treatment of malaria in pregnancy (IPTp) in pregnant women and infants as well as parenteral artemisinin monotherapy and quinine for severe malaria WHO (2015). 

In the next few years, the most advanced malaria vaccine (RTS,S/AS01) will be available in the market (Penny et al., 2015). However, although useful, the vaccine is only moderately effective (Penny et al., 2015), and therefore, optimizing drug treatment of malaria will remain pivotal to malaria control in the foreseeable future.

It is well known that efficacy of antimalarial drugs in the ideal situation of clinical trials is much higher than their effectiveness under the real-life situation, otherwise known as community effectiveness (Krause and Sauerborn, 2000). For any drug, including antimalarial, to be effective, it has to be of good quality, prescribed in compliance with evidence-based instructions after a correct diagnosis, and taken at an appropriate dosage, for an adequate duration (Krause and Sauerborn, 2000). Accordingly, community effectiveness is determined by drug efficacy, availability, and quality, as well as physicians’ adherence and patients’ adherence.

The aim of this review is to provide an updated narrative review of systematic reviews on the extent of the problem of suboptimal antimalarial community effectiveness in sub-Saharan Africa (SSA) with emphasis on the causes and possible solutions. Selected recent primary studies will also be cited to illustrate certain points. The results and methodological qualities of the included reviews are summarized in Table 1. 

Community effectiveness of antimalarial agents can be assessed using two measures, namely systems effectiveness (Research, 2011) and effective coverage (Tanahashi, 1978; Shengelia et al., 2005). Systems effectiveness of antimalarials assesses the proportion of the community that gets cured of malaria fever after receiving drugs from formal healthcare centres (Galactionova et al., 2015). On the other hand, effective coverage, which is much wider, assesses the overall proportion of the community who are cured of malaria fever. This measure incorporates cure from self-treatment or medicines obtained from informal healthcare providers in addition to systems effectiveness (Galactionova et al., 2015).

Although artemisin in derivatives, the most frequently prescribed antimalarials, are still very effective in SSA; community effectiveness of malaria therapy is currently very low. A recent mathematical modeling based on available data (Galactionova et al., 2015) revealed a high average rate of access to malaria therapy by patients with fever (up to 60%) in the sub-Saharan African region. On the other hand, effective coverage  was  found  to  be low (about 40% on the average) in the region, ranging from 8% in Somalia to 72% in Botswana. A similar pattern was observed in systems effectiveness, which varies from 0.1% in Chad to about 68% in Botswana (Galactionova et al., 2015).  The details of the data for other countries are presented in Table 2.

1. Delay in adoption of evidence-based international policies on management of malaria. For example, by the end of 2013, intermittent preventive treatment of malaria in infants was adopted by only one country in SSA (Burkina Faso) (WHO, 2014). Similarly, although WHO recommended seasonal malaria chemoprevention to 16 countries in the region, only six (Chad, Congo, Mali, Niger, Senegal, and Togo) have complied so far (WHO, 2014).

2. Poor compliance of the healthcare practitioners with first-line treatment policy: Compliance among healthcare providers represents the worst affected component of community effectiveness, with a median of 28% (Galactionova et al., 2015). This attitude has been shown to lead to antimalarial treatment failure. Countries with a low rate of compliance among healthcare givers have been observed to show a wide difference between access and effective coverage. A good example of this situation is the particular case of Nigeria, a nation with a very high access to antimalarial treatment (84%), but low effective coverage (41%), which is mainly attributable to low compliance (12%) with first-line treatment policy among its health practitioners. On the other hand, few countries, including Uganda, Botswana and Sao Tome and Principe, have high rates of both access to treatment and compliance with their respective first line treatment policies, resulting in high effective coverage (Galactionova et al., 2015). The details are shown in Table 2.

Numerous recent studies in sub-Saharan Africa have reported instances of non-compliance with the recommended national malaria treatment policy. For example, contrary to WHO recommendation, about 40% of individuals suspected to have malaria are not confirmed using laboratory test (WHO, 2014). Accordingly, individuals are still presumptively treated with antimalarials (Ezenduka et al., 2014; Isiguzo et al., 2014; Tabernero et al., 2014). Additionally, prescription of ACTs to febrile patients who tested negative for malaria parasites remains common (Hamer et al., 2007; Ndyomugyenyi et al., 2007). These two practices may lead to over treatment with ACTs and a possible increase in the risk of emergence of resistance.

In addition,  recent  reports  in  SSA  have  documented poor adherence of health staff to appropriate management of malaria in pregnancy (Mbonye et al., 2013; Hill et al., 2014) and non-implementation of the guidelines on IPTp (Harrison et al., 2013). Frequent prescription of artemisinin monotherapy (Builders et al., 2014; Afriyie et al., 2015; Elmannan et al., 2015; Romay-Barja et al., 2015) and lack of adoption of first-line  ACT among healthcare providers in SSA have also been reported (Harrison et al., 2012).

The reported high rate of presumptive treatment of malaria by physicians in Africa is mainly attributed to lack of trust in the results of laboratory tests (Chandler et al., 2008; Rowe et al., 2009; Kyabayinze et al., 2010). Another factor contributing to poor adherence to guidelines by healthcare providers is insufficient knowledge. For example, Agbo et al. (2012) have reported poor knowledge of treatment guidelines among health staff at primary healthcare centres in Nigeria. Poor knowledge of healthcare providers about IPTp (Diala  et  al.,  2013;   Rabiu   et   al.,   2015)  and  appropriate treatment of malaria in pregnancy (Rabiu et al., 2015) has also been documented.

3. Poor quality of antimalarial drugs in SSA: A recent review of 251 antimalarial quality reports from some malaria-endemic countries (Tabernero et al., 2014) has found out that about 30.1% of the antimalarials sampled were of poor quality, of which 39% were fake. However, the total picture of the problem is far from clear, due to unavailability  of  data  from  the  majority   of   the affected nations (60%) as well as the poor methodological quality of most of the studies (Tabernero et al., 2014). In SSA, it has been estimated that up to 17% of AL purchased at informal health sectors are of poor quality. On the other hand, the estimated prevalence of fake SP is even much higher, at 33% (Tabernero et al., 2014). Most of the fake antimalarials originated in South-east Asia (Newton et al., 2011; Karunamoorthi, 2014). Renschler et al. (2015) estimated that in 2013 over 122,000 under-five children died in SSA from poor quality antimalarials.

The lucrative nature and the perceived low risk (with lenient punishment) associated with the business of making and marketing fake drugs, ineffective law enforcement and drug regulatory agencies as well as corruption are the major factors associated with the continuing existence of the problem in the sub-Saharan African region (Karunamoorthi, 2014; Tabernero et al., 2014).

4. Suboptimal effectiveness and resistance to antimalarials: In 2009, the first cases of artemisinin-resistant P. falciparum infection were observed in Cambodia (Frenk, 2010) the same region where chloroquine and SP resistance originated before it spread to Africa and other parts of the world. The resistance has been linked to a mutation in the kelch13 gene (gene ID PF3D7_1343700) (Ariey et al.,  2014;  Mok  et  al., 2015; Straimer et al., 2015). Since then, the resistant mutants have spread to other East Asian nations (WHO, 2014), but it is yet to be documented in SSA. However, there are reports of reduced effectiveness of specific ACTs in some parts of African region (Bonnet et al., 2009; Zwang et al., 2009; Group, 2011). The report of a severe case of malaria not responding to artemisinin derivatives observed in a Vietnamese man who returned from Angola is a quite disturbing development (Van Hong et al., 2014).

A meta-analysis by our team suggested that the efficacy of ACTs varies from one country to another (Bello et al., 2010). For example, studies from East African nations, where resistance to amodiaquine is common, suggest the superiority of AL (Table 3). On the other hand, reports from some West African nations (where amodiaquine resistance is low) indicated that ASAQ is non-inferior to  AL (Happi et al., 2006; Ndiaye et al., 2009; Faye et al., 2010). Such variation in response to a particular ACT has been reported even from the same country (Bonnet et al., 2009).

One disadvantage of the use of ASAQ is the selection of mutants that are resistant to both chloroquine and amodiaquine (Frank et al., 2011; Menard et al., 2012; Van Tyne et al., 2013). It is well-known that amodiaquine undergoes cross-resistance with chloroquine (Happi et al., 2006) and resistance to amodiaquine, just like that of chloroquine, has been associated  with  mutations in the pfcrt and pfmdr genes (Djimdé et al., 2001; Sidhu et al., 2002). On the other hand, there is evidence suggesting that the use of AL instead of ASAQ (Alifrangis et al., 2009; Mwai et al., 2009) or even the use of concurrent multiple first-line antimalarial therapies (e.g., AL and ASAQ) as practised in some West African countries (Salissou et al., 2014) may confer an advantage in reversing chloroquine resistance.

Due to their reduced host immunity with con-sequent elevation and recurrence of parasitaemia, malnourished, especially underweight, young children, are found to be less responsive to ACTs and may require a higher dose of artemether (White, 2002; Verret et al., 2011).

5. Poor patients’ adherence to antimalarial therapy: According to a recent systematic review and meta-analysis, adherence to ACTs was significantly lower among patients who procured the drugs from patent medicine stores as compared to their counterparts who purchased the medicines from public health centres (Yakasai et al., 2015). The authors suggested that the finding might be due to the fact that patients received less qualitative instructions from patent medicine vendors. Patient adherence to ACTs also varied between different populations (Banek et al., 2014).

Self-medication with antimalarials is also common (Mussa and Gedif, 2013). In sub-Saharan Africa, medicine vendors play a role in the delivery of 15 to 85% of child healthcare products. Many of these distributors do not possess an updated licence (Palafox et al., 2014). The availability of a particular antimalarial in these shops is mainly driven by the patients demand and preference rather than the dictation of the national guidelines (Palafox et al., 2014).

Subsidy of antimalarials was first advocated by Gelband et al. (2004). The Affordable Medicines Facility for malaria (AMFm), an initiative aimed at subsiding the first-line ACTs, was created in 2008 with support from Global Fund (Gelband and Laxminarayan, 2015). However, although ACTs are subsidized or even given free in public health centres in SSA, access to the drugs is limited by frequent stockouts (Palafox et al., 2014). As a consequence, in African countries, non-ACT drugs remain more widely available and less expensive than ACT or artemisinin monotherapy (Rao et al., 2013; Palafox et al., 2014; Lussiana, 2015; Palafox et al., 2015). Accordingly, many patients, being poor and buying drugs from their pockets tend to buy the less expensive non-ACTs.

6.   Poor access to antimalarials: It has been documented that up to 15 million pregnant women did not receive malaria prophylaxis in 2013 (WHO, 2014). Multiple studies have identified barriers to optimal utilization of IPTp, including out-of-pocket payments (due to lack of health insurance), lost time, stockouts, the absence of a clear policy and poor knowledge of the  providers  (Hill  et al., 2013).

Any strategy that can improve the quality or access to recommended antimalarials and increase provider adherence to malaria treatment guidelines, as well as patient adherence to the treatment, can lead to improvement of community effectiveness of the drugs.

Adoption and implementation of policies that will reduce the costs of genuine drugs (e.g., extension of the subsidy of recommended antimalarials to private health sector) will go a long way to making antimalarial counterfeiting business not attractive (Karunamoorthi, 2014). Another strategy that can help in reducing the menace is creation and enforcement of laws designed to severely punish the culprits as well as honor informants who assist in the successful conviction of those found guilty of the crime (WHO, 2005). A recent systematic review has indicated the superior effectiveness of using a multifaceted approach to tackling drug counterfeiting compared to individual interventions (El-Jardali et al., 2015). The problem of substandard and varying batch-to-batch pharmaceutical products maybe reduced through efficient internal and external quality control.  

Provider adherence to antimalarial treatment guidelines, including increased  implementation  of   IPTp,  has  been shown to improve following enhanced training of healthcare personnel (Mbacham et al., 2014; Mbonye et al., 2014). Also, the common practice of malaria overtreatment with ACTs may be reduced by subsidizing rapid diagnostic tests (Lussiana, 2015).

Similarly, improvement in patient adherence to anti-malarial treatment has been documented with strategies such as community education and a combination of visual media/verbal information (Fuangchan et al., 2014).

Availability of artemisinin-derived products can be optimized by expanding the subsidy to the private sector and increasing the yield of artemisinin from plant origin and supporting the semi-synthetic production of artemisinin (Fuangchan et al., 2014).

Optimal therapy of malaria can also be achieved by variation of the doses of the constituents of ACT. For instance, there is evidence that the use of an optimized fixed dose combination of ASAQ is associated with success in therapy (Sirima et al., 2009; Group, 2015), while loose non-fixed dose formulation is associated with recrudescence at day 28 of therapy (Group, 2015). Systematic reviews revealed the effect of changes in dosing on the efficacy of AL (Dose et al., 2015) and dihydroartemisinin-piperaquine (Group, 2013).

The continuing search for an effective alternative to artemisinin derivatives is highly needed due to the imminent threat of the spread of artemisinin resistance from South East Asia to other malaria-endemic nations, especially in SSA. Being a non-lucrative business, development of new drugs for parasitic infections (diseases of underdeveloped nations) is not attractive to pharmaceutical companies (Pink et al., 2005). Drug repositioning-exploration of registered drugs for new indications is a potentially cost-effective strategy for discovery of new interventions against such diseases. Using molecular docking against P. falciparum targets, our research team has applied such approach to search for new treatments for malaria with some promising results (Yunusa et al., 2015).

There is a large amount of data on the subject area of community effectiveness of antimalarial drugs in sub-Saharan Africa. Therefore, an updated review of systematic reviews on the subject area was conducted citing selected recent primary studies to illustrate some points. A qualitative narrative approach was chosen rather than a quantitative approach to synthesizing the data due to a high degree of heterogeneity of the studies as well as the duplication of many primary studies included in the reviews. One limitation of this approach of reviewing secondary literature was that the quality of the evidence presented in the review depends on the quality of the systematic reviews. Generally, the methodological quality of the reviews was fair and comparable to that found in other reviews  of  systematic  reviews  (Burda  et al., 2011).

Community effectiveness of antimalarial drugs remains low in sub-Saharan Africa. Although various factors have been documented to contribute to this picture, provider, and patient non adherence to first line treatment is the major factor that plays a key role in the development of the problem. Accordingly, community education and enhanced training of healthcare providers are pivotal in combating the problem.

ACT, Artemisin-based combination therapy; AL, artemether-lumefantrine; ASAQ, artesunate + amodiaquine; IPTp, intermittent preventive treatment of malaria in pregnancy; SP, sulfadoxine-pyrimethamine; SSA, sub-Saharan Africa.

The authors have not declared any conflict of interests.