HLA-B*58:01-Guided Therapy for Gout: Effectiveness, Safety, and Cost-Effectiveness

Official title

A Prospective Interventional Study Comparing Genotype-Guided Therapy Versus Usual Care to Prevent Severe Cutaneous Adverse Reactions Associated With Allopurinol and Carbamazepine in Vietnam

Overview

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), are rare but life-threatening complications that can occur after starting allopurinol for gout. The HLA-B58:01 allele is a strong genetic risk factor for allopurinol-associated SCARs in Asian populations. This study evaluates the feasibility and clinical value of HLA-B58:01 screening before first-time allopurinol use in Vietnamese adults with gout. Adults (≥18 years) diagnosed with gout (ACR/EULAR 2020 criteria) and initiating urate-lowering therapy will be enrolled at Hai Phong International General Hospital (January 2025-June 2027). Participants who undergo HLA-B58:01 genotyping (PCR-based assay) will be treated according to test results: HLA-B58:01 negative participants receive allopurinol; HLA-B58:01 positive participants receive febuxostat. A comparison group consists of patients treated with febuxostat without HLA testing. Participants will be followed for 12 months with assessments at baseline, 1, 3, 6, and 12 months to monitor serum uric acid, gout flares, and safety outcomes (SCARs and other adverse events, including liver and kidney function). The study also includes an economic evaluation to estimate the cost-effectiveness of HLA-B58:01 screening for preventing SCARs and optimizing gout treatment.

Detailed description

Background and rationale: Allopurinol is a first-line urate-lowering therapy for gout but is a leading cause of severe cutaneous adverse reactions (SCARs), including SJS/TEN and DRESS. These reactions carry substantial morbidity, mortality, and healthcare costs. Genetic susceptibility-particularly carriage of HLA-B\*58:01-has been consistently associated with allopurinol-induced SCARs, and pre-treatment HLA screening has reduced SCARs in several Asian settings. However, implementation evidence in Vietnam remains limited. This study is designed to generate local clinical and economic evidence to support an HLA-guided prescribing strategy.

Study objectives:

Describe the prevalence of HLA-B\*58:01 among adult Vietnamese patients with gout initiating allopurinol for the first time.

Compare effectiveness and safety outcomes between an HLA-guided strategy (allopurinol for HLA-B58:01 negative; febuxostat for HLA-B58:01 positive) and a non-tested febuxostat strategy.

Evaluate the cost-effectiveness of HLA-B\*58:01 screening in preventing SCARs and informing treatment selection.

Study setting and timeframe: Single-center study at Hai Phong International General Hospital, Vietnam, from January 2025 to June 2027.

Design overview:

Descriptive cross-sectional component to estimate HLA-B\*58:01 positivity among tested, eligible patients.

Prospective comparative follow-up over 12 months to evaluate real-world effectiveness and safety of urate-lowering strategies.

Cost-effectiveness analysis using direct medical costs.

Participants:

Inclusion criteria include age ≥18 years, gout diagnosis according to ACR/EULAR 2020, first-time indication for allopurinol, and willingness to provide clinical data and undergo HLA testing (for tested groups). Exclusion criteria include prior allopurinol exposure or prior allopurinol hypersensitivity, severe comorbid/complex conditions likely to confound treatment (e.g., end-stage kidney disease, advanced malignancy, bone marrow transplantation, current immunosuppression), or inability to adhere to follow-up.

Interventions/Groups:

Group 1 (HLA-B\*58:01 negative; allopurinol): participants tested negative and start allopurinol.

Group 2 (HLA-B\*58:01 positive; febuxostat): participants tested positive and use febuxostat as an alternative.

Group 3 (No HLA test; febuxostat): participants treated directly with febuxostat without HLA testing.

Procedures and follow-up schedule:

HLA-B\*58:01 genotyping is performed on whole blood using PCR with sequence-specific primers; results are classified as positive or negative.

Follow-up visits at baseline, 1, 3, 6, and 12 months.

Clinical and laboratory monitoring includes serum uric acid and safety labs (AST/ALT, creatinine/eGFR) at predefined time points; gout flare frequency and severity are recorded (including pain assessment using VAS).

SCARs are actively surveilled and clinically diagnosed; supportive laboratory findings include eosinophilia and hepatic/renal involvement when applicable.

Outcome measures:

Genetic outcome: prevalence of HLA-B\*58:01 positivity among tested participants.

Effectiveness outcomes: change in serum uric acid over time; proportion achieving target uric acid control; frequency and severity of gout flares during follow-up.

Safety outcomes: incidence of SCARs (SJS, TEN, DRESS); other adverse events including liver enzyme elevation and renal function deterioration; mild hypersensitivity manifestations (e.g., pruritus, urticaria).

Economic outcomes: direct costs of HLA testing, drug therapy, laboratory monitoring, and SCAR management (hospitalization, medications, procedures, investigations). Cost-effectiveness metrics include the cost per unit of SCAR risk reduction and comparative total costs between strategies.

Sample size considerations:

A descriptive sample size is calculated to estimate HLA-B\*58:01 prevalence, and a comparative sample size is calculated for effectiveness/safety comparisons between allopurinol and febuxostat strategies; the planned comparative cohort is approximately 114 participants per treatment strategy group.

Ethics:

The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Participants provide informed consent; confidentiality is maintained; participants may withdraw at any time without affecting standard clinical care.

Interventions

• Diagnostic test HLA-B*58:01 Genotyping
  Whole-blood sample is collected for HLA-B58:01 genotyping using a PCR-based assay with allele-specific primers. Results are classified as HLA-B58:01 positive or negative and are used to guide urate-lowering therapy selection (allopurinol for negative; febuxostat for positive).
• Drug Allopurinol Tablet
  Oral allopurinol is initiated as urate-lowering therapy in participants who are HLA-B\*58:01 negative. Dosing and titration follow routine clinical practice with consideration of kidney function and serum urate targets. Participants are followed for 12 months with scheduled visits to assess serum urate control, gout flares, and safety outcomes including active surveillance for severe cutaneous adverse reactions (SCARs).
• Drug Febuxostat
  Oral febuxostat is used as an alternative urate-lowering therapy for participants who are HLA-B\*58:01 positive to avoid allopurinol-associated SCAR risk, and for a comparison cohort treated without HLA testing. Participants are followed for 12 months with scheduled visits to evaluate serum urate response, gout flares, and safety (including SCAR surveillance and routine liver/kidney function monitoring).

Primary outcome measures

• Proportion of Participants Achieving Target Serum Uric Acid <5.0 mg/dL (≈300 µmol/L) [Time frame: At Month 12 after initiation of urate-lowering therapy]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years.

Diagnosis of gout according to the 2020 ACR/EULAR classification criteria.

Indicated for initiation of urate-lowering therapy (ULT) and allopurinol-naïve (no prior allopurinol exposure).

Able and willing to comply with scheduled follow-up visits (baseline, Months 1, 3, 6, and 12).

Provides written informed consent for participation.

For the genotyping arms: provides consent for blood sampling and HLA-B\*58:01 genotyping.

Exclusion criteria

• Prior use of allopurinol or history of hypersensitivity reaction to allopurinol.

Known hypersensitivity to febuxostat (for participants who would receive febuxostat).

Current or recent severe skin reaction (suspected/confirmed SCAR) from any cause.

End-stage kidney disease requiring dialysis or kidney transplantation.

Severe hepatic impairment or active severe liver disease (e.g., AST/ALT >3× ULN at baseline).

Severe uncontrolled medical conditions that, in the investigator's judgment, could interfere with treatment or follow-up (e.g., decompensated heart failure, active malignancy requiring intensive treatment).

Use of systemic immunosuppressive therapy (e.g., high-dose corticosteroids, biologics, chemotherapy) at enrollment.

Pregnancy or breastfeeding.

Participation in another interventional clinical study that could affect the outcomes of this study.

Inability to provide informed consent or inability to adhere to study procedures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07369622 · HLA-GOUT-SCARS-2026 · HPMU-HLA-GOUT

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗