Background/Purpose: Allopurinol is the leading choice of urate-lowering therapy (~ 95%) for gout which affects 8.3 million US adults. However, allopurinol is associated with a rare but potentially fatal reaction: allopurinol hypersensitivity syndrome (AHS). Studies have shown that HLA-B5801 allele carriage and renal impairment are strongly associated with AHS, suggesting utility of considering these factors in treatment decisions to prevent AHS and AHS-related deaths.  We examined the cost-effectiveness of HLA-B5801 genotyping and renal dosing in preventing AHS and AHS-related deaths.

Methods: We built a decision model to compare 4 treatment strategies for 1 million hypothetical patients starting allopurinol in the US.  All key parameters and costs were derived from the literature, including the risk of AHS: 0.163%, the risk of death among AHS cases: 26%, the probabilities of HLA-B5801 allele carriage: 0.01 (Caucasians) and 0.07 (Asians), relative risk (RR) of AHS among HLA-B5801 positive patients: 96.6, sensitivity for predicting AHS by renal dosing: 90% [1], HLA-B5801 genotyping cost: $45.11 and the average AHS hospitalization cost: $50,152. Sensitivity analyses were conducted by varying the risk of AHS, RR of AHS among HLA-B5801 positive patients, sensitivity for predicting AHS by renal dosing, and AHS hospitalization cost.

Results: Initiating treatment in all patients with the standard dose resulted in 1630 AHS cases and 424 AHS related deaths. Compared with the standard dose strategy, the combined use of HLA-B5801 genotyping and renal dosing prevented 95% of AHS cases and AHS-related deaths, and saved $32,500,684. It led to incremental cost-effectiveness ratios (ICERs) of -$21,009 per AHS case avoided and -$80,647 per death avoided among Caucasians (i.e., cost-saving).  Compared with renal dosing alone, the combined use of HLA-B5801 genotyping and renal dosing avoided 80 more AHS cases and 21 more AHS-related deaths at an incremental cost of $41,072,740, resulting in ICERs of $513,409 per AHS case avoided and $1,955,845 per death avoided among Caucasians. The corresponding effectiveness and ICERs were more favorable among Asians (Table). Sensitivity analyses suggested the results were robust to variation in these model parameters.

Conclusion: The combined use of the HLA-B5801 genotyping and renal dosing of the starting dose of allopurinol was able to avert the majority of AHS cases and AHS-related deaths.  The ICERs were especially favorable among Asians due to a higher probability of HLA-B5801 allele carriage. Since renal dosing was responsible for the majority of the reduction of AHS and AHS-related deaths at no incremental costs, this strategy alone was the most cost-effective.  However, the combined use of the HLA-B5801 genotyping and renal dosing was considered cost-effective given that $7 million in the US is the median acceptable cost per life saved [2]. 

Table  Results of the Base Case Analysis*
Population	Strategy	Incremental cost (per million patients)	AHS		Death
			Cases avoided	ICER (per case)	Deaths avoided	ICER (per death)
Compared with the standard starting dose for all patients strategy
US Caucasians	1. Standard starting dose (300mg/day) for all patients	–	–	–	–	–
	2. Renally-adjusted starting dose (1.5 mg allopurinol per unit eGFR (mg/ml/min)) for all patients	-$73,573,424	1467	-$50,152	382	-$192,601
	3. Standard starting dose for HLA-B5801 negative patients	$4,737,399	805	$5,885	209	$22,667
	4. Renally-adjusted starting dose for HLA-B5801 negative patients	-$32,500,684	1547	-$21,009	403	-$80,647
US Asians	1. Standard starting dose for all patients	–	–	–	–	–
	2. Renally-adjusted starting dose for all patients	-$73,573,424	1467	-$50,152	382	-$192,601
	3. Standard starting dose for HLA-B5801 negative patients	-$26,754,490	1433	-$18,670	373	-$71,728
	4. Renally-adjusted starting dose for HLA-B5801 negative patients	-$35,649,873	1610	-$22,143	419	-$85,083
Compared with the renally-adjusted starting dose for all patients strategy
US Caucasians	2. Renally-adjusted starting dose for all patients	–	–	–	–	–
	4. Renally-adjusted starting dose for HLA-B5801 negative patients	$41,072,740	80	$513,409	21	$1,955,845
US Asians	2. Renally-adjusted starting dose for all patients	–	–	–	–	–
	4. Renally-adjusted starting dose for HLA-B5801 negative patients	$37,923,551	143	$265,200	37	$1,024,961
*Negative dollar amounts = cost-saving References: [1] Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, Dalbeth N. Starting dose is a risk factor for allopurinol hypersensitivity   syndrome: A proposed safe starting dose of allopurinol. Arthritis Rheum. 2012 Apr 5. doi: 10.1002/art.34488 [2]  W. Kip Viscusi. The value of life. The Harvard John M. Olin Discussion Paper Series. 2005. http://www.law.harvard.edu/programs/olin_center/papers/pdf/Viscusi_517.pdf

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/utility-of-hla-b5801-genotyping-and-renal-dosing-of-the-starting-dose-of-allopurinol-in-preventing-allopurinol-hypersensitivity-syndrome-a-cost-effectiveness-analysis/