G6PD Deficiency at Sumba in Eastern Indonesia Is Prevalent, Diverse and Severe: Implications for Primaquine Therapy against Relapsing Vivax Malaria

Abstract

Safe treatment of Plasmodium vivax requires diagnosis of both the infection and status of erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity because hypnozoitocidal therapy against relapse requires primaquine, which causes a mild to severe acute hemolytic anemia in G6PD deficient patients. Many national malaria control programs recommend primaquine therapy without G6PD screening but with monitoring due to a broad lack of G6PD deficiency screening capacity. The degree of risk in doing so hinges upon the level of residual G6PD activity among the variants present in any given area. We conducted studies on Sumba Island in eastern Indonesia in order to assess the potential threat posed by primaquine therapy without G6PD screening. We sampled 2,033 residents of three separate districts in western Sumba for quantitative G6PD activity and 104 (5.1%) were phenotypically deficient (<4.6U/gHb; median normal 10U/gHb). The villages were in two distinct ecosystems, coastal and inland. A positive correlation occurred between the prevalence of malaria and G6PD deficiency: 5.9% coastal versus inland 0.2% for malaria (P<0.001), and 6.7% and 3.1% for G6PD deficiency (P<0.001) at coastal and inland sites, respectively. The dominant genotypes of G6PD deficiency were Vanua Lava, Viangchan, and Chatham, accounting for 98.5% of the 70 samples genotyped. Subjects expressing the dominant genotypes all had less than 10% of normal enzyme activities and were thus considered severe variants. Blind administration of anti-relapse primaquine therapy at Sumba would likely impose risk of serious harm.

Validation of the rapid test Carestart(tm) G6PD among malaria vivax-infected subjects in the Brazilian Amazon

“…Although a previous study on the Cambodian population found that G6PDd was associated with lower hemoglobin levels (33) , we could discern no clear relationship between G6PDd and hemoglobin levels in the present study. However, in another study, Satyagraha et al (34) found that G6PDd was associated with higher hemoglobin levels, whereas, in contrast, other studies have found no correlation between G6PDd and hemoglobin levels (35) (36) .…”

Epidemiology of Plasmodium vivax in Indonesia

“…This hugely diverse X-linked disorder is highly prevalent among many of Indonesia's hundreds of ethnic groups. The relative sensitivity to primaquine among any of these is not known, but threatening hemolytic reactions to primaquine therapy are widely known by anecdote in Indonesia 8. In the absence of the ability to screen patients for G6PDd where most malaria patients live, Ministry of Health policy recommends a relatively low dose of primaquine, but many providers fail to offer even that for fear of causing harm.…”

Malaria diagnosis for malaria elimination

“…Aspects of malaria diagnosis beyond the focus of this review include monitoring antimalarial drug resistance markers and developing products to assess glucose-6-phosphate dehydrogenase deficiency (G6PDd) to improve safety of primaquine (and ultimately tafenoquine) treatment of P. vivax and P. ovale hypnozoites. The Worldwide Antimalarial Resistance Network (http://www.wwarn.org) and recent publications by Domingo et al [6] and Satyagraha et al [7] on testing for G6PDd provide excellent material on these topics. by reduction of annual parasite incidence (API) (Control areas: API !5 cases/1000 population; Preelimination: API < 5/1000; Elimination: API < 1/ 1000; Prevention of Reintroduction: zero locally acquired cases; WHO Certification after three years of sustained zero local transmission [10 && ,13 && ]).…”