Safety of single low-dose primaquine in glucose-6-phosphate dehydrogenase deficient falciparum-infected African males: Two open-label, randomized, safety trials

Abstract

Background: Primaquine (PQ) actively clears mature Plasmodium falciparum gametocytes but in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals can cause hemolysis. We assessed the safety of low-dose PQ in combination with artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP) in G6PDd African males with asymptomatic P. falciparum malaria.

Methods and findings: In Burkina Faso, G6PDd adult males were randomized to treatment with AL alone (n = 10) or with PQ at 0.25 (n = 20) or 0.40 mg/kg (n = 20) dosage; G6PD-normal males received AL plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. In The Gambia, G6PDd adult males and boys received DP alone (n = 10) or with 0.25 mg/kg PQ (n = 20); G6PD-normal males received DP plus 0.25 (n = 10) or 0.40 mg/kg (n = 10) PQ. The primary study endpoint was change in hemoglobin concentration during the 28-day follow-up. Cytochrome P-450 isoenzyme 2D6 (CYP2D6) metabolizer status, gametocyte carriage, haptoglobin, lactate dehydrogenase levels and reticulocyte counts were also determined. In Burkina Faso, the mean maximum absolute change in hemoglobin was -2.13 g/dL (95% confidence interval [CI], -2.78, -1.49) in G6PDd individuals randomized to 0.25 PQ mg/kg and -2.29 g/dL (95% CI, -2.79, -1.79) in those receiving 0.40 PQ mg/kg. In The Gambia, the mean maximum absolute change in hemoglobin concentration was -1.83 g/dL (95% CI, -2.19, -1.47) in G6PDd individuals receiving 0.25 PQ mg/kg. After adjustment for baseline concentrations, hemoglobin reductions in G6PDd individuals in Burkina Faso were more pronounced compared to those in G6PD-normal individuals receiving the same PQ doses (P = 0.062 and P = 0.022, respectively). Hemoglobin levels normalized during follow-up. Abnormal haptoglobin and lactate dehydrogenase levels provided additional evidence of mild transient hemolysis post-PQ.

Conclusions: Single low-dose PQ in combination with AL and DP was associated with mild and transient reductions in hemoglobin. None of the study participants developed moderate or severe anemia; there were no severe adverse events. This indicates that single low-dose PQ is safe in G6PDd African males when used with artemisinin-based combination therapy.

Trial registration: Clinicaltrials.gov NCT02174900 Clinicaltrials.gov NCT02654730.

Fig 1

Clinical trial profile for Burkina Faso (A) and The Gambia (B). Abbreviations: AL, artemether-lumefantrine; G6PD, glucose-6-phosphate dehydrogenase; PQ, primaquine; DP, dihydroartemisinin-piperaquine.

Fig 2

Hemoglobin levels during 28-day follow-up Burkina Faso (A) and The Gambia (B). Hemoglobin concentrations (g/dL) during follow-up are expressed relative to that at enrolment for each individual (grey dotted lines) and for each treatment group (colored lines). Abbreviations: 0M, day 0 morning; 0A, day 0 afternoon, etc.; Hb, hemoglobin; G6PD, glucose-6-phosphate dehydrogenase; PQ, primaquine; AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine.

Fig 3

Absolute changes in hemoglobin levels during 28-day follow-up for Burkina Faso (A) and The Gambia (B). Hemoglobin concentrations (g/dL) on days 3, 7, 14 and 28 during follow-up are expressed relative to that at enrolment for each treatment group. Asterisks indicate a statistically significant reduction compared to baseline by repeated measures mixed models. Abbreviations: Hb, hemoglobin; G6PD, glucose-6-phosphate dehydrogenase; PQ, primaquine.

Fig 4

Absolute reticulocyte counts during 28-day follow-up for Burkina Faso (A) and The Gambia (B). Absolute reticulocyte counts (x10³/μL) during follow-up are expressed relative to that at enrolment for each individual (grey dotted lines) and for each treatment group (colored lines). The value not displayed in the G6PD-deficient 0.40 mg/kg PQ group was 216 x10³/μL. Abbreviations: 0M, day 0 morning; 0A, day 0 afternoon, etc.; G6PD, glucose-6-phosphate dehydrogenase; PQ, primaquine; AL, artemether-lumefantrine; DP, dihydroartemisinin-piperaquine.

Fig 5. Haptoglobin, lactate dehydrogenase (LDH) and total bilirubin levels as parameters of hemolysis during follow-up in Burkina Faso.

Each individual represents one vertical column. Abnormal levels were defined as: haptoglobin <0.3 g/L; LDH ≥250 U/L; total bilirubin ≥20.53 μmol/L. Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; PQ, primaquine; AL, artemether-lumefantrine.