|POLICY AND PRACTICE
|Year : 2014 | Volume
| Issue : 1 | Page : 75-80
Mass primaquine preventive treatment for control of Plasmodium vivax malaria in the Democratic People’s Republic of Korea: a country success story
Shushil Dev Pant1, Kim Yun Chol2, Yonas Tegegn3, Partha Pratim Mandal1, Ri Kwang Chol2
1 Office of the WHO Representative, 14-Munsudong, Pyongyang, Democratic People’s Republic of Korea
2 Ministry of Public Health, Democratic People’s Republic of Korea
3 Office of the WHO Representative, Bangkok, Thailand
|Date of Web Publication||24-May-2017|
Shushil Dev Pant
Office of the WHO Representative, 14-Munsudong, Pyongyang
Democratic People’s Republic of Korea
In 1998, the resurgence of Plasmodium vivax malaria in the Democratic People’s Republic of Korea quickly increased to an epidemic, with 601 013 cases reported I during 1999–2001. The introduction of mass primaquine preventive treatment (MPPT) in 2002 was followed by a rapid reduction of malaria disease burden. The intervention has been well accepted by the community. Doctors were part of a strong functional health system with the ability to deliver interventions at the household J level. MPPT was considered for control of malaria after a study conducted in two J neighbouring endemic villages (ris) involving 320 healthy adults demonstrated that presence of parasitaemia was significantly lower among those receiving MPPT than those who did not. Similarly, in a mass blood survey conducted in the study sites during May, 2002 involving 5138 persons in study and 4215 in comparison areas, the total positive results were 7–10 times rarer in the treatment group both before and after the malaria transmission season. In addition, the number of malaria cases in the MPPT treatment ris was strikingly lower than control ris in every month during the malaria transmission season of 2002. The prevalence of G6PDD deficiency in DPR Korea is low, haemolytic events are rare and deaths due to MPPT have not been reported. MPPT in itself is a powerful intervention and the decision to deploy it depends on the epidemiology of malaria, urgency of malaria control and resources available in the country.
Keywords: Malaria, Democratic People’s Republic of Korea, mass primaquine preventive treatment, Plasmodium vivax
|How to cite this article:|
Pant SD, Chol KY, Tegegn Y, Mandal PP, Chol RK. Mass primaquine preventive treatment for control of Plasmodium vivax malaria in the Democratic People’s Republic of Korea: a country success story. WHO South-East Asia J Public Health 2014;3:75-80
|How to cite this URL:|
Pant SD, Chol KY, Tegegn Y, Mandal PP, Chol RK. Mass primaquine preventive treatment for control of Plasmodium vivax malaria in the Democratic People’s Republic of Korea: a country success story. WHO South-East Asia J Public Health [serial online] 2014 [cited 2020 Jan 24];3:75-80. Available from: http://www.who-seajph.org/text.asp?2014/3/1/75/206889
| Background|| |
The resurgence of Plasmodium vivax malaria in the Democratic People’s Republic of Korea followed the outbreak in 1998, when 2100 malaria cases were reported. This outbreak occurred after the country had been malaria free for more than 25 years. At the time, there was no outbreak-response plan, and limited national expertise had been retained for malaria programme management. Entomologists, microscopes, and people with the skills to read malaria slides were scarce. There were limited resources and capacity to scale up vector-control interventions. In the absence of a rapid and appropriate response, the outbreak soon spread nationwide. A total of 601 013 cases were reported over 1999–2001. Most of the people affected were adults and only 7–12% of cases were children aged under 15 years. Agriculture workers were the predominant occupational group affected. However, no mortality associated with malaria was reported.
In this setting, the World Health Organization (WHO) assisted the Ministry of Public Health to introduce mass primaquine preventive treatment (MPPT), starting with pilot studies in 2002. The decision to deploy MPPT was also strongly influenced by the encouraging experiences of other countries that had prevalent P. vivax infection, with dual strains of short and long incubation periods – notably neighbouring China, where about 30 million people were treated between 1973 and 1983. Introduction of MPPT in the Democratic People’s Republic of Korea contributed to significant reduction of P. vivax malaria in subsequent years. This review describes the evolution of the intervention and its contribution to malaria control in the country.
| Materials and methods|| |
International publications citing studies or reviews of disease-control programmes in the Democratic People’s Republic of Korea are limited. This paper aims to share the country’s success story, based on the limited documentation available. The majority of references for development of the document came from the assignment reports of the WHO malaria experts. These experts worked in the country and were supported to review the epidemiology of malaria after its resurgence there; to design the study to assess the effectiveness of MPPT; to develop the plan of implementation; and to monitor the progress made in malaria control from 1998 to 2012. Information shared during detailed discussion with the manager of the National Malaria Programme and malaria experts in the country has also been used as reference to enrich the document. Where possible, the information provided by the national programme has been verified against the documents in WHO archives. Publications from neighbouring countries and experiences of countries that have also successfully implemented MPPT to control malaria have also been included, to improve understanding of the MPPT concept, in an attempt to make this document more comprehensive and useful for policy decisions.
| The hypothesis: MPPT reduces malaria transmission|| |
Malarial infections in the Democratic People’s Republic of Korea during January to April (winter) are dormant and rarely reported. In addition the vectors of malaria begin to hibernate from the end of November and mosquitoes are rarely spotted until the end of April. Thus, malaria transmission is extremely rare during winter months.
According to the Ministry of Public Health, based on a research conductedin 2000, P. vivax malaria parasites that are prevalent in the Democratic People’s Republic of Korea exhibit two different durations of incubation period. For 20–30% of the P. vivax infections the incubation period is 2–3 weeks, while for 70–80% of infections it is 6–12 months. The report of this research has not been shared, but the national programme is confident of the reliability of the data. However, in the absence of means for parasite genotyping, these conclusions are open to debate.
Infections with short-incubation parasites manifest in the same transmission season and the majority of infections (caused by long-incubation parasites) are therefore asymptomatic in the respective winter and manifest at the beginning of malaria transmission season (May to August). In other words, in a given year, 70–80% of reported cases were infected in the previous year and 20–30% of cases are new infection or relapse of the short-incubation type. Infections with long-incubation parasites, and cases that will relapse in the transmission season, were dormant during the immediate preceding winter.
Mass treatment with primaquine during winter will thus reduce the number of individuals in the community who are harbouring hypnozoites, thereby reducing the local parasite reservoir. Despite an increase in vector density and humanbite rate in June to August, most anopheles bites are non-infectious. As a result, the entomological inoculation rate becomes low and malaria transmission decreases.
| Study of the hypothesis|| |
A study was conducted in 2001 to test the above hypothesis. The study aimed to evaluate the effectiveness of MPPT in reducing reinfection or the relapse rate among treated and non-treated cases. Two neighbouring endemic villages (ris) were selected as the treatment and control sites. A total of 320 healthy adults without patent disease or contraindications to primaquine administration (pregnancy, patients with lupus, arthritis, leukaemia or hepatitis, or with a history of haemolysis/hypersensitivity after taking primaquine) were selected for the treatment arm. Other details of the characteristics of the sample are not documented. Each case in the treatment arm received 15 mg primaquine per day for 14 days in the month of March. They were followed up for parasitaemia in subsequent months. The results were compared with 320 adult controls who did not receive primaquine. Owing to limited laboratory capacity, the cases could not be reclassified into new, recrudescence or relapse.
[Table 1] shows the results of the prospective study. The presence of parasitaemia was significantly lower P < 0.0001) among those receiving MPPT. The study demonstrated strong evidence that MPPT was an effective intervention to reduce malaria transmission.
|Table 1: Study of the effectiveness of primaquine prophylactic treatment for reducing reinfection or relapse|
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| Piloting of MPPT in malaria transmission areas|| |
MPPT was introduced during February to April 2002 in seven malaria-endemic counties of five provinces. The counties selected for the piloting were: Kangnam, Sukchon, Sonchon, Sinchon, Hwangju, Anbyon and Panmum. Malaria outbreaks were reported from all of the ris of the seven counties in the preceding year. For a pilot study, each selected county was further divided into treatment ris (total 91 ris in seven counties) and control ris (total 85 ris in seven counties). In the Democratic People’s Republic of Korea, the villages are isolated and cross-border contamination of control areas is unlikely. Children under the age of 5 years, pregnant women, and patients with lupus, arthritis, leukaemia, hepatitis, or a history of haemolysis/hypersensitivity after taking primaquine were excluded from MPPT. In treatment ris, primaquine was administered to all eligible 391 357 inhabitants. The control ris were represented by 421 875 people above the age of 5 years.
In 2002, the government conducted a mass blood survey in the study sites during May (5138 persons in study areas, 4215 in comparison areas) and September (3716 persons in study areas, 2994 persons in control areas). The result from the survey are shown in [Table 2]. The total number of positive results was 7–10 times lower in the treatment sample both before and after the malaria transmission season. The results of the assessment also concluded that the likelihood of being infected with malaria in MPPT areas was 4–17 times lower than in untreated areas (see [Figure 1]).
|Table 2: Slide-positive rate (SPR) amongst primaquine-treated and control population|
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|Figure 1: Malaria cases and incidence by counties among treatment and control ris, 2002|
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The total number of malaria cases in the pilot areas was studied every month after the introduction of MPPT. The number of cases of malaria in the treatment ris was strikingly lower than in the control ris in every month during the malaria transmission season of 2002, as shown in [Table 3] ; the totals in this table also show that there are 90% fewer cases of malaria in treatment ris compared to control ris.
|Table 3: Malaria cases and incidence by counties among treatment and control ris, 2002|
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| Assessment of side-effects and safety|| |
The prevalence of glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency in the Korean peninsula has historically been reported as low. According to a WHO report, the trait of G6PD deficiency has a prevalence between 0’5 and 2.9 % in Korea; however the source of this information is not quoted directly in the WHO report. In 2002, a study was conducted in the Democratic Peoples Republic of Korea to assess the safety of different durations and doses of primaquine treatment. The first group (10 022 persons) received primaquine 0.25 mg/kg/ day for 7 days and a secondr group (10 033 persons) received primaquine 0.5 mg/kg/day in two divided doses for 14 days. The overall reported rate of side-effects was slightly lower in the first group (4.8%) as compared to the second one (6.5%). No severe side-effects or deaths were reported.
In 2002, at the onset of MPPT, a total of 391 357 people from 91 ris of seven malaria counties were targeted for MPPT. The intervention was undertaken from 18 April to 3 May 2002. Nearly 400000 follow-up cards to record probable side-effects were printed in Korean language and distributed to ri levels. These cards were filled in for each individual receiving primaquine treatment, by their respective doctors. An analysis of the content of these cards revealed that the prevalence of various side-effects was very low and did not exceed 4%. Most importantly, no cases of severe haemolysis were reported, as shown in [Table 4]. Cases with suspected haemolytic symptoms discontinued the drugs and were referred to higher centres for treatment. All of them recovered in the subsequent 3–5 days and were excluded from future rounds of MPPT. The national programme has confirmed that no death related to MPPT has been reported in the country so far.
|Table 4: Prevalence of side-effects among persons treated with primaquine, 2002|
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| Delivery of MPPT|| |
Encouraged by the results of the studies on the effectiveness and safety of MPPT, the national programme implemented MPPT every year from 2002 to 2007. MPPT was completed each year before April. Owing to limited resources, the country could not conduct the mass campaign in 2008, 2011 and 2012.
In every ri of the Democratic People’s Republic of Korea, there is at least one ri hospital with about 6–10 doctors. The health care of all members of a unit of about 150–250 households CHH) is a primary responsibility of each doctor.
A task force plans and delivers MPPT in each ri. The task force consists of a supervisor from province or county level and all the HH doctors of the target ri. Volunteers from the community are an integral part of the planning and delivery process. The HH doctors/volunteers visit house to house, to identify and record inhabitants eligible for the mass treatment in the respective year. The target excludes children aged under 5 years, pregnant women, people with a history of side-effects With primaquine, and people with a history of liver or blood disorder. Prior to implementation of MPPT, HH doctors/volunteers were trained on recording and reporting, calculation of dose, ensuring drug compliance and monitoring of side-effects of the drugs.
A daily primaquine dose of 0.25 mg/kg was administered after breakfast for 14 consecutive days,under direct observations. Before ingestion of the daily dose, the doctors inquired about the symptoms of side-effects of the drugs and looked for any signs of haemolysis. Any such observation was recorded and all individuals with suspected haemolytic or any other serious side-effects were immediately excluded from treatment and referred for appropriate care.
It was a major challenge to break a 7.5 mg primaquine tablet to provide a dose of 0.25 mg/kg/day to a child. However, the HH doctors and volunteers tned to adhere to the national guideline as far as practical.
The proportion of people completing a full course of primaquine in the mass campaign was always over 94%; it was difficult to achieve 100% coverage of the targeted population, as individuals with suspected haemolytic symptoms were excluded from further treatment. In addition, there was a difference between baseline data and the actual size of household numbers, owing to death or migration of members.
| Impact of MPPT|| |
The burden of malaria began to decline after introduction of MPPT in 2002. The total number of cases was reduced by 80% following two round of MPPT in 2002 and 2003. A similar trend was observed in the subsequent years. Compared to 2001, the total malaria burden had decreased by 90% in 2012. An increase in the number of malaria cases was observed when MPPT could not be conducted in a particular year. Details of the impact of MPPT during 2002–2012 are shown in [Table 5].
|Table 5: Reduction in the number of malaria cases after introduction of MPPT|
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Presumptive treatment with chloroquine for all fever cases also contributed to reduction of malaria transmission. In an effort to confirm cases before treatment, expansion of malaria microscopy centres started from the year 2001, and capacity-building in malaria microscopy was a high priority for the government. Up to 2004, 40–60% of suspected malaria cases were tested annually and those with a positive result received radical treatment. The microscopy confirmation improved to 70–90% among suspected cases in subsequent years. However, data on the accuracy of the results of microscopy are not available. A drug-effectiveness study conducted in 2005 and 2012 confirmed that chloroquine is effective against the existing P. vivax strain prevalent in the Democratic People’s Republic of Korea.
In addition, during 2002–2009, there were attempts to improve coverage of vector-control interventions. Owing to limited resources, the interventions were only rolled out to selected areas and were inadequate to control malaria transmission in the country. DDT was used from 2001 to 2003 and only 10 000 people benefited from indoor residual spraying. There are reports that bed nets (insecticide treated and untreated) were also widely used; however, there are no data available on coverage and use to make conclusions on the effect the nets had to contain the outbreak. Communities were encouraged to reduce vector breeding sites and burn moxa (mugwort, Artemisia vulgaris, Artemisia leaf) to repel mosquitoes away from the communities. In the absence of data and studies on the effectiveness of traditional vector-control interventions, it is difficult to measure their contribution to reducing the burden of malaria.
With support from the Global Fund Round 8 Malaria grant, 711 960 long-lasting insecticidal nets have been distributed to malaria-affected communities in the Democratic People’s Republic of Korea from 2010 to 2012. During the same period, more than 450 000 households and 90 000 agricuhure and night-time workers have been protected with insecticide-treated clothes each year. The pyrethroid group of insecticides was preferred for ease of operation, and because they are effective against malaria vectors. Malaria microscopy services have been expanded to 1023 centres and about 90% of suspected cases are being confirmed. The contribution these efforts have made to reduce malaria transmission is under study. [Table 5] also demonstrates that the number of malaria cases increased in the years MPPT was not conducted (2008, 2011, 2012). Irrespective of the coverage of other malaria-control interventions, MPPT is essential to reduce the burden of malaria disease in the Democratic People’s Republic of Korea.
| Conclusion|| |
MPPT is a success story of the Democratic People’s Republic of Korea’s programme to control P. vivax malaria. Since the introduction of the intervention, a drastic decrease in malaria burden has been observed in the country. A strong health system is essential for proper planning of the mass campaign, with monitoring and achievement of high coverage, and for drug compliance and monitoring of the side-effects.Inadequate resources interrupted MPPT in 2008, 2011 and 2012, and an increase in malaria cases was observed in each of these years. Further resources need to be mobilized to ensure continuity of MPPT to achieve further gains in malaria control.
The contraindications and compliance to the long regimen of primaquine treatment are the major limitations to the ability of MPPT to have an impact. MPPT needs to be complemented by other interventions to eliminate P. vivax among individuals with contraindications to primaquine treatment. At the same time, resistance of the local P. vivax strain to primaquine needs to be studied at intervals, to ensure the intervention is effective. The urgency of malaria control, as well as the resources available in the country and ethical issues related to mass primaquine administration, need to be carefully considered before a decision is made to implement MPPT.
Source of Support: Nil.
Conflict of Interest: None declared.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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