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. 2024 Sep 5;18(9):e0012486. doi: 10.1371/journal.pntd.0012486

Table 1. Sources of evidence and parameter values used to inform the linked-evidence model.

Question Evidence and Source Parameter name in model & distribution [low, high]a
1. Is there direct evidence that using a qualitative G6PD test reduces P. vivax infections in the 6 months following treatment? No direct evidence exists
2. What is the prevalence of G6PD activity <30% of AMM in the target group? Estimated median G6PDd allele frequency in malaria endemic countries is 8.0%, with marked variability in country-specific estimates from <0.5% to >20% [8].
 (a) What proportion of males have G6PD activity <30% of AMM?

  • 1.0% at 1% G6PDd allele frequency

  • 5.0% at 5% G6PDd allele frequency

  • 10.0% at 10% G6PD allele frequency [7]

 Dist [14] ~ Dirichlet

  • Dirichlet(97.0;2.0;1.0)

  • Dirichlet(93.0;2.0;5.0)

  • Dirichlet(88.1;1.9;10.0)
 (b) What proportion of females have G6PD activity <30% of AMM?

  • 0.2% at 1% G6PDd allele frequency

  • 1.1% at 5% G6PDd allele frequency

  • 2.5% at 10% G6PDd allele frequency [7]

 Dist [14] ~ Dirichlet

  • Dirichlet(93.0;6.8;0.2)

  • Dirichlet(87.6;11.3;1.1)

  • Dirichlet(80.6;16.9;2.5)
3. Can G6PD tests be used to accurately classify G6PD activity? The majority of studies assessing the performance of near-patient G6PD tests use ultraviolet spectrophotometry as the reference diagnostic method. Evidence shows that the G6PD activities reported by spectrophotometry are site-specific and subject to inter-replicate, and intra- and inter-laboratory variability [16].
Variations in repeatability could result in misclassification of individuals, the magnitude of which is dictated by the proportion of individuals with G6PD activity near the classification threshold. However, in the absence of a perfect test to assess G6PD activity, it is assumed that the rate of misclassification using spectrophotometry is negligible.
 (a) What is the sensitivity of qualitative G6PD tests at <30% G6PD activity? Estimate from systematic review and meta-analysis of the lateral flow assay from Access Bio/CareStart (8 studies): 0.96 (95% CI 0.90–0.99) [17]. G6PD_sn ~ Beta(112.0,7.0)
[0.75–1.00]
 (b) What is the specificity of qualitative G6PD tests at <30% G6PD activity? Estimate from systematic review and meta-analysis of the lateral flow assay from Access Bio/CareStart (8 studies): 0.95 (95% CI 0.92–0.96) [17]. G6PD_sp ~ Beta(279.8, 10.9)
[0.90–1.00]
4. Does treatment with PQ result in fewer future P. vivax infections? Meta-analysis (23 studies from 16 countries) revealed mean incidence rate of P. vivax recurrences between days 7 and 180 post-treatment was 1.84 recurrences per person-year (95% CI 1.74–1.95) in patients not receiving PQ [18]. Recur_no_pq ~ Norm(1.844, 0.055)/2
[0.75–1.00]
 (a) Does treatment with 0.25 mg/kg PQ daily for 14 days reduce P. vivax infections in the next 6 months? (Total PQ dose of 3.5 mg/kg) Meta-analysis (23 studies from 16 countries) revealed mean incidence rate of P. vivax recurrences between day 7 and 180 post-treatment was 0.47 recurrences per person-year (95% CI 0.42–0.52) in patients receiving a total dose of 2—<5 mg/kg PQ [18]. Recur_pq ~ Norm(0.470, 0.025)/2
[0.20–0.275]
 (b) Does treatment with 0.50 mg/kg PQ daily for 7 days reduce P. vivax infections in the next 6 months? (Total PQ dose of 3.5 mg/kg) See 4(a) above.
Systematic review found no difference in P. vivax recurrences at six to seven months post-treatment for 0.5 mg/kg/day for seven days compared to 0.25 mg/kg/day for 14 days [19].
 (c) Does treatment with 0.75 mg/kg PQ weekly for 8 weeks reduce P. vivax infections in the next 6 months? Multi-centre clinical trial (four countries) showed reduced risk of recurrence 12-months following treatment: incidence rate 0.047 per person-year (95% CI 0.012–0.187, n = 50) vs 1.32 per person-year (95% CI 1.15–1.48, n = 464) for placebo [20]. However, patient distribution between study sites differed for patients receiving 8-wk PQ and placebo, with study sites having different relapse periodicity and annual parasite index. Results are not comparable to recurrence rate for 7- or 14-day PQ, or no PQ, reported in row 4 and 4(a) above due to different follow-up period and no statistical adjustment for potential confounders. Recur_8wk_pq ~ Norm(0.785, 0.032)/2
[0.20–1.00]
5. What are the consequences of not having access to near patient G6PD testing? Local policy is applied.
In the model this is 14-day PQ without G6PD testing.
6. Does treatment result in adverse effects, specifically severe haemolysisb?
 (a) What is the rate of severe haemolysis following treatment with 0.25 mg/kg PQ daily for 14 days in individuals with normal G6PD activity? For patients with G6PD activity > 30%, meta-analysis (18 studies from 15 countries) revealed incidence of severe haemolysis was 0.0% (0/893; 95% CI 0.0–0.4%) [21] Hem_risk_n_low ~ Beta(1,893)
[0.00–0.004]
 (b) What is the rate of severe haemolysis following treatment with 0.5 mg/kg PQ daily for 7 days in individuals with normal G6PD activity? For patients with G6PD activity > 30%, meta-analysis (18 studies from 15 countries) revealed incidence of severe haemolysis was 0.3% (5/1464; 95% CI 0.1–0.8%) [21] Hem_risk_n_mod ~ Beta(5,1459)
[0.00–0.008]
 (c) What is the rate of severe haemolysis following treatment with 0.75 mg/kg PQ weekly for 8 weeks in individuals with normal G6PD activity? Limited data. No severe haemolysis detected in 9 Indonesian patients with (measured) G6PD activity >30% AMM [20].
 (d) What is the rate of severe haemolysis following treatment with 0.25 mg/kg PQ daily for 14 days in individuals with deficient G6PD activity? A review of 20 studies that included confirmed G6PD-deficient individuals indicated 11.2% (27/241) of G6PD-deficient individuals experienced severe adverse events following daily PQ, but PQ dosage was not specified [3]. Most severe adverse events were haemolysis, with or without a requirement for blood transfusion and results were across different PQ dosing regiments. Hem_risk_d_low ~ Beta(27,241)
[0.05–0.25]
 (e) What is the rate of severe haemolysis following treatment with 0.5 mg/kg PQ daily for 7 days in individuals with deficient G6PD activity? See 6(d) above Hem_risk_d_mod ~ Beta(20,80)
[0.10–0.50]
 (f) What is the rate of severe haemolysis following treatment with 0.75 mg/kg PQ weekly for 8 weeks in individuals with deficient G6PD activity? Overall incidence of severe adverse events following single or weekly PQ doses (irrespective of G6PD status) was 0.42% (16/3,771) (95% CI 0.22–0.63) [3]. Likely that all adverse events occurred in G6PD-deficient individuals, however the number of G6PD-deficient patients within the studies is unknown so no incidence rate can be calculated.
No severe adverse events following weekly PQ amongst 41 patients (4 countries) who were G6PD deficient according to fluorescent spot test and had confirmed G6PD activity <30% AMM or did not have G6PD activity measured [20].		 Hem_risk_d_8wk ~ Beta(1,99)
[0.00–0.04]

a Distributions have means and 2.5th and 97.5th percentiles that match mean and 95% confidence intervals reported in literature; low and high values included only for variables included in one-way sensitivity analysis

b Severe haemolysis is defined as a haemoglobin reduction of more than 25% to a concentration <7 g/dL between day 0 and days 1–14 post-treatment

AMM: Adjusted male-median