes. Addition of ethyl acetate extract of grapefruit juice into an incubation mixture resulted in decreased activities of CYP3A4, CYP1A2, CYP2C9, and CYP2D6. All four furanocoumarins clearly inhibited CYP3A4-catalyzed nifedipine oxidation in concentration- and time-dependent manners, suggesting that these compounds are mechanism-based inhibitors of CYP3A4. Of the furanocoumarins investigated, furanocoumarin dimers, GF-I-1 and GF-I-4, were the most potent inhibitors of CYP3A4. Inhibitor concentration required for half-maximal rate of inactivation (K(I)) values for bergamottin, DHB, GF-I-1, and GF-I-4 were calculated, respectively, as 40.00, 5. 56, 0.31, and 0.13 microM, whereas similar values were observed on their inactivation rate constant at infinite concentration of inhibitor (k(inact), 0.05-0.08 min(-1)). Apparent selectivity toward CYP3A4 does occur with the furanocoumarin dimers. In contrast, bergamottin showed rather stronger inhibitory effect on CYP1A2, CYP2C9, CYP2C19, and CYP2D6 than on CYP3A4. DHB inhibited CYP3A4 and CYP1A2 activities at nearly equivalent potencies. Among P450 forms investigated, CYP2E1 was the least sensitive to the inhibitory effect of furanocoumarin components. A sesquiterpene nootkatone has no significant effect on P450 activities investigated except for CYP2A6 and CYP2C19 (K(i) = 0.8 and 0.5 microM, respectively).