Background
Malaria continues to be one of the major public health problems in many regions of the world, particularly the developing countries [
1]. African region accounts for about 90% of global malaria cases and deaths, in which majority are from Sub-Saharan African (SSA) countries [
2] (carries about 80% of the global malaria burden).
A majority (90%) of Tanzanians (both mainland and Zanzibar) live in moderate to high malaria endemic region [
2]. About 10 to 12 million people in Tanzania contact malaria every year and 80,000 of them die, in majority children.
Anopheles gambiae and
Anopheles arabiensis are the two species of Anopheles mainly responsible for malaria transmission in Tanzania. Ninety-six percent of malaria in Tanzania is caused by
Plasmodium falciparum and the remaining 4% due to
Plasmodium malariae and
Plasmodium ovale [
2]. Co-existing of different species of
Plasmodium determine appropriate treatment approach [
3] and is one of the criteria to be considered in the development and review of guidelines.
Proper diagnosis and prompt treatment with effective anti-malarial drugs are one of the major tools in the control of malaria. The emergence of resistance of
P. falciparum to anti-malarial drugs has led to changes of drugs from chloroquine to sulfadoxine–pyrimethamine (SP) and currently artemisinin-based combination therapy (ACT) [
4,
5]. In 2006, ACT was introduced in Tanzania and artemether–lumefantrine (ALU) was accepted as the first-line and dihydroartemisinin–piperaquine (DHA-P) as the second-line for management of uncomplicated malaria in both adult and children [
6]. Since the introduction of ALU, the innovator’s product Coartem
® (Novartis Pharma AG, Basel Switzerland) was prequalified by the Tanzanian government and the product was available in all public health facilities. Due to high cost and poor availability of the innovator’s product, the government of Tanzania prequalified the use of generic ALU, which is now more widely available in public health facilities than Coartem
®. Artefan
® (Ajanta, Pharma Ltd, India) was the first generic drug to be prequalified by the government of Tanzania and is still available in the supply chain.
For the purpose of ensuring good performance and detection of emergence of resistance of anti-malarial drugs, especially those used as a first-line and second-line in a country, the World Health Organization (WHO) recommends frequent monitoring of their effectiveness. Early parasite clearance after initiation of ACT is considered to be an indicator of treatment outcome [
7,
8]. Peripheral parasitaemia on day 1, day 2 and day 3 following initiation of ACT can be used to assess treatment outcome in individuals with uncomplicated malaria [
4]. Peripheral parasitaemia on day 1 and 2 or parasite density on day 3 of > 25% parasite density of day 0, is regarded as early treatment failure. Moreover, early parasite clearance is used as an indicator of
P. falciparum resistance to artemisinin. Proportion of patients with detectable parasitaemia on day 3, 72 h following initiation of anti-malarial therapy is used to predict resistance (i.e. if 10% of the patients have peripheral parasitaemia on day 3 is regarded to be a sign of
P. falciparum resistance to artemisinin [
5,
9]. Adequate clinical and parasitological response (cure rate) is mainly defined by the absence of peripheral parasitaemia on day 28.
Generic artemisinin-based combinations play a great role in the management and control of malaria in developing countries as they are highly affordable and readily available. However, availability of substandard anti-malarial drugs in SSA, including Tanzania, has been reported and they pose a threat to the gained successes in malaria control [
7,
8]. Poor quality anti-malarial drugs expose parasites to a sub-therapeutic drug pressure, thus providing windows for parasite selection, treatment failures and spread of tolerance/resistance and may also be a threat to patients’ safety [
8,
10]. In 2012, Minzi et al. reported compliance of bioequivalence criteria of Artefan and Coartem in relation to AUC and Cmax, as per FDA recommendations but the generic product could not meet the 95% confidence interval bioequivalence criterion leaving a room of doubt on the effectiveness of the generic product [
11]. The objective of this study was to compare malaria treatment outcome of Artefan and Coartem in the management of uncomplicated malaria amongst Tanzanian children.
Discussion
After the introduction of artemisinin-based combination therapy (ACT) as the first-line and second-line option in the management of uncomplicated and complicated malaria by the WHO together with other methods of malaria prevention such as insecticide-treated nets (ITN) and indoor spraying, prevalence of malaria has decline in many countries. Protecting the efficacy of ACT for the treatment for falciparum malaria is among the top global public health priorities. The presence of falsified and substandard drugs has been reported in many parts of the world, including sub-Saharan Africa (SSA) [
16]. The WHO has identified anti-malarials as one group of drugs at highest risk of being falsified or sub-standard, because of high demand especially in moderate to high endemic regions. Previous studies reported the presence of poor quality and substandard anti-malarial drugs in the Tanzanian market [
17,
18]. Regular surveillance and assessment of the performance of generic anti-malarials through therapeutic efficacy studies is of importance for malaria control.
In this study, the therapeutic efficacy of generic anti-malarial Artefan and innovator’s product Coartem were compared. Early parasite clearance was excellent for both drugs with no detected peripheral parasitaemia on day 3 (72 h, following initiation of therapy) using microscopy. Temperature clearance was also outstanding for both Artefan and Coartem, with only 1 (1.1%) patient in the Artefan arm having temperature above 37.5 °C on day 3. The early parasite clearance in this study on day 3 was the same as what was reported in Uganda, in which early parasite clearance following treatment with artemether-lumefantrine was excellent [
4].
Resistance of
Plasmodium species to artemisinin has been reported in eastern and southern Asian countries [
19], but not yet in Africa. In the present study, none of the study participants treated with Artefan or Coartem had peripheral parasitaemia on day 3. This may indicate absence of resistant strains of
P. falciparum to artemisinin in Tanzania. This is in line with the WHO 2009 anti-malarial protocol, that if 10% of the study participants have peripheral parasitaemia on day 3, it is an indicator of emergence of artemisinin resistance to
Plasmodium species [
13].
Early treatment failure (ETF) was not observed in both Artefan and Coartem treatment arms, whereas late clinical failures (LCF) were 3.6% and 1.3% in Artefan and Coartem arms, respectively. However, late parasitological failures (LPF) were high in both Artefan (15.4%) and Coartem (22.7%) arms. Artemisinin products (for this study artemether) have a short half-life. Since most of the LCF and LPF occurred on day 21 and 28 with only one LPF occurring on day 14, its means the partner drug (lumefantrine) offers a prolonged protection against malaria of two to 3 weeks. From the survival analysis, cumulative hazard proportion curve shows that children using Coartem might be at higher risk of parasitological failure compared to children using Artefan. The observed differences in late treatment failures (LCF and LPF) between Artefan and Coartem were not statistically significant, an indication that the generic anti-malarial Artefan is effective for management of uncomplicated malaria in Tanzanian children.
The observed LCF in this study is comparable to what was reported in Ethiopia [
20]. In the Ethiopian study, LCF were 1.4% on day 21 and 2.8% on day 28. On the other hand, the results of LCF are less compared to 17.8% which was in Uganda [
4]. Moreover, late parasitological failures observed in this study are higher compared to what was reported in Ethiopia by Kinfu et al. and Mekonnen et al., in which LPF of 0.0% and 4.5%, respectively, were observed after 28 days follow following treatment with ALU [
20,
21]. In addition, the observed LPF is much lower compared 32.9% that was reported in Uganda [
4]. The observed differences in these studies could be due to endemicity of malaria in the respective study areas and nature of the study. Most of the studies were efficacy studies in which community health workers were deployed work with parents and guardians in making sure that all children take their medicines as prescribed.
The WHO recommends the use of microscopy as a golden standard for diagnosis of malaria in middle and low income countries. In this study, microscopy was also used to assess the performance of anti-malarial drugs. Using microscopy, the observed adequate clinical and parasitological response (ACPR) were 83.3% in children in the Artefan and 77.3% in the Coartem arms. PCR uncorrected cure rate were > 80% for Artefan and 75% for Coartem. These results indicate that both generic Artefan and innovator’s product Coartem are effective for the treatment of uncomplicated malaria in children.
High adequate clinical and parasitological responses and malaria cure rate of ALU have been reported in different therapeutic efficacy studies. For instance, 100% adequate clinical and parasitological response were reported in South West Ethiopia in children under 5 years of age (23), and very low (45.4%) in Uganda [
4]. PCR uncorrected cure rate were also reported to be very high (98.8%) in northwest Ethiopia [
22] and south west Ethiopia (96.3%) [
23]. The ability of artemisinin to clear the biomass of Plasmodium within short hours of treatment and prevention of maturation of the gametocytes by the partner drug (lumefantrine) offer the maximum performance of ALU.
Based on mid upper arm circumference (MUAC), most of the participants in this study had good nutrition status. The difference in clearing malaria parasites between those with poor nutrition status and good nutrition status could not be established. Studies have shown conflicting conclusions on the role of nutrition in relation to malaria parasite clearance with some linking poor parasite clearance and malaria morbidity and mortality with poor nutrition status [
24,
25], while other studies reporting negative association between parasite clearance with malaria-induced morbidity and mortality with poor nutrition status [
26,
27]. Nevertheless, emphasis must be put on taking food stuffs which are rich in iron in order to minimize incidences of anaemia in children suffering from malaria [
28].
The limitation of this study is that it was designed to mimic the routine standard of care for management of uncomplicated malaria in Tanzania. In this approach, patients are given anti-malarial drugs with instruction to take the prescribed doses at home. Therefore, information on the parasite density during day 1 and day 2 after drug administration were not collected. In addition, adherence to the prescribed drugs was based on self-reports from patients, parents or guardians. Also, microscopy instead of molecular techniques, such PCR, was used to identify Plasmodium species. Therefore, the reported cure rate in both arms of the study are PCR uncorrected.
Authors’ contributions
MK, OM, AK and EA conceived and deigned the study. MK participated in data collection. MK, RM and SP participated in data analysis. All authors participated in developing the manuscript. All authors read and approved the final manuscript.