Transition of radical, preventive and presumptive treatment regimens for malaria in China: a systematic review

The preferred reporting items for systematic review were used to select books, articles and annual malaria control reports to be included in this review. Published books, malaria control annals, manuals and guidelines for malaria prevention and treatment were manually searched from the library and archives of Yunnan Institute of parasites, and also the authors individual collections, including books, annual reports, manuals and guidelines for malaria control. A computerized systematic strategy was adopted to search articles in Chinese from CNKI, WanFangdata and Xueshu.baidu, and articles in English from PubMed and Google Scholar. Both clinical trials and control interventions were retrieved to be included in the review using the terms in both Chinese and English: China AND malaria AND radical treatment, China AND malaria AND prevention, China AND malaria AND presumptive treatment, China AND malaria AND mass drug administration. Only clinical trials and control interventions that were conducted in China were included. All books, research articles published in journals, unpublished documents such as annual reports, manuals and guidelines for malaria control before 20 December 2019 in Chinese and English language were included in this review [9].

The primary objective of this review was to present radical, preventive and presumptive treatment regimens for malaria that have been used in China, and their transitions in the history from malaria hyperendemicity to elimination in China. Contents on radical, preventive and presumptive treatment in books, original articles and annual malaria control reports written in Chinese and English, and conducted in China were included in this systematic review [9, 10].

Contents on clinical treatment for laboratory confirmed malaria patients in books, original articles and annual malaria control reports written in Chinese and English were excluded from this systematic review [9, 10].

All key contents from the selected articles were recorded in a data extraction file created in Microsoft word. The key contents extracted from each selected paper included treatment regimen, targeted population, efficacy and safety outcome and impact as well as author or agency, publication date, study design and document type, study or intervention location, sample size. The extracted data of treatment regimens were listed in a table. The main interventions, target populations and their impact were presented in each one of five phases from malaria hyperendemicity to elimination [9, 10].

Since this is a systematic review of literature, ethical approval was not required.

In China, control and elimination of malaria were divided into five phases: (1) baseline survey and preliminary control (1949–1959),(2) epidemic control (1960–1979), (3) further reduction of malaria burden (1980–1999), (4) consolidation of achievements gained (2000–2009), and (5) elimination (2010–now) [8]. In the early stages of malaria control programmes in China, a principle of local community–based programmes was emphasized in the planning. Local control strategies were guided by the community-based health sector, who took into account the malaria burden and environmental and socio-economic conditions. The investment for malaria control in China comes from seven levels (national, provincial, prefecture, county, township, administrative village and natural village). The investment from community level (administrative village and natural village) was through the supply of labour to which no funding was given. No statistical information for the mean annual budget dedicated to combat malaria prior to 2003 was available. Both limited resources and drug availability were, therefore, key critical factors to be considered for malaria treatment prior to 2003. After this period, the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) provided five malaria project grants with the mean annual budget of US$8.96 million. This allowed China to purchase enough equipment, bed nets, drugs, and other supplies for malaria control in addition to funding training and supporting intervention activities.

Decision-making and transition through the various treatment phases was basically left to local governments. The higher administration authorities (i.e. national, provincial and prefecture level) delegated the responsibility to reduce malaria burdens to local government (i.e. below the prefecture or municipal level) on a yearly basis. The local governments (usually county or district level) were encouraged to reach targeted reductions, e.g. a reduction of 10% below that of the previous year by using innovative methods of control, which also included clinical trials on new treatment regimens using available registered drugs [11]. Either the county health facility or sometimes even a township hospital could decide on treatment regimens and targets prior to 2003. Regimens for radical, preventive and presumptive treatments are listed in Table 1. In order to simplify description, all dosages mentioned in this paper are for adults. The dosages for children were usually based on age in China in Table 2 [11].

In December 1951, the Government Administration Council published “The Work Protocol of Malaria Control in Ethnic Minority Areas” as a working protocol for malaria burden surveys and interventions. The central government mobilised health professionals to enter hyperendemic areas of ethnic minority communities in southwest China [8]. Initially, these health professionals from the central government did a baseline epidemiological survey together with recruited and trained local health staff. At the same time, control interventions were also conducted e.g. in Yunnan province, two treatment regimens were adopted: (1) presumptive treatment was given to people with enlarged spleens and clinical disease suggestive of malaria in the last 6 months; (2) the remainder of the community received weekly preventive treatment. However, data on drugs used and treatment regimens was not well documented. Early accessible data indicates that drug usage depended on what could be obtained due to poor supply during these years. The various drugs available included quinacrine hydrochloride, quinine sulfate, acrichinum, paludrine and/or plasmoquine (Table 1) [12, 13]. By 1955, China had completed the baseline survey and reduced malaria burden by about 50% in the main endemic areas across the whole country. The outcomes and information gained from early control strategies and the baseline survey helped the Ministry of Health develop “The First National Malaria Control Programme” in 1956 [8, 12].

By 1960, China established a functional health system for malaria control. However, natural disasters and political factors challenged the effectiveness of the malaria control programme. Firstly, alternating droughts and floods created plenty of breeding sites for anopheline mosquitoes of Anopheles sinensis and Anopheles anthropophagus resulting in an epidemic of P. vivax in northern China in the early 1960s [8]. Secondly, The Great Cultural Revolution campaign suspended malaria interventions which led to the occurrence of epidemics in some parts including northern and southwestern China with the annual malaria incidence (API) increasing from 5.96 per 1000 in 1966 to 29.61 per 1000 person-years in the whole country in 1970 [8, 13]. Subsequently, clinical trials were undertaken to evaluate radical treatment regimens against relapse of P. vivax (Table 1). All of these clinical trials reported significant reduction in malaria burden [8, 11‐19]. Based on the analysis of these results, the national malaria advisory committee (NMAC) recommended the treatment regimens of 1200 mg or 1500 mg chloroquine (CQ) for 3 days together with 180 mg primaquine (PQ) for 8 days for both standard clinical and radical treatments [11]. In addition, the NMAC recommended a regimen of 50 mg pyrimethamine once every 10–15 days for prevention [8, 11]. During this phase, local treatment regimens including preventive and radical treatments were used in all endemic areas of central and southern provinces of China. Normally, preventive treatment was administered during the transmission season, usually from June to September in most areas; and radical treatment was given during winter or spring, which is before or at the start of a new malaria transmission season. In hyperendemic areas, a high coverage was emphasized for both preventive and radical treatments [8, 12‐23]. For example, 20–50% of a total population of 60 million people in Jiangsu Province received radical treatments and 3.3–10% of them received preventive treatments from 1973 to 1979. A total of 27,974,966 people received radical treatments in 1975 alone. These interventions reduced P. vivax incidence from 113.6 per 1000 person-years in 1972 to 9.0 per 1000 person-years in 1979 [23]. In five central Chinese provinces, which included Henan, Jiangsu, Shandong, Hubei and Anhui, approximately 60 million (range of 47–80 million) radical treatment regimens and 90 million (range of 66.7–124 million) preventive treatment regimens were given between 1974 and 1979. These treatment regimens reduced malaria burden by 86.06%, from 13.73 million cases in 1973 to 1.91 million cases in 1979 [8]. Yunnan Province was always an intensive transmission area due to its unique ecology and the presence of suitable vector complexes. The six species of anopheline vectors identified in this province were An. sinensis, An. anthropophagus, Anopheles minimus, Anopheles dirus, Anopheles jeyporiensis and Anopheles kunmingensis were identified as malaria vectors. Another two species, Anopheles maculatus and Anopheles pseudowillmori were suspected vectors. Comprehensive control measures were needed and MDA was the main approach in this province [12, 13]. Yunnan Province initially conducted a pilot trial in Menghai County on the China-Myanmar border. The trial utilized MDA with available drugs, including atebrin, pamaquine, and cyclochloroguanidum (these drugs are no longer in production) to treat a population of 17 662 for both radical and preventive treatments. The combination of indoor residual spraying with insecticides and MDA successfully resulted in no indigenous malaria infection in 1962. With the success of this trial, the whole province was included in a scaled up version of this study, thus effectively decreasing malaria burden by 86% [13].

At the start of this phase, MDA was still the overall approach, but focus gradually shifted from a broad coverage of the population to specific at risk communities. The number of treatment regimens dispensed gradually declined along with the reduction in the malaria burden. From 1980 to 1999, a total of 269.8 million preventive and 129.96 million radical treatment regimens were administered nationwide. These included 31.98 million radical treatment regimens to people who had a history of malaria episode in the previous year, 91.40 million preventive treatment regimens to residents in hyperendemic communities and 6.58 million preventive treatment regimens to specific populations such as migrants. As a result, this large-scale radical and preventive treatments reduced malaria burden by 99.31% and lowered the annual malaria incidence from 3378.3 per million person-years in 1980 to 23.4 per million person-years in 1999 [8]. In Yunnan Province alone, the number of malaria cases dropped from about 40 000 in 1980 to 10 000 in 1999 [13].

In 1987, a randomized controlled trial for malaria prevention was conducted on travellers crossing the China-Myanmar border [24]. Initially, a radical treatment regimen of 1500 mg CQ for 3 days together with 180 mg PQ for eight days was used to clear malaria parasites from all participants (n = 161), before the transmission season (February). Then each person in the preventive group received two tablets (50 mg, dosage for an adult) of sulfadoxine -pyrimethamine (SP) once every 15 days (Table 1). Those in the control group (n = 290) were given two vitamin C tablets each as placebo. The study reported that only one P. falciparum case occurred in the preventive treatment group, compared to 23 P. falciparum and 9 P. vivax cases in the control group [24].

Another two radical treatment trials were conducted to prevent relapse of the temperate strain of P. vivax found in high altitude areas in Yunnan Province in 1980s. The strain of P. vivax was recognised as having long incubation periods. In one trial, participants (n = 4871) who had a malaria episode within the last 12 months were given an adult dosage of 180 mg primaquine for 8 days (Table 1) before the transmission season. Nothing was given to the control group (n = 620). This trial reported that no cases of relapse occurred among the radical treatment group but eight (1.3%) cases were detected in the control group within 1 year [25]. In another trial, 180 mg of primaquine was administered over 8 days to the radical treatment group resulting in a relapse rate of only 1.0% (2/208) compared to 8.0% (16/201) in the control group [25]. Based on these two trials, the authors concluded that administration of 180 mg primaquine for 8 days before transmission season can prevent relapse of P.vivax strains with long incubation periods [25].

During this phase, the national guidelines recommended two preventive treatment regimens, 600 mg piperaquine once a month and 300 mg CQ once every 7–10 days for malaria endemic areas [26]. For radical treatment of P. vivax, a single regimen of 180 mg PQ for 8 days was recommended for every endemic area before the transmission season [26]. The national guidelines did not recommend any presumptive treatment regimens [26]. However, in practice, only a single regimen of 600 mg piperaquine once a month was used for prevention [27‐33]. The regimen of 1200 mg CQ for 3 days plus 180 mg PQ for 8 days was used for radical treatment in central and northern China (Table 1) [34‐36]. Whereas in Yunnan Province, which was considered to have high transmission intensity in remote areas, the radical treatment regimen was 1500 mg CQ for 3 days plus 180 mg PQ for 8 days, and presumptive treatment with dihydroartemisinin-piperaquine and CQ/PQ was still being administered to suspected P. falciparum and P. vivax malaria cases, respectively (Table 1) [27‐33].

In 2007 a cluster intervention trial was conducted to evaluate curative efficacy of the regimen using 1200 mg CQ for 3 days together with 180 mg PQ for 8 days in Anhui Province. This trial divided 15 villages into three groups (five villages/group). In the first group, radical treatment regimen was given to individulas who had a history of malaria in the last 12 months. In the second group, the regimen was administered to the malaria cases together with other family members and those living in the neighboring households. In the third group, the treatment regimen was given to all villagers. When the annual malaria incidence data were compared between 2007 and 2006, there was a significant (P < 0. 01) decline in malaria incidence in the third group but not in the first and second groups (P > 0. 05) [37]. Following the results of this trial, the radical treatment regimen of 1200 mg CQ for 3 days plus 180 mg PQ for 8 days was scaled up to control malaria resurgence in all individuals living in Anhui and Henan Provinces. As incidence declined in the whole of China, radical treatment was scaled back to those with malaria in the last 12 months, their family members and neighbours [35‐37].

Yunnan Province reported 25,070 malaria cases from 2006 to 2009, and a total of 334,316 presumptive treatment regimens (56,272 courses of dihydroartemisinin- piperaquine and 278,044 CQ/PQ) were administered to febrile patients (Table 1) [38]. Another 250,456 radical treatment regimens of 180 mg primaquine for eight days were administered against relapse of P. vivax malaria, and 158,601 preventive regimens with piperaquine were administered to people at high risk, e.g. those who cross the border to endemic areas of neighbouring countries [38, 39]. These multiple treatment strategies resulted in a reduction in malaria burden by 77.9% in Yunnan Province, i.e. annual parasite incidence (API) declined from 2.80 per 10,000 person-years in 2006 to 0.62 per 10,000 person-years in 2009. This dramatic decline in incidence in Yunnan Province allowed China to announce that its malaria control program could progress to elimination phase from 2010 [38].

During this phase, the national guidelines recommended the use of artemisinin based combination therapy (ACT) for 3 days to treat P. falciparum infection and 1200 mg CQ for three days plus 180 mg PQ for 8 days for treatment of P. vivax and P. ovale infections [40]. All cases of suspected malaria were now tested either by microscopy or by rapid malaria antigen tests to confirm the diagnosis before treatment. The radical treatment regimen of 180 mg PQ for eight-days was only administered to people with confirmed P. vivax by Polymerase Chain Reaction (PCR) in last year. In border areas of Yunnan and mountainous areas of Hainan Province, this radical treatment regimen was also administered to family members, neighbouring household residents or travellers from malaria endemic areas to clear potential parasitic foci [38‐44]. The presence of malaria in countries having common borders with Yunnan Province makes elimination of malaria more difficult in this region of China [44, 45]. In Yunnan province, 118,728 preventive treatment regimens of 600 mg piperaquine once a month reduced imported malaria from 1256 in 2011 to 388 cases in 2013 [44, 45]. The preventive treatment regimen of 600 mg piperaquine (Table 2) once a month is currently being used to prevent re-introduction of malaria into China by travellers from other endemic countries [41, 44, 45].

In the available literature in Chinese, no record of human ethics applications and approvals for malaria treatment interventions were found. Investigations on safety of treatment regimens were also uncommon. This might be that public health benefits are much more important than that of individuals in Chinese ethical requirements. Only a few incidences of adverse side effects were reported resulting from radical, preventive and presumptive treatment. In one report, 43.3% people who received piperaquine phosphate for prevention had mild side effects of dizziness, nausea and cheek numbing (Table 3) [46]. Two other reports describe these mild adverse side effects and identified this as the reason for poor compliance to MDA of radical, preventive and presumptive treatment in Yunnan Province [47, 48]. In order to increase compliance and improve safety of the administered drugs, the intended target communities were identified, notified and encouraged to support the activity. At all stages of the drug administration, verbal consent was obtained from individuals before drugs were given. In addition, directly observed therapy by community health workers and local public health officers was used during the daily administration of medications [23]. Some adverse events were reported, such as dizziness and nausea etc. but a few severe and fatal cases did occur due to PQ-induced acute haemolysis (Table 3) [49‐55].

Honghe Prefecture on the China-Vietnam border with a population 4.55 million was a malaria hyperendemic area. A total 43,071 cases were recorded with an annual malaria incidence at 26.61 per 1000 person-years in 1953 [56]. The intervention of radical, preventive and presumptive treatments followed the changes in accordance with the five phases from hyperendemicity to elimination as described above. Malaria transmission was interrupted in 2012 and the Prefecture is now malaria free. According to “China National Guidelines for Malaria Elimination Evaluation and Certification”, Yunnan Provincial Health and Family Planning Commission convened a panel of experts from government health and information management departments to monitor and evaluate the laboratory’s diagnostic competency. This panel of experts reviewed epidemiological and entomological data and determined that Honghe Prefecture had achieved malaria elimination status, and certified malaria free on 4th November, 2015 [12]. This is an example of how radical, preventive and presumptive treatment, integrated intervention with vector control by indoor residual spraying (IRS) with insecticides since 1950s. After the 1980s, these treatment regimens, IRS and the addition of insecticide-treated bed nets (ITN) successfully achieved malaria elimination status from a previously hyperendemic region (Fig. 1).

Engagement of the broader community by Government achieved high coverage of intervention of radical, preventive and presumptive treatment in China. Before the 1978 economic reforms, the People’s Commune financially and publicly supported the development of the rural cooperative medical system (RCMS), which was a branch of the primary health care system (PHCS) targeting rural areas in China. The People’s Commune notified communities through public education programmes on radical, preventive and presumptive treatment among communities before drug administration. Village health workers (VHW) and village malaria control workers (VMCW) were involved in the process of drug administration [12]. House-to-house visits every day were conducted to directly observe therapy was core to this methodology for increasing coverage, compliance and safety of MDA [12, 23]. In the daily house visits, individuals were questioned about adverse effects of the treatment taken the previous day. A decision would then be made by the VHW or VMCW on whether the next dose should be given. If there was an adverse effect reported, such as black tea coloured urine after administration of PQ in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, treatment would be stopped immediately. A proper rescue treatment followed according to the national guidelines and to the type of adverse reaction and severity of clinical symptoms [11, 26]. Those showing minor symptoms such as low grade haemoglobinuria, dosing with PQ would be discontinue, while those with more severe side effects would be given a blood transfusion. This approach ensured good coverage and safety of the treatment intervention [8, 23, 57]. Currently, with improved laboratory diagnostic capacity and only imported malaria, radical treatment in China changed to targetting individuals with confirmed P. vivax or P. ovale within the last year. Preventive treatment also changed and only travelers to other endemic countries received anti-malarial drugs. Administration of presumptive treatments is now no longer encouraged or used.