Recent updates in the WHO guidelines for malaria case management

Abstract

This is a brief review that highlights recent updates in malaria case management. Recent WHO revisions include a new artemisinin-based molecule (artesunate-pyronaridine), revising the recommendations for treating uncomplicated malaria during the first trimester of pregnancy and optimising primaquine dose to prevent relapses. The review also highlights innovative ideas to improve the implementation of guidelines for severe malaria and pre-referral treatment with rectal artesunate. Some issues under review for guideline revisions have also been pointed out.

INTRODUCTION

This short review highlights the most important recent updates to guides and recommendations regarding the use of drugs in malaria case management. More details are provided in the latest version of the consolidated WHO Guidelines for Malaria which is posted online and frequently updated. The review is also linking guidelines with some plans and policy changes regarding malaria case management.

TREATMENT OF UNCOMPLICATED MALARIA

1: Introduction of artesunate-pyronaridine (ASPY)

Up to late 2022, the WHO treatment guidelines for malaria the recommended artemisinin combination therapies (ACTs) were as follows [1]:

PREVIOUS RECOMMENDATION

Treat children and adults with uncomplicated P. falciparum malaria (except pregnant women in their first trimester) with one of the following recommended ACTs:

artemether + lumefantrine

artemether+ amodiaquine

artemether + mefloquine

artemether + piperaquine

artemether + sulfadoxine-pyrimethamine (SP)

Concerns about artemisinin resistance have led to global initiatives to develop new partner drugs to protect artemisinin derivatives in ACT. In 2019, WHO issued an Information Note on ASPY, an additional ACT that received a positive scientific opinion from the European Medicine Authority. The Note also mentioned that this preparation had been added as an antimalarial drug for prequalification, stating that:

ASPY can be considered a safe and efficacious artemisinin-based combination therapy (ACT) for the treatment of uncomplicated malaria in adults and children weighing 5 kg and over in all malaria-endemic areas. Countries can consider including this medicine in their national treatment guidelines, procure it, and monitor its safety and efficacy. Deployment should be conducted under a pharmacovigilance system as required for the introduction of all new medicines [2].

In June 2022, the WHO Guidelines for Malaria still did not formally recommend ASPY, but mentioned this drug as an ACT that could be considered for treating uncomplicated malaria in adults and children weighing 5 kg and over in endemic areas [3].

In November 2022, the WHO malaria guidelines formally recommended ASPY[4].

UPDATED RECOMMENDATION, (November 2022):

ASPY is recommended as an artemisinin-based combination therapy option for the treatment of uncomplicated P. falciparum malaria.

The list of ACTs for uncomplicated malaria now includes six molecules [4]:

UPDATED RECOMMENDATION, (November 2022)

Treat children and adults with uncomplicated P. falciparum malaria with one of the following ACTs:

• artemether-lumefantrine (AL)

• artesunate-amodiaquine (AS+AQ)

• artesunate-mefloquine (ASMQ)

• dihydroartemisinin-piperaquine (DHAP)

• artesunate + sulfadoxine-pyrimethamine (AS+SP)

• ASPY (2022)

*Artesunate + sulfadoxine-pyrimethamine and ASPY are not recommended for use in the first trimester of pregnancy.

The recommendation of ASPY was based on evidence, including a Cochrane review that evaluated the efficacy of ASPY to alternative ACTs for treating people with uncomplicated Plasmodium falciparum malaria, and the safety of ASPYand other pyronaridine treatments compared to alternative treatments [5]. ASPY was efficacious against uncomplicated P. falciparum malaria; achieved a polymerase chain reaction (PCR)-adjusted treatment failure rate of less than 5% at days 28 and 42; and may be at least as good as or better than, other marketed ACTs.

Another study was a single-arm, open-label, cohort event monitoring study conducted at six health centres in Cameroon, the Democratic Republic of Congo, Gabon, the Ivory Coast and the Republic of Congo between June 2017 and April 2019. ASPY had good tolerability and effectiveness in this study. These findings supported ASPYas an operationally valuable addition to the management of acute uncomplicated malaria [6]. ASPY has shown significant treatment effects and was non-inferior in efficacy compared to the currently recommended ACTs. Adding this new ACT is expected to provide an alternative treatment for uncomplicated malaria treatment, reducing the pressure on the partner medicines in the face of emerging artemisinin partner drug resistance.

Cautions with ASPY

Safety studies indicated that ASPYincreases the risk of episodes of abnormally raised ALT. The observational data did not signal an excess of clinically significant adverse effects. There is a lack of information on drug tolerability in patients with pre-existing liver conditions (e.g., hepatitis) or from those with risk factors for liver disease. Also, coadministration of potential hepatotoxic medicines (including paracetamol commonly used in patients with malaria), might have a cumulative adverse effect on the liver. WHO added the following points to the recommendation

• ASPY should be avoided by individuals with known liver disease (clinically apparent liver disease) because ASPY is associated with liver transaminitis.

• Pharmacovigilance should be strengthened where ASPY is used for the treatment of malaria.

2: Treatment of uncomplicated falciparum malaria during the first trimester of pregnancy

Compared with quinine, ACTs have significantly better effects concerning efficacy, effectiveness and tolerability compared to quinine in women in their second and third trimesters of pregnancy as confirmed by systematic reviews showing that treatment failures are more likely with quinine than with AL in the second and third trimesters of pregnancy [7]. Thus, ACTs were recommended for treating uncomplicated falciparum malaria during pregnancy’s second and third trimester. However, for the first trimester of pregnancy, up to late 2022, the WHO guidelines stated [1]:

PREVIOUS RECOMMENDATION

Treat pregnant women with uncomplicated P. falciparum malaria during the first trimester of pregnancy with seven days of quinine + clindamycin.

This recommendation avoided exposing women in the first trimester to artemisinin because animal studies had reported that artemisinin was found to deplete embryonic erythroblasts at relatively low doses, leading to malformation or embryonic death [8,9]. The adverse effects included embryo resorption, pregnancy loss and congenital anomalies, including shortening of the long bones and heart defects (ventricular septal and great vessel defects) [10–12].

Dellicour et al. [13] conducted a meta-analysis of prospective observational studies comparing the risk of miscarriage, stillbirth and major congenital anomaly (primary outcomes) among first-trimester pregnancies treated with artemisinin derivatives versus quinine or no antimalarial treatment. They found no evidence of embryotoxicity, or teratogenicity based on the risk of miscarriage, stillbirth or major congenital anomalies associated with artemisinin during the first trimester of pregnancy. There was no difference in the risk of miscarriage associated with the use of artemisinin anytime during the first trimester (n = 37/671) compared with quinine (n = 96/945). There was also no difference in the risk of stillbirth (artemisinin, n = 10/654; quinine, n = 11/615; adjusted hazard ratio (aHR) = 0.29 [95% CI 0.08–1.02], p = 0.053). There was also no difference in the risk of miscarriage and stillbirth combined (pregnancy loss) [aHR = 0.58 (95% CI 0.36–1.02), p = 0.099]. The corresponding risks of miscarriage, stillbirth and pregnancy loss in a sensitivity analysis restricted to artemisinin exposures during the embryo sensitive period (6–12 wk gestation) were as follows: miscarriage aHR = 1.04 (95% CI 0.542.01), I2 = 0%, p = 0.910; stillbirth aHR = 0.73(95%CI 0.262.06), p = 0.551; and pregnancy loss aHR = 0.98 (95%CI 0.522.04), p = 0.603. The prevalence of major congenital anomalies was similar for first-trimester artemisinin [1.5% (95%CI 0.6%3.5%)] and quinine exposures [1.2%(95%CI 0.6%2.4%)].

The findings of an updated comprehensive meta-analysis of pregnancies exposed to artemisinin during the first trimester provided evidence for updating this recommendation. This analysis included seven eligible studies that included 12 cohorts [14]. All 12 cohorts contributed individual patient data, including 34,178 pregnancies, 737 with confirmed first-trimester exposure to artemisinin-based treatments and 1,076 with confirmed first-trimester exposure to non-artemisinin therapies. Adverse pregnancy outcomes occurred in 42/736 (57%) of artemisinin-exposed pregnancies compared with 96/1,074 (89%) of non-artemisinin-exposed pregnancies in the first trimester (aHR 0.71, 95% CI 0.49–1.03). Similar results were seen for the individual components of miscarriage (aHR = 0.74, 0.47–1·17), stillbirth (aHR = 0.71, 0.32–1.57) and major congenital anomalies (aHR = 0.60, 0.13–2.87). The risk of adverse pregnancy outcomes was lower with artemether–lumefantrine than with oral quinine in the first trimester of pregnancy [25/524 (4.8%) vs. 84/915 (9.2%); aHR 0.58, 0.36–0.92].

Because treatment with AL was associated with fewer adverse pregnancy outcomes than quinine and because of ACTs’ known superior tolerability and effectiveness in non-pregnant women and during the second and third trimester, AL was considered the preferred treatment for uncomplicated P. falciparum malaria in the first trimester. Treatment in the first trimester of pregnancy has been updated in the version of November 2022 of the WHO Guidelines for Malaria [4].

UPDATED RECOMMENDATION (November 2022):

Treat pregnant women with uncomplicated P. falciparum malaria with artemether-lumefantrine during the first trimester.

It should be noted that the current evidence is insufficient to make a recommendation for routine use of the other ACTs (artesunate-amodiaquine, artesunate-mefloquine and dihydroartemisinic piperaquine) in the first trimester of pregnancy because data on exposures to other ACTs are limited. These other ACTs may be considered for use where AL is not recommended for uncomplicated malaria or is not available, given the demonstrated poorer outcomes of quinine treatment, along with the challenges of adherence to a 7-day course of treatment [15].

ACTs containing sulfadoxine-pyrimethamine are contraindicated during the first trimester of pregnancy because antifolates are contraindicated in the first trimester of pregnancy [16,17].

ASPY is also omitted because there is currently no documented record of the use of ASPY during the first trimester of pregnancy.

It should also be emphasised that parenteral artesunate is still the recommended treatment for severe malaria in all stages of pregnancy.

Despite this updated recommendation, WHO still calls for continued pharmacovigilance and clinical research, including prospective controlled trials on the efficacy and safety of antimalarial medicines for the treatment of malaria in pregnancy, which should be supported and funded. The implementation of the new recommendation should also be closely monitored, taking into account the local socio-cultural factors that influence the patient uptake of antimalarial drugs during pregnancy [18].

MANAGEMENT OF SEVERE MALARIA

1: Guidelines for the management of severe malaria

Management of severe malaria includes clinical assessment, specific antimalarial treatment, additional treatments for complications and supportive care. The current WHO standards that guide the management of severe malaria are included in three publications: (1) The consolidated WHO Guidelines for Malaria,16 October 2023 (or latest update) [19]; (2) Severe Malaria Supplement in the European Journal of Tropical Medicine & International Health (2014) [20] and (3) Management of severe malaria: a practical handbook, 2013 [21].

The WHO Guidelines target policymakers who guide the development of national treatment policies and guidelines. It is not intended to be used as a manual or treatment handbook for health professionals. The Supplement provides a series of literature reviews and consensus opinions from a WHO consultation in 2011, covering aspects of severe malaria, including epidemiology, definitions, clinical disease in different groups, pathophysiology, pathology, management and pharmacology of antimalarial medicines. Finally, the practical handbook focuses on the practical management of severe malaria. It is intended for health professionals who are responsible for the management of severe malaria patients, working in hospitals or health centres with in-patient facilities. It covers all aspects of management from triage to diagnosis and treatment, nursing care, follow-up and post-treatment rehabilitation. No major updates were introduced to these resources but the WHO Malaria Policies Advisory Group (MPAG) discussed implementation challenges at the country level, including suboptimal uptake of WHO Guidelines at the national level, weaknesses of the health system such as medication availability and referral systems, capacity of the health workforce where training and training updates are important, enhancing the quality of care and curtailing the continued use of monotherapy [22]. In conclusion, MPAG endorsed the following updates to guides on the management of severe malaria:

1. Recognition of the need for a national policy for the management of severe malaria based on the WHO global guidelines for malaria.

2. Providing guidance on approaches to work with private practitioners.

3. The need to better communicate with caretakers and patients on the importance of timely care-seeking from a qualified care provider and adherence to the recommendations of service providers concerning malaria case management from diagnosis to cure.

4. The importance of clear guidance for post-discharge treatment and follow-up, noting public health follow-up in areas of elimination.

5. The use of an episode of severe malaria to emphasise personal protection and prevention with vector control.

6. Investigation of issues linked to quality of care for severe malaria where case-fatality rates indicate a signal.

7. Consideration of the approach to severe vivax malaria.

2: Pre-referral treatment with rectal artesunate (RAS)

Many children in endemic areas do not have access to a qualified healthcare provider and do not receive the necessary care in the timely detection of danger signs and access to effective treatment. Without rapid pre-referral treatment that can be administered at the community level, many children with severe malaria die. Since 2005, WHO has recommended immediate administration of a standard dose of an effective antimalarial medicine as a pre-referral treatment of patients with severe malaria before referring them to a facility at which complete treatment can be administered. RAS suppositories were used for pre-referral treatment of severe malaria in children aged < 6 years and were included as an option in the third edition of the guidelines for the treatment of malaria were recommended in 2015 [1]. Quality assured RAS became available in 2018, and several countries in Africa have included its use in their national treatment guidelines. Afterward, several operational studies were undertaken, and after the analysis of these studies, a field guide was issued for the use of RAS [23].

OPTIMISATION OF THE DOSE OF PRIMAQUINE

The conventional primaquine regimen of 0.25 mg base/kg bw per day for 14 days to prevent malaria relapses is based on studies of long-latency Korean P. vivax. In South-East Asia and Oceania, P. vivax relapses at 3-week intervals and is more resistant to primaquine. This led to the use of higher doses of primaquine. In light of changing epidemiology worldwide and more aggressive targets for malaria control and elimination, there is growing interest in reviewing the use of primaquine for radical cure of P. vivax in all settings.

1: Short standard dose of primaquine

PREVIOUS RECOMMENDATION:

To prevent relapse, treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged <6 months, women breastfeeding infants aged <6 months, women breastfeeding older infants unless they are known not to be G6PD deficient, and people with G6PD deficiency) with a 14-day course of primaquine in all transmission settings.

Based on a review of updated evidence a short-course standard dose primaquine treatment has been added as a recommended option in 2022 [4]:

UPDATED RECOMMENDATION, (November 2022):

To prevent relapse, an additional treatment option of using primaquine 0.5 mg/kg/day for 7 days is recommended to treat P. vivax or P. ovale malaria in children and adults (except pregnant women, infants aged <6 months, women breastfeeding infants aged <6 months, women breastfeeding older infants unless they are known not to be G6PD deficient, and people with G6PD deficiency).

Important points to note about this recommendation:

• The G6PD status of patients should be used to guide the administration of primaquine for preventing relapse.

• The shorter regimen can lead to better adherence compared to the standard 14-day regimen and thus to fewer relapses.

• Health facilities should continue to monitor for vomiting, anaemia, haemolysis and adherence to treatment.

• Safety monitoring is critical, so strengthening of pharmacovigilance systems is generally needed.

• Surveillance is essential for the risk of false-negative results with G6PD tests and for the lack of G6PD testing.

This recommendation by WHO was based on an analysis of the evidence provided by several systematic reviews [24–26].

2: Short-course standard high-dose primaquine treatment

Based on evidence of a significantly increased risk of severe adverse events (i.e., moderate to large undesirable effect) for the standard high dose (1 mg/kg) given as a seven-day regimen, WHO recommends AGAINST using this dose.

UPDATED RECOMMENDATION, (November 2022):

To prevent relapse, WHO recommends AGAINST an additional treatment option of using primaquine 1.0 mg/kg/day for 7 days to treat P. vivax or P. ovale malaria.

RESPONSE TO THE EMERGENCE ANTIMALARIAL DRUG RESISTANCE

Antimalarial drug resistance is defined as the ability of a parasite strain to survive and/ or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended, but usually within the subject’s tolerance. Factors in the parasite, the host, the drug and the environment cause this resistance. Treatment-related factors include drug pressure related to the frequency of drug use and doses and duration of treatment, which exposes the parasite population to subtherapeutic levels of the drug. Another risk factor is the use of monotherapy. Artemisinin partial resistance is seen as delayed parasite clearance following treatment with artemisinin-based monotherapy or with an ACT.

In the absence of partner drug resistance, delayed clearance alone does not lead to ACT treatment failure. However, artemisinin partial resistance puts the partner drug at risk because it exposes the parasites to the partner drug alone. Partner drug resistance causes treatment failure, even in the absence of artemisinin partial resistance.

Currently, the emergence of resistance to antimalaria drugs is posing a severe threat in Africa. The WHO strategy for the response to antimalarial drug resistance in Africa highlights different interventions needed to support this [27]. These include strengthening subregional networks for monitoring efficacy and resistance and enhancing the capacity of national teams to generate better quality and standardised data on antimalarial drug efficacy and parasite resistance. A few therapeutic efficacy studies in Africa have reported higher-than-expected treatment failure rates to the ACTs. However, it is difficult to interpret this data because of the need for molecular markers for resistance to the ACT partner drugs. These markers would help confirm and track resistance and distinguish between new infections and recrudescence. The tests are frequently not done according to standard WHO study protocols.

The currently available data show three areas with a clear selection of parasites carrying mutations in PfKelch13 (K13) associated with delayed clearance post-treatment with artemisinin-containing regimens:

The Horn of Africa: The R622I mutation has been identified in multiple countries, including Eritrea, Ethiopia, Sudan and Somalia.

Uganda: Various K13 mutations seem to be proliferating, with certain areas showing a prevalence of validated markers indicating partial resistance to artemisinin in most of the sampled parasites.

Rwanda and Tanzania: The R561H K13 mutation is spreading, although the 675V mutation is becoming more prevalent in western Rwanda. The 561H mutation has also been identified in Tanzania, particularly in Kagera, near the Rwandan border.

In the four African countries with confirmed artemisinin partial resistance: Eritrea, Rwanda, Uganda and Tanzania, there is >5% prevalence of validated markers for artemisinin partial resistance and evidence of delayed parasite clearance. In Ethiopia and Sudan, artemisinin partial resistance is suspected, as studies have detected over 5% of patients carrying K13 mutations (R622I) validated to be associated with artemisinin partial resistance, but delayed clearance has yet to be confirmed.

The emergence of resistance to antimalarial drugs in Africa could result in a dramatic rebound in malaria morbidity and mortality as no replacement drug is available. One mechanism to mitigate this grave consequence is to optimise the use of the current ACTs to prevent the emergence and/or the spread of resistance while new antimalarial drug classes are being developed. Modelling studies have concluded that deploying multiple first-line therapies (MFTs) for uncomplicated malaria is a promising strategy to reduce drug pressure and extend the useful therapeutic life of the current ACTs. This could lead to slowing the spread of resistance without putting lives at risk [28–31]. The MFT strategy consists of the simultaneous use of two or more therapies combining drugs with different or opposing selection pressures for malaria case management. Several options for implementing MFT have been described. Embedding the MFT strategy into health systems presents several challenges, including capacity building, planning for the proper distribution channel of the ACTs, involvement of the private sector, logistics and management [32]. Roll Back Malaria and WHO are coordinating antimalarial resistance surveillance and response efforts in Africa, with the aim of assessing the activities, plans and priorities of global partners, and identifying areas requiring better coordination and support.

RECOMMENDATIONS UNDER PROCESSING BY WHO

At present, WHO is processing revisions of the malaria treatment guidelines, to address the following issues related to malaria case management [33]:

• Introduction of the new product tafenoquine as an anti-relapse drug besides primaquine. Tafenoquine is a new, longer acting antihypnozoite medication for the radical cure of P. vivax malaria. Administered in a single dose of 300 mg in combination with a schizonticide, tafenoquine has a considerable advantage over the 14-day course of primaquine in terms of convenience. Like primaquine and tafenoquine cause haemolysis in persons with (G6PD) deficiency [34–36].

• Further optimisation of primaquines dosage.

• Guidelines on the use of the near-patient G6PD testing.

These issues are being tackled together because they are closely related. Updates by WHO indicate that the decision on these management tools has progressed to an advanced stage in the WHO recommendation process [37].

CONFLICT OF INTEREST

There are no conflicts of interest.

FUNDING

None.

ETHICAL APPROVAL

Ethics approval and consent to participate are not applicable.