ABSTRACT
Dihydroartemisinin-Piperaquine (DHP) combination is the first-line treatment for uncomplicated malaria in Indonesia and has been used since 2010. This study was conducted to determine the efficacy of DHP combination for uncomplicated malaria treatment in a community-based evaluation.
Recruitment was done by active or passive case detection. All uncomplicated malaria patients were treated with DHP once a day, for 3 days, administered orally (as is done in primary health care). Patients were followed up until day 28 post-treatment. The primary end point was a 28-day cure rate.
In this study, 484 subjects were screened through active and passive cases detection. A total of 45 subjects infected by P. vivax and 2 subjects infected by P. falciparum agreed to participate through written informed consent. There was no difference between clinical malaria and asymptomatic malaria in all analyzed characteristics. One patient had a D3 parasite density greater than 25% D0, although no parasites were found on the following day (D4). This study found 46 patients (97.9%) who had adequate clinical and parasitological responses. No adverse event was reported during the follow up of this study.
DHP was effective, safe, and well tolerated in the treatment of uncomplicated malaria at primary health care.
Keywords: Dihydroartemisinin-Piperaquine, malaria, primary health care
INTRODUCTION
Malaria is still a public health problem in Indonesia. Actions to control and eliminate malaria need to be supported by evaluating the accuracy of the diagnosis and the efficacy of the antimalarials used. The use of artemisinin-based combination therapy (ACTs) has become the main choice in Indonesia. It is widely accepted that ACTs provides the best available treatment for uncomplicated malaria (1). ACTs can slow down the development of resistance. ACTs is also very fast in clearing plasmodium in the blood, and has a gametocide effect to inhibit the spread of malaria transmission (2).
The artesunate-amodiaquine combination is an Artemisin derivative that was widely used in malaria endemic countries in early 2000s, including Indonesia. However, there have been many reports stating a decreased efficacy of the Artesunate-Amodiaquine combination. Thwing, in their study in South Kenya, found that 31.1% of the Artesunate-Amodiaquine combination treatment has failed (3). A related research in Timika also reported treatment failure by 22% (4). Artemisin combination side effects are often the reasons why patients did not adhere to the treatment process (5). The decrease in efficacy of the Artesunate-Amodiaquine combination has been followed up by changes in treatment patterns, replacing the drug combination with other artemisinin derivatives, namely the dihydroartemisinin-piperaquine (DHP) combination (1).
As the most reliable antimalarial combination at this time, the use of the DHP combination should receive serious attention. Hasugian found that the efficacy of the DHP combination treatment was still superior to the artesunate-amodiaquine combination (4). Similarly, Tjitra found that the efficacy of the DHP combination was still above 95% (6). Overall, although there have been reports of decreased efficacy, this DHP combination is still superior to other artemisinin derivatives. Therefore, routine monitoring of the therapeutic efficacy of ACTs is essential in making timely changes of treatment policy. It can also help to detect early changes in the parasite susceptibility to antimalarial drugs (1). This study was also conducted as an effort to achieve the elimination of malaria by 2030 in Indonesia.
METHODS
Study Design
This study was a prospective observation of the clinical and parasitological response to directly observed treatment for malaria. The World Health Organization (WHO) standard protocol for the assessment of the efficacy of antimalarial drugs for 28 days was modified according to existing conditions in public health services (7).
This was a part of a research to establish a diagnostic model for patients with asymptomatic malaria in hypo endemic area from 2015 to 2019. The therapy observation data was specifically collected from February 2018 to December 2018 in 2 Primary Health Care and 5 villages in the study area. The study was conducted in Batubara District, one of 13 malaria hypoendemic areas in North Sumatra Province. The study subjects were taken from the districts with the highest malaria prevalence, namely Tanjung Tiram and Labuhan Ruku Districts. This study was approved by the Health Research Ethical Committee, Medical Faculty, Universitas Sumatera Utara (decision number: 262/KOMET/FK USU/2015). Data collection was only done after obtaining medical approval after an explanation (informed consent) by the subject or the subject’s parents.
Patient Selection
Subjects were people who live permanently around research location, selected by random sampling. They were obtained in two ways: Active case detection and passive case detection. Active case detection was carried out by visiting people who have a history of suffering from malaria in the last 2 years based on secondary data. Meanwhile, passive case detection was done by waiting for patients to visit the public health center. Subjects were collected by simple random method. Examination would be carried out after the subject received an explanation and gave an informed consent. The main criteria for subjects to be included in this study were: Subjects with age greater than 1 year and has written informed consent to participate in the study. Pregnant or lactating mothers and anyone with signs or symptoms of severe malaria were excluded from the study.
The diagnosis of malaria was established by performing microscopic examination by at least two trained microscopic experts. If differences in results are found, the final decision will be determined by the third examiner. All subjects were observed for 28 days. Follow-up microscopic examination was carried out on a fixed schedule on day 0, 1, 2, 3, 4, 7, 14, 21, 28, and every day the subject felt unwell. Thick and thin blood stains with Giemsa’s stain were examined on the same day as the blood draw. The parasite density was calculated by counting the number of asexual parasites/gametocytes against the number of white blood cells (WBC) in thick blood films. Parasite density was expressed as the number of asexual parasites per microliter (µL) of blood. Density was calculated by dividing the number of asexual parasites by the number of WBCs counted, then multiplying by 5000 (assuming a WBC density of 5000 WBCs/µL). When the number of parasites was less than 10 per 200 WBCs in follow-up examination, counting was done against at least 500 WBCs. Blood slides were considered negative when the examination of 1000 WBCs did not reveal any asexual parasites.
The hemoglobin level is measured by the dipstick method [Easy Touch GHb meter, Lot HB15414B4T: Control: (N) 12-15 g/mL]. Axillary temperature was measured by digital thermometer. Condition of fever is defined by axillary temperature ≥37.5 °C. Meanwhile, other characteristics were obtained through interviews and observation.
A fixed-dose DHP regimen was given to subjects with uncomplicated malaria. One tablet of DHP (D-ARTEPPTM from Guillin Pharmaceutical Co. Ltd), consisted of 40 mg dihydroartemisinin and 320 mg piperaquine. DHP dosage was 2-4 mg/kg body weight/day dihydroartemisinin and 16-32 mg/kg body weight/day piperaquine, given for 3 days orally, in single dose per day on day 0, 1, and 2. All DHP doses were administered under supervision by a nurse or midwife designated by the principal investigator. Side effects are defined as signs and symptoms that occur after treatment has been initiated. Serious side effects are defined as death, life-threatening reactions, events requiring hospitalization or resulting in disability, or medical events requiring intervention.
The primary endpoint of this study was the treatment efficacy by day 28. The outcomes were evaluated with reference to the classification system suggested by the WHO, as follows: Early treatment failure (ETF), late clinical failure (LCF), late parasitological failure (LPF) and adequate clinical and parasitological response.
Statistical Analysis
Categorical variables were presented as absolute and proportions (%). Quantitative variables were presented as means and standard deviations. Chi-square test was used to analyze significant differences of proportion, and t-test was used for differences in numerical values. Statistical analyses were conducted using SPSS 20 for Windows and checked before analysis.
RESULTS
The baseline characteristics of enrolled study was summarized in Table 1. Among 484 subjects who were admitted as subjects of this study, 47 (9.7%) tested positive for malaria by microscopy, 45 (95.7%) tested positive by Plasmodium vivax and 2 (4.3%) tested positive by Plasmodium falciparum. All patients were successfully received followed up treatments with no drop-outs. There was no difference in sex (p>0.05) between the two groups. Subjects in the Malaria (+) group were younger, even though the age difference with Malaria (-) group was small (p>0.05). There was also no difference in fever (p>0.05), although difference between two groups’ mean axillary temperatures were apparent (p<0.05). Meanwhile, there was a difference in the mean hemoglobin, where malaria patients appeared to have lower hemoglobin level. All patients who had fever at day 0 were not feverish anymore after taking DHP in the next day (D1). There were no adverse reactions or severe malaria.
The baseline characteristics of patients was summarized in Table 2. There were 24 patients without fever (asymptomatic malaria) and 23 patients with fever (clinical malaria). However, there was no characteristics difference between the two groups. There was no significant difference in all variables analyzed in the two groups (p>0.05).
The mean parasitic density on D0 started to decrease on D1 until D3, in both of clinical malaria and asymptomatic malaria. The decreased also occurred in gametocyte. There were no significant differences of parasitic density and gametocytes in all malaria patients (p>0.05). During D4, D7, D14, D21 and D28, there were no parasites found in the blood smears in all patients. The mean hemoglobin was higher in asymptomatic malaria than clinical malaria, although there was no significant difference (p>0.05).
The efficacy of the DHP combination in this study was shown in Table 3. There were 3 patients who had the same parasite density at D2 as D0, namely 2 patients with clinical malaria and 1 asymptomatic malaria. However, none of the patients had a higher parasite density at D2 than in D0. However, it was found that many patients had a higher density of parasite D2 than D1.
Meanwhile, it was found that one patient had a parasite density greater at D3 than 25% D0 density. Technically, this indicates early failure of treatment. At that time, the patient was unwilling to start second-line treatment. Interestingly, on the 4th day of blood tests, parasites were no longer found. the same results were obtained at the next examination. Up to follow-up on day 28, there was no finding of treatment failure, neither LCF nor LPF.
DISCUSSION
The main issue at the moment is malaria elimination. Efforts that have been made include improving the quality of diagnosis and evaluating the efficacy of treatment. The efficacy of antimalarials is assessed by the reduced density of plasmodium in the blood after antimalarial administration accompanied by the disappearance of clinical signs and symptoms of malaria. Decrease in drug efficacy can occur due to resistance. Antimalarial resistance occurs due to inadequate use of drugs, either due to insufficient doses or due to incomplete treatment. Early detection of decreased drug efficacy can prevent drug resistance.
DHP is the foremost ACT for uncomplicated malaria in many countries, including Indonesia. Dihydroartemisinin is one of the highly active artemisinin derivatives and the main in vivo metabolite of artesunate or artemeter. Piperaquine is bisquinoline which maintains activity against chloroquine resistant Plasmodium. Both drugs are very active against the asexual stage of Plasmodium (8). In general, therapeutic efficacy studies on DHP have shown good results for malaria infection, as well as the post-treatment prophylactic effect of delaying reinfection (4,9,10).
This study did not find any differences in the characteristics of both the malaria and non-malaria groups, as well as in the clinical malaria and asymptomatic malaria groups. Hemoglobin levels in malaria patients appear to be lower. This is consistent with the pathogenesis of malaria, although there was no significant difference in hemoglobin levels between clinical malaria and asymptomatic malaria groups. Body temperature above 37.5 oC can still be used as an initial screening for malaria (p<0.05), although this variable cannot differentiate between clinical malaria patients and asymptomatic malaria (p>0.05). This suggests that microscopic examination is the standard for the diagnosis of malaria.
Several studies have reported the side effects of the drugs, which are nausea, diarrhea, and vomiting. Other side effects reported are anemia, dizziness, coughing and difficulty of sleeping (11-13). Although there is no evidence of cardiotoxicity, piperaquine can make the QT interval lengthen (14-16). This combination should also get serious attention when given to patients with age over 70 years, body weight <5 kg, and liver and kidney disorders (15,16).
This study actually also observed at adverse events, adherence, fever clearance time and parasite clearance time as indicators of treatment. Adverse events were assessed by direct interview. Adverse events were defined as a condition of any unfavorable, unintended sign, symptom, syndrome or disease that develops or worsens concomitant with the use of study medicines, regardless of whether it is related to the study medicines. But throughout the observations in this study, there were no adverse events of the drugs that bothered the patients, so all patients were adherent to taking medication according to the rules. The same results were obtained in several other studies (17-20).
By 24 hours after treatment, all of the patients were afebrile. Therefore, the time needed to relieve fever is around 24 hours. Other studies have also found a fast fever-reducing effect on DHP (6,17,18). Measurement of parasite clearance time cannot be done because the patient was only willing to draw blood once a day. Even the calculation of parasite density every day cannot be done exactly per 24 hours. However, asexual parasites were no longer seen in 2 patients (4.3%) in D2, 13 patients (27.7%) in D3 and 32 patients (68%) in D4, respectively. Meanwhile, gametocytes were no longer seen in 2 patients (4.3%) in D2, 13 patients (27.7%) in D3 and 32 patients (68%) in D4, respectively.
This study found an interesting phenomenon, namely fluctuation in parasite density after treatment. Parasitic density is expected to decrease gradually from the start of treatment (D0) until all parasites are gone on the third day after treatment (D3). However, this study found the same parasite density in D2 as D0 in 3 patients (3/47; 6.38%). It was even found that 20 people (20/47; 42.55%) had a greater parasite density in D2 compared to D1. Parasite was still found in D3 in 16 people (16/47; 34.04%).
This result is different from several other studies which found that asexual parasite disappearance in some patients started in D1 and disappeared completely in D3 (17,21). However, these results differ from the decrease in the number of sexual parasites (gametocytes), where gametocytes begin to disappear in D3 (21) and have not even shown a decrease up to D7 (17).
In this study, a once per day, 3-dose treatment of DHP was a simple, highly efficacious, and generally well-tolerated treatment for uncomplicated malaria, even one of them had a density greater than 25% density at D0. Results of this study clearly indicate that DHP is still highly effective (46/47 or 97.87%).
The treatment efficacy in this study was still good, even the efficacy was still above 95%. The same results were found in several studies (6,8,18,19,22-26). Some studies have even stated that giving this combination of drugs can reduce recurrence by up to 42 days (24,27). The results of this study can also provide an idea that the level of patient compliance in the treatment process is still good. This is important to note because patient adherence to treatment greatly affects the efficacy of the drug (24).
CONLUSION
This study found one patient who was categorized as ETF, who needs serious attention. This information reflects a possible decrease in the ability of antimalarials to eliminate parasites in the patient’s blood. This can be seen from the fluctuation of parasite density after antimalarial administration. A decrease in the ability of these drugs can indicate an early sign of drug resistance. For this reason, an effort is needed to determine what risk factors affect the density fluctuation of the parasite so the drug resistance process can be prevented.
Observation of drug efficacy is one part of many efforts needed to break the chain of malaria transmission. One of the inhibitors of the malaria elimination process is the occurrence of antimalarial resistance. Observation of early signs of drug resistance in primary care, is the answer for malaria elimination.
ACKNOWLEDGMENTS
This research was funded by Ministry of Research, Technology and Higher Education through Research Institute, Universitas Sumatera Utara. We thank the health workers in health care services in Batubara district, and also to the holders of the malaria program in Batubara district, North Sumatera. We also thank all the participants in this study.
*Ethcis
Ethics Committee Approval: This study was approved by the Health Research Ethical Committee, Medical Faculty, Universitas Sumatera Utara (decision number: 262/KOMET/FK USU/2015).
Informed Consent: Each participant was clearly informed about the objective of the study, and verbal permission from the head of each household was obtained.
Peer-review: Externally and internally peer-reviewed.
Financial Disclosure: The author declared that this study received no financial support.
