Evaluating the safety of malaria treatment in glucose-6-phosphate dehydrogenase-deficient individuals: evidence and tools to support malaria elimination

There have been remarkable achievements in the global fight against malaria over the past decade, with a growing number of countries moving towards malaria elimination. Sustaining these gains and eliminating malaria will require the right set of interventions and strategies that target the entire Plasmodium falciparum (P. falciparum) parasite reservoir, including both the mosquito vector and the human host. Primaquine is the only available drug that clears mature P. falciparum gametocytes in humans, thereby preventing transmission to the mosquito vector. However, the drug’s oxidative capacity to cause hemolytic effects in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, has limited its deployment because of safety concerns. G6PD deficiency is an X-linked enzyme defect that affects over 400 million people worldwide and is relatively common in malaria endemic areas. To reduce P. falciparum malaria transmission in eliminating settings and areas threatened by artemisinin resistance, the World Health Organization (WHO) recommends adding a 0.25 mg/kg dose of primaquine, lowered from a previously higher 0.75 mg/kg dose, to standard artemisinin-based combination therapy (ACT) without G6PD testing. This policy change, issued in 2012, was based on data gathered passively from limited pharmacovigilance systems and lacks substantive evidence to support the safety of the recommendation. The objective of this dissertation was to evaluate the safety of malaria treatment in G6PD-deficient individuals and contribute evidence to support the programmatic use of primaquine for falciparum malaria. The study designs and populations presented in this dissertation include: 1) a secondary analysis of data from a double-blind, placebo-controlled trial of preventive antimalarial treatment in asymptomatic infants (n = 1557) in Tanzania (Chapter 1); 2) a pilot study evaluating a pharmacovigilance safety monitoring tool for the rollout of single low-dose primaquine among confirmed, uncomplicated malaria cases (n = 102) in Swaziland (Chapter 2); and 3) a pooled analysis of individual-level patient data in malaria-infected patients (n = 604) from two randomized controlled trials in Senegal and Tanzania and two active pharmacovigilance programs in Bangladesh and Swaziland (Chapter 3). In the trial of asymptomatic infants in Tanzania, findings demonstrated that treatment with an antimalarial drug known to have oxidative potential like primaquine reduced hemoglobin levels at 7 and 14 days post-treatment, relative to placebo and other antimalarial treatments. Also, at day 7, G6PD deficiency was associated with higher odds of moderate anemia (hemoglobin <8 g/dL) and greater absolute reductions in hemoglobin. However, there was no evidence that G6PD deficiency exacerbated the adverse effects of oxidative treatment. Measuring the risk of adverse effects in G6PD-deficient individuals associated with oxidative treatment is challenging due to limited data.The pilot study of the Primaquine Roll Out Monitoring Pharmacovigilance Tool (PROMPT) served to facilitate the systematic collection of primaquine safety data. Results illustrated the feasibility and acceptability of implementing active safety monitoring to support surveillance of possible adverse events, including clinically important drops in hemoglobin, following primaquine treatment. Data that include sufficient G6PD-deficient individuals through the wider adoption of PROMPT can allow for pooled analyses powered to reliably detect statistically significant increased risks of hemolysis.In the pooled analysis of data collected using PROMPT, results supported the addition of a single dose of 0.25 mg/kg primaquine to ACT in the treatment of uncomplicated P. falciparum malaria. An analysis of randomized clinical trial data among G6PD-deficient individuals found that the addition of 0.25 mg/kg primaquine to ACT did not significantly increase risk of hemolysis. An analysis using all available data showed that falls in hemoglobin following treatment appeared greater in G6PD-deficient individuals compared to G6PD-normal individuals but that doses ≤0.5 mg/kg, (double the WHO recommended 0.25 mg/kg dose) did not result in greater hemolysis in G6PD-deficient versus G6PD normal individuals. Taken together, the studies outlined in this dissertation serve to better characterize the safety profile of primaquine to support its safe use as a gametocytocide for P. falciparum malaria elimination