Plasmodium vivax relapses contribute to about half of all the malaria cases reported annually in India1. It has unique feature of causing relapses due to persistent liver stages of the parasite (hypnozoites), which makes control of vivax malaria challenging. Relapse rates of up to 40% have been reported from different parts of India2-3. In vivax malaria, relapses are known to dominate over the primary attacks4 and if 65% of vivax malaria cases are treated with antirelapse therapy, elimination would be possible in a decade5.

Currently, primaquine is the only registered and marketed antirelapse agent; however, it is known to cause haemolysis in G6PD deficient individuals6-7. For targeted malaria elimination, it is important to administer prima-quine in safe and effective doses in all the vivax malaria cases to prevent relapses. We present a case of vivax ma-laria with G6PD deficiency, in which primaquine was administered weekly in WHO recommended dosage. Weekly primaquine was found to be safe in G6PD de-ficient patient, and there were no clinical or laboratory manifestations of haemolysis.

Case ReportA 23-yr-old male patient reported to malaria clinic at

the National Institute of Malaria Research, New Delhi, with positive laboratory report for P. vivax malaria. He was referred by a physician for deciding the line of treat-ment, since he was G6PD deficient. Blood smear was pos-itive for P. vivax malaria with parasite count of 12,960/µl. He was treated with chloroquine (10 mg/kg on Day 0 and 1; and 5 mg/kg on Day 2). He had three episodes of vivax malaria within a period of six months (Fig. 1). His G6PD level was 1.27 U/g of haemoglobin, around 26% of the lower limit of normal range (4.60–13.50 U/g) of G6PD. Primaquine was not prescribed to him during the previous episodes due to G6PD deficiency.

To prevent further relapses, the patient was advised primaquine in the dose of 0.75 mg/kg body weight every week for 8 wk as per WHO guidelines, which considers it as a safe regimen in G6PD deficiency, under supervi-sion of a physician. Before administering primaquine, haemoglobin level was 13.9 g (at baseline) which dropped to 12.9 on Day 7 of administration. It recovered by third week (Fig. 2). There were no adverse events like nau-sea, pain in abdomen, dark coloured urine or significant fall of haemoglobin after administering primaquine. Compliance to weekly primaquine was ensured by making phone calls. After completion of primaquine course for 8 wk, no episode of clinical malaria occurred for one year.

J Vector Borne Dis 54, September 2017, pp. 287–290

Fig. 1: Days to relapse before primaquine therapy.

Fig. 2: Hb levels following primaquine therapy.

Case Reports

Safety of weekly primaquine in G6PD deficient patient with relapsing vivax malaria: A case report

Deepali Savargaonkar, Md. Zohaib Ahmed, Anupkumar R. Anvikar & Neena Valecha

ICMR-National Institute of Malaria Research, New Delhi, India

Key words G6PD deficiency; Plasmodium vivax; primaquine; relapse

J Vector Borne Dis 54, September 2017288

G6PD genotyping was carried out8-9 using PCR-RFLP followed by sequencing. The results were analysed with BLAST tool (G6PD accession no. NM_001042351.2, http://ensembl.org) which confirmed the absence of three mutations, i.e. G6PD Mediterranean, G6PD Oris-sa and G6PD Kerala Kalyan, that are common in India8 (Fig. 3). However, due to lack of sufficient blood sample, further investigation of G6PD mutation by exon-wise PCR and nucleotide sequencing could not be performed.

DISCUSSION

Plasmodium vivax relapses contribute to a signifi-cant burden of malaria in India. The national antimalarial drug policy of India recommends use of primaquine at dose of 0.25 mg/kg daily for 14 days for preventing re-lapses. However, it is contra-indicated in G6PD deficient individuals due to its haemolytic potential10. Primaquine can cause haemolysis in G6PD deficient individuals and even in heterozygous females with G6PD levels 40–60% of normal6,11-12. As suitable point of care test for G6PD is not available, many practitioners are reluctant to pre-scribe primaquine due to risk of haemolysis in G6PD de-ficient patients13. The Indian national treatment guidelines also recommends primaquine without testing for G6PD but with educating the patient regarding the warning sig-nals of haemolysis and after weighing risks vs benefits of treatment14.

In this report, a case of relapsing vivax malaria with G6PD deficiency is reported. The patient had three epi-sodes of malaria in last six months, i.e. relapses were ob-served, 4, 5 and 6 months after the primary episode of malaria (Fig. 1). The relapses occurred in the months of January, February and March 2015. These months have been reported as the months of relapse through a transmis-sion model5.

In India, frequent as well as long latency relapses have been reported2, 15. WHO has advised use of weekly primaquine as antirelapse therapy in patients with G6PD deficiency. This weekly treatment should be given un-der medical supervision and patient should have access to health facility with facilities for blood transfusion16. Primaquine in the dose of 0.75 mg weekly is safe and effective in preventing relapse, since the total dose of primaquine administered matters instead of per dose strength17-18. There are no reports from India regarding haemolysis due to weekly primaquine therapy in G6PD deficiency. A review of risks and benefits of primaquine mentions that the incidence of serious adverse events with primaquine therapy in known G6PD deficient patients was 11.2%, but a majority of these received a daily dose

Fig. 3: Ethidium bromide stained 3% agarose gel showing the re-striction enzyme digested amplified products in three com-mon G6PD mutations. Lane 1 sample lacks the digestion site and produced —(a) 377 and 198 bp products in exon 6/7 with MboII; (b) 107, 75 and 66 bp products with HaeIII; and (c) 74 and 60 bp products with MnlI restriction enzymes respective-ly. However, Lane 2 (Control) produced—(a) 277, 119 and 100 bp products in exon 6/7; (b) 123, 107 and 66 bp products in exon 3/4; and (c) 80 and 60 bp products in exon 9 upon digestion. M1, M2 and M3—Molecular markers of size 100, 50 and 20 bp respectively; U—Undigested product [575 bp in (a), 352 bp in (b), and 275 bp in (c)]; 1—Patient sample DNA; 2—G6PD deficient controls.

(c)

M1 M2 U 1 2 M3

(a)

M1 U 1 2 M2

M1 U 1 2 M2(b)

575 bp

377 bp277 bp

198 bp119 bp100 bp

352 bp

123 bp107 bp75 bp66 bp

275 bp

80 bp74 bp60 bp

289Savargaonkar et al: Weekly primaquine in G6PD deficient patient

of primaquine19. The drug induced haemolysis in G6PD deficient patient can be related to the variant of G6PD, dose and duration of the medicine, disease factors and patient factors like anaemia20. The patient in this case had a mild G6PD deficiency, low parasite count and was not anaemic, and received a weekly dose; hence, there was no significant fall in haemoglobin.

Globally, few studies have reported safety21 and ef-ficacy of primaquine weekly dose22 in G6PD deficient subjects. From India, this is the first reporting on safety of weekly dose of primaquine in a patient of vivax malaria with G6PD deficiency. The patient belongs to Rajasthan, where G6PD deficiency has been reported up to 11.25%23.

In India, the reported G6PD deficiency prevalence is 0–27% and the common genetic variants are: G6PD Mediterranean (60.4%), G6PD Orissa (24.5%) and G6PD Kerala Kalyan (13.3%)8, 24. About half the malaria cases in India are due to P. vivax, and relapses contribute to a significant number. G6PD deficiency of up to 27%, cou-pled with non-availability of suitable point of care G6PD test creates dilemma in prescribing primaquine without G6PD testing.

In this case, though patient was G6PD deficient, weekly primaquine (0.75 mg/kg) was well tolerated and no episode of haemolysis was observed as Hb levels were within normal limits. Primaquine has shorter half life (t ½ ~ 5 h), and even if haemolysis occurs, it is self limiting19. There is need of generating more data to assess the safety of weekly primaquine in malaria patients with G6PD de-ficiency. This will help in developing confidence among practitioners for prescribing primaquine in such patients.

This case report demonstrates the safety of weekly primaquine in G6PD deficient patient and highlights the need of studying safety of primaquine, 0.75 mg/week in more number of cases which will help in guiding the na-tional policy.

ACKNOWLEDGEMENTS

The authors thank the National Institute of Malaria Research (NIMR), New Delhi for providing laboratory facilities. Help from the staff of Malaria Clinic of NIMR is also acknowledged. Thanks are also due to the National Institute of Immunohematology, Mumbai, India for pro-viding training on G6PD genotyping.

Conflict of interestThe authors declare that there is no conflict of

interests.Ethical statement: Verbal consent was obtained from

patient for weekly primaquine therapy and publication.

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Correspondence to: Dr. Deepali Savargaonkar, Scientist ‘C’, ICMR–National Institute of Malaria Research, Sector–8, Dwarka, New Delhi–110 077, India. E-mail: doctor_deepali@rediffmail.com

Received: 30 April 2017 Accepted in revised form: 27 July 2017