Effect of weekly versus daily primaquine on Plasmodium vivax malaria recurrences: A real-life cohort study

ABSTRACT

Background:

Although primaquine (PQ) is indicated for G6PD-deficient patients, data on weekly PQ use in Brazil are limited.

Methods:

We aimed to investigate malaria recurrences among participants receiving daily and weekly PQ treatments in a real-life setting of two municipalities in the Amazon between 2019 and 2020.

Results:

Patients receiving weekly PQ treatment had a lower risk of recurrence than those receiving daily PQ treatment (risk ratio: 0.62, 95% confidence interval: 0.41-0.94), using a model adjusted for study site.

Conclusions:

Weekly PQ use did not increase the risk of malaria recurrence. Further studies with larger populations are warranted.

Keywords:
Weekly primaquine; Recurrences; Brazilian Amazon; Elimination; G6PD deficiency

A great challenge to the elimination of Plasmodium vivax malaria has been imposed by glucose 6-phosphate dehydrogenase deficiency (G6PDd) in malaria-endemic areas¹. The use of 8-aminoquinolines, such as primaquine (PQ) and tafenoquine (TQ), which are required for the radical cure of P. vivax malaria, is associated with severe and often life-threatening hemolysis, even in patients with enzymatic variants that are considered to be mild to moderate^2,3. A weekly PQ treatment (0.75 mg/kg/week for 8 weeks) has been suggested for G6PD-deficient patients, provided that close monitoring of severe hemolysis is possible in areas where more severe enzyme variants prevail⁴. This regimen is usually tolerable, with the decrease in hemoglobin level being transient within the first weeks, which allows patients to recover after each dose^5-7.

Although safer for G6PDd patients than the standard treatment (daily PQ), a recent systematic review could not show whether a weekly PQ treatment is as effective as the 14-day PQ treatment in preventing recurrences of P. vivax malaria⁸. Additionally, data related to its efficacy in a real-world setting are not available. Thus, this study aimed to compare the incidence of malaria recurrence among patients using daily the standard PQ treatment (0.5 mg/kg/day for 7 days) and those using weekly PQ treatment in real-life situations in two municipalities in the Brazilian Amazon.

This study was part of the Safeprim mixed-method study, which evaluated the implementation of G6PDd screening tools in malaria treatment units (MTUs) of two municipalities in the Brazilian Amazon^9,10. The CareStart^TM qualitative test (Acess Bio, New Jersey, USA) was implemented in Rio Preto da Eva, Amazonas state (February 2019 to early January 2020), while the Standard^TM G6PD quantitative test (SD Biosensor, Korea) was implemented in both Mâncio Lima, Acre state (January to December 2020) and Rio Preto da Eva (January to August 2020). At the MTUs, when the thick blood smear tested positive for P. vivax, the PQ regimen was chosen by the healthcare workers based on the results of the G6PD test: chloroquine plus daily (0.5 mg/kg/day for 7 days) or weekly (0.75 mg/kg/week for 8 weeks) PQ was administered to patients with normal and deficient G6PD status, respectively, in accordance with the Brazilian Ministry of Health guidelines¹¹. A deficient result was obtained if a patient presented no color or a very faint color change on CareStart reading window and if the Standard biosensor screen showed a G6PD level of <4.0 IU/gHb.

All patients’ data were collected and transferred to the national malaria reporting system (SIVEP-Malaria) by the healthcare teams in each municipality. During the implementation of CareStart^TM, data were collected using REDCap forms in which all mandatory fields were automatically transferred to SIVEP-Malaria, which at that time did not include information on G6PD deficiency. For the Standard^TM test, data were entered directly into the SIVEP-Malaria database, which was later adapted to receive G6PDd information as well.

Descriptive statistics were used to analyze the demographic data. To assess the recurrence rates between patients with normal G6PD levels and G6PD deficiency, patients were followed up for 180 days after the end of treatment using a model adjusted by study site as the grouping variable. Probabilistic data linkage was used for the deduplication of successive cases from the same patient, as described elsewhere¹². A Cox proportional hazards model was used in the analysis of time-to-event data adjusted for the study site. All analyses were performed using the R software v.4.1.0, R Studio v.1.4.1717, and Stata v17. This study was approved by the Ethics Review Board of Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil (CAAE: 92012818.1.0000.0005).

The results of 122 G6PD-deficient and 1,322 normal G6PD patients were reported between February 2019 and December 2020 in both municipalities. Table 1 summarizes the patients’ demographic characteristics.

TABLE 1:
Demographic characteristics of the study participants.

	PQ Treatment
	Total	Weekly	Daily
Variable	n=1,444	n=122	n=1,322
Municipality (n=1,444; 100%)
Rio Preto da Eva, AM	450 (31.2%)	83 (68.0%)	367 (27.8%)
Mâncio Lima, AC	994 (68.8%)	39 (32.0%)	955 (72.2%)
Age (SD)	27.3 (18.0)	30.2 (19.8)	27.0 (17.9)
Gender (female) (n=1,444; 100%)	558 (38.6%)	53 (43.4%)	505 (38.2%)
School education (n=1,288; 89.20%)
Illiterate	23 (1.8%)	8 (7.0%)	15 (1.3%)
Incomplete elementary school	928 (72.0%)	76 (66.7%)	852 (72.6%)
Complete primary education	106 (8.2%)	10 (8.8%)	96 (8.2%)
Incomplete high school	77 (6.0%)	8 (7.0%)	69 (5.9%)
Complete high school	127 (9.9%)	12 (10.5%)	115 (9.8%)
Incomplete higher education	9 (0.7%)	0 (0.0%)	9 (0.8%)
Complete higher education	18 (1.4%)	0 (0.0%)	18 (1.5%)
Zone of residence (n=1,299; 89.96%)
Rural	1,165 (89.7%)	79 (87.8%)	1,086 (89.8%)
Urban	134 (10.3%)	11 (12.2%)	123 (10.2%)
Parasitemia (mm 3 ) at baseline (n=1,253; 86.77%)
<199	242 (19.3%)	16 (14.3%)	226 (19.8%)
200-300	311 (24.8%)	21 (18.8%)	290 (25.4%)
301-5,000	235 (18.8%)	15 (13.3%)	220 (19.3%)
501-10,000	346 (27.6%)	33 (29.5%)	313 (27.4%)
10,001-100,000	119 (9.5%)	27 (24.1%)	92 (8.1%)
At least one recurrence by day 180 (n=1,444; 100%)	285 (19.7%)	20 (16.4%)	265 (20.0%)
Number of recurrences in 180 days (n=285;19.74%)
1	223 (78.2%)	15 (75.0%)	208 (78.5%)
2	42 (14.7%)	3 (15.0%)	39 (14.7%)
3	17 (6.0%)	2 (10.0%)	15 (5.7%)
4	3 (1.1%)	0 (0.0%)	3 (1.1%)

• G6PD: glucose 6-phopsphate dehydrogenase; AM: Amazonas; AC: Acre; SD: standard deviation.

When comparing the recurrence rates between patients with normal G6PD and those with G6PD deficiency and considering them as a proxy for daily versus weekly PQ treatment, 20 of 122 patients (16.4%) who were taking PQ weekly had recurrence within 180 days compared with 265 of 1,322 patients (20.0%) who were taking PQ daily (risk ratio: 0.62, 95% confidence interval: 0.41-0.94, using a model adjusted for the study site. Figure 1 shows the time to the first recurrence between the groups.

FIGURE 1:
Time to first recurrence between groups using weekly and daily PQ regimens within 180 days. Cox-proportional hazard model was used adjusted by study site. HR: hazard ratio; CI: confidence interval.

The recurrence rates were lower in patients receiving weekly (16.4%) versus daily (20%) PQ. The weekly use of PQ was recently added to the updated Brazilian Ministry of Health guidelines¹¹; however, routine screening for G6PDd is not currently performed prior to the treatment of malaria. The safer option (weekly PQ treatment) allows clinical recovery between doses, since hemoglobin values usually return to baseline within the first 2-3 weeks⁷.

Non-adherence to standard treatment in the Brazilian Amazon can contribute to the recurrence of malaria^13,14. Patients with G6PDd can be prone to recurrence when the test is not performed, possibly due to treatment discontinuation owing to the patients’ fear of undergoing hemolysis when using daily PQ treatment [Nascimento et al., personal communication]. With the recent availability of single-dose tafenoquine for the radical cure of P. vivax, adherence among patients with normal G6PD levels may be ensured; however, this depends on the availability of suitable and reliable G6PDd screening tools at the point of care¹⁵. Nevertheless, adherence to the longer weekly course of PQ in G6PDd patients still needs to be addressed, and further improvements should be discussed by policymakers and local healthcare staff.

This study has several limitations. This was an exploratory analysis; hence, the main study was not specifically designed to perform this comparison. Treatment supervision cannot be ensured for both daily and weekly treatments, as this mostly depends on the availability of personnel in both municipalities. The entry of data into the national malaria database was dependent solely on the teams in each municipality. However, as a real-life evidence study, we aimed to assess the implementation pragmatically, including all aspects. Even the use of a screening tool and patients already diagnosed with G6PD deficiency could influence the weekly treatment, thus causing it to be more supervised than the standard treatment. Although the study was conducted during the coronavirus disease 2019 (COVID-19) pandemic, the malaria diagnosis was not interrupted since it was provided at the basic unit level.

In conclusion, patients receiving weekly PQ treatment had a lower risk of recurrence than those receiving daily PQ treatment in these two municipalities. However, further studies are necessary to assess its efficacy in larger populations with different healthcare levels.

ACKNOWLEDGMENTS

This study was conducted in a collaboration between municipal, state, and federal health agencies. We thank Juscelino ‘Marcelo’ Torres and Brenda Alves for their important field work. We also thank all healthcare professionals and patients from both municipalities, the Municipal Secretariats of Health of Rio Preto da Eva and Mâncio Lima, and their departments. We also thank Secretaria de Estado de Saúde do Acre (SESACRE), Laboratório Central do Amazonas (LACEN-AM) and Fundação de Vigilância do Amazonas Dra Rosemary Costa Pinto (FVS-RCP) and their departments for their support on implementation.

REFERENCES

• ¹
  Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, et al. Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malar J. 2013;12:418.
• ²
  Brito-Sousa JD, Santos TC, Avalos S, Fontecha G, Melo GC, Val F, et al. Clinical Spectrum of Primaquine-induced Hemolysis in Glucose-6-Phosphate Dehydrogenase Deficiency: A 9-Year Hospitalization-based Study From the Brazilian Amazon. Clin Infect Dis. 2019;69(8):1440-2. Available from: https://dx.doi.org/10.1093/cid/ciz122
  » https://doi.org/10.1093/cid/ciz122
• ³
  Monteiro WM, Franca GP, Melo GC, Queiroz AL, Brito M, Peixoto HM, et al. Clinical complications of G6PD deficiency in Latin American and Caribbean populations: systematic review and implications for malaria elimination programmes. Malar J . 2014;13:70. Available from: http://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-13-70
  » https://doi.org/10.1186/1475-2875-13-70
• ⁴
  World Health Organization. Testing for G6PD deficiency for safe use of primaquine in radical cure of Plasmodim vivax and P. ovale malaria. WHO Policy Br. [Internet]. 2016;Available from: http://apps.who.int/iris/bitstream/10665/250297/1/WHO-HTM-GMP-2016.9-eng.pdf
  » http://apps.who.int/iris/bitstream/10665/250297/1/WHO-HTM-GMP-2016.9-eng.pdf
• ⁵
  Alving A, Johnson C, Tarlov A, Brewer G, Kellermeyer R, Carson P. Mitigation of the haemolytic effect of primaquine and enhancement of its action against exoerythrocytic forms of the Chesson strain of Piasmodium vivax by intermittent regimens of drug administration: a preliminary report. Bull World Health Organ. 1960;22(6):621-31.
• ⁶
  Kheng S, Muth S, Taylor WRJJ, Tops N, Kosal K, Sothea K, et al. Tolerability and safety of weekly primaquine against relapse of Plasmodium vivax in Cambodians with glucose-6-phosphate dehydrogenase deficiency. BMC Med. 2015;13:203. Available from: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-015-0441-1
  » https://doi.org/10.1186/s12916-015-0441-1
• ⁷
  Taylor WRJ, Kheng S, Muth S, Tor P, Kim S, Bjorge S, et al. Hemolytic Dynamics of Weekly Primaquine Antirelapse Therapy Among Cambodians With Acute Plasmodium vivax Malaria With or Without Glucose-6-Phosphate Dehydrogenase Deficiency. J Infect Dis. 2019;220(11):1750-60. Available from: https://academic.oup.com/jid/article/220/11/1750/5573052
  » https://academic.oup.com/jid/article/220/11/1750/5573052
• ⁸
  Milligan R, Daher A, Graves PM. Primaquine at alternative dosing schedules for preventing relapse in people with plasmodium vivax malaria. Cochrane Database Syst Rev. 2019;7:CD012656.
• ⁹
  Brito-Sousa JD, Murta F, Vitor-Silva S, Sampaio VS, Mendes MO, Brito MAM, et al. Real-life implementation of a G6PD deficiency screening qualitative test into routine vivax malaria diagnostic units in the Brazilian Amazon (SAFEPRIM study). PLoS Negl Trop Dis. 2021;15(5):e0009415. Available from: https://dx.plos.org/10.1371/journal.pntd.0009415
  » https://doi.org/10.1371/journal.pntd.0009415
• ¹⁰
  Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Avaliação implementação de teste para diagnóstico de deficiência de enzima G6PD - SAFEPRIM [Internet]. 2020. Available from: https://www.vivaxmalaria.org/implementation-of-rapid-tests-for-diagnosis-of-glucose-6-phosphate-dehydrogenase-deficiency-in
  » https://www.vivaxmalaria.org/implementation-of-rapid-tests-for-diagnosis-of-glucose-6-phosphate-dehydrogenase-deficiency-in
• ¹¹
  Brazilian Ministry of Health. Guia de tratamento da malária no Brasil. Brasília Ministério da Saúde [Internet]. 2020; Available from: https://www.saude.gov.br/images/pdf/2020/marco/17/guia-tratamento-malaria-.pdf
  » https://www.saude.gov.br/images/pdf/2020/marco/17/guia-tratamento-malaria-.pdf
• ¹²
  Balieiro AAS, Siqueira AM, Melo GC, Monteiro WM, Sampaio VS, Mueller I, et al. Short-Time Recurrences of Plasmodium vivax Malaria as a Public Health Proxy for Chloroquine-Resistance Surveillance: A Spatio-Temporal Study in the Brazilian Amazon. Int J Environ Res Public Health. 2021;18(10):5061. Available from: https://www.mdpi.com/1660-4601/18/10/5061/htm
  » https://www.mdpi.com/1660-4601/18/10/5061/htm
• ¹³
  Osorio-De-Castro CGS, Suárez-Mutis MC, Miranda ES, Luz TCB. Dispensing and determinants of non-adherence to treatment for non complicated malaria caused by Plasmodium vivax and Plasmodium falciparum in high-risk municipalities in the Brazilian Amazon. Malar J . 2015;14:471. Available from: http://www.malariajournal.com/content/14/1/471
  » http://www.malariajournal.com/content/14/1/471
• ¹⁴
  Dinelly KMO, Vitor-Silva S, Brito-Sousa JD, Sampaio VS, Silva MGO, Siqueira AM, et al. Evaluation of the effect of supervised anti-malarial treatment on recurrences of Plasmodium vivax malaria. Malar J . 2021;20(1):266. Available from: https://doi.org/10.1186/s12936-021-03793-0
  » https://doi.org/10.1186/s12936-021-03793-0
• ¹⁵
  Lacerda MVG, Llanos-Cuentas A, Krudsood S, Lon C, Saunders DL, Mohammed R, et al. Single-Dose Tafenoquine to Prevent Relapse of Plasmodium vivax Malaria. N Engl J Med. 2019;380(3):215-28. Available from: https://doi.org/10.1056/NEJMoa1710775
  » https://doi.org/10.1056/NEJMoa1710775

• Financial Support: This study was funded by the Bill and Melinda Gates Foundation [Grant OPP1183951 to MVGL]. JDB-S is supported by the Research Support Foundation of Amazonas (FAPEAM) through a fellowship for postgraduate support program. FAPEAM also funded this work through POSGRAD and Pró-Estado [to WMM] public calls. WMM, VSS and MVGL are fellows of the National Council for Scientific and Technological Development (CNPq). The Oswaldo Cruz Foundation (Fiocruz) also funded this work through project nº 1702179682 (Produtos Inovadores/INOVA public call). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Publication Dates

• Publication in this collection
  29 Apr 2022
• Date of issue
  2022

History

• Received
  10 Jan 2022
• Accepted
  08 Mar 2022