What are the benefits and risks of atovaquone-proguanil for treating uncomplicated malaria caused by the Plasmodium falciparum parasite?

What is the aim of this review?

The most common, and most serious, type of malaria is caused by Plasmodium falciparum. In its mild (uncomplicated) form, the symptoms are fever, headaches, muscle pain, and vomiting. The disease can become severe and life-threatening if it is not treated soon enough or with the right medicines.

This review aimed to find out whether atovaquone-proguanil is effective and safe for treating uncomplicated cases of P falciparum malaria. We aimed to achieve this by comparing the results of studies that had compared atovaquone-proguanil to other malaria treatments.

Key messages

Atovaquone-proguanil is as effective for treating uncomplicated Plasmodium falciparum malaria as artesunate-mefloquine. It may be less effective than artemether-lumefantrine, artesunate-amodiaquine, and artesunate-atovaquone-proguanil, though more robust evidence is needed to confirm this. Side effects seem similar with atovaquone-proguanil.

What was studied in this review?

The World Health Organization (WHO) recommends treating uncomplicated malaria with oral (by mouth) artemisinin-based combination medicines (called ACTs).

ACTs are not always available worldwide and, in some places, Plasmodium falciparum is becoming resistant to recommended treatments (the medicines stop working). We looked at the evidence about the benefits and harms of combinations of medicines that are not artemisinin-based, but contain atovaquone-proguanil. This is an oral treatment commonly used by people from non-malaria areas to prevent them catching malaria when they travel to malaria areas. We wanted to find out whether it works as well for treating uncomplicated Plasmodium falciparum malaria as ACTs and other malaria treatments.

We searched for randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) that compared atovaquone-proguanil against other malaria treatments. These studies provide the most robust evidence about the effects of a treatment. We compared results, summarized the evidence, and rated our confidence in the evidence.

What are the main results of the review?

We found 17 studies involving 4763 adults and children in Africa, South America, and South East Asia. People were followed for 28 days to one year.

Fifteen studies compared atovaquone-proguanil against 12 different antimalarial treatments (ACTs in five studies; other therapies that combined several medicines in two studies; single medicines in nine studies).

Five studies compared atovaquone-proguanil plus another medicine (artesunate or chloroquine) against atovaquone-proguanil alone (three studies); atovaquone-proguanil plus a different medicine (one study); a combination of therapies that did not include atovaquone-proguanil (one study); or single medicines (two studies).

In 15 studies, the researchers and people who were treated knew which medicines participants received. Pharmaceutical companies funded 10 studies.

Atovaquone-proguanil against ACTs recommended by the WHO

Atovaquone-proguanil may work less well to clear Plasmodium falciparum parasites from the blood or prevent them from returning (treatment success) than artemether-lumefantrine (rates of success compared 28 and 42 days after treatment; one study). However this evidence was based on one small study.

Atovaquone-proguanil may work as well as, or less well than, artesunate-amodiaquine depending on whether new infections appearing after the start of treatment were counted or not (rates of success compared three and 28 days after treatment; one study). However this evidence was based on one small study of children aged under five years.

When new infections after the start of treatment were excluded, there is strong evidence of little to no difference in treatment success between atovaquone-proguanil and artesunate-mefloquine after 42 days (two studies). When new infections were counted, atovaquone-proguanil may be better than artesunate-mefloquine, but this evidence was based on the imprecise results of one study.

Atovaquone-proguanil against atovaquone-proguanil plus artesunate

Compared to atovaquone-proguanil plus artesunate, atovaquone-proguanil may be less successful at treating uncomplicated malaria after three and 28 days, however this evidence is based on the results of two small studies. It is probably less successful at treating uncomplicated malaria after 42 days (two studies).

Side effects

Studies reported several side effects, such as nausea and vomiting, or headaches. Overall, they were similar between groups.

How-up-to date is this review?

The evidence is current to 30 January 2020.

Authors' conclusions: 

Atovaquone-proguanil was effective against uncomplicated P falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates. Artesunate-atovaquone-proguanil and the development of parasite resistance may represent an area for further research.

Read the full abstract...
Background: 

The World Health Organization (WHO) in 2015 stated atovaquone-proguanil can be used in travellers, and is an option in malaria-endemic areas in combination with artesunate, as an alternative treatment where first-line artemisinin-based combination therapy (ACT) is not available or effective. This review is an update of a Cochrane Review undertaken in 2005.

Objectives: 

To assess the efficacy and safety of atovaquone-proguanil (alone and in combination with artemisinin drugs) versus other antimalarial drugs for treating uncomplicated Plasmodium falciparum malaria in adults and children.

Search strategy: 

The date of the last trial search was 30 January 2020. Search locations for published trials included the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, and LILACS. To include recently published and unpublished trials, we also searched ClinicalTrials.gov, the metaRegister of Controlled Trials and the WHO International Clinical Trials Registry Platform Search Portal.

Selection criteria: 

Randomized controlled trials (RCTs) reporting efficacy and safety data for atovaquone-proguanil or atovaquone-proguanil with a partner drug compared with at least one other antimalarial drug for treating uncomplicated Plasmodium falciparum infection.

Data collection and analysis: 

For this update, two review authors re-extracted data and assessed certainty of evidence. We meta-analyzed data to calculate risk ratios (RRs) with 95% confidence intervals (CI) for treatment failures between comparisons, and for safety outcomes between and across comparisons. Outcome measures include unadjusted treatment failures and polymerase chain reaction (PCR)-adjusted treatment failures. PCR adjustment differentiates new infection from recrudescent infection.

Main results: 

Seventeen RCTs met our inclusion criteria providing 4763 adults and children from Africa, South-America, and South-East Asia. Eight trials reported PCR-adjusted data to distinguish between new and recrudescent infection during the follow-up period. In this abstract, we report only the comparisons against the three WHO-recommended antimalarials which were included within these trials.

There were two comparisons with artemether-lumefantrine, one trial from 2008 in Ethiopia with 60 participants had two failures with atovaquone-proguanil compared to none with artemether-lumefantrine (PCR-adjusted treatment failures at day 28). A second trial from 2012 in Colombia with 208 participants had one failure in each arm (PCR-adjusted treatment failures at day 42).

There was only one comparison with artesunate-amodiaquine from a 2014 trial conducted in Cameroon. There were six failures with atovaquone-proguanil at day 28 and two with artesunate-amodiaquine (PCR-adjusted treatment failures at day 28: 9.4% with atovaquone-proguanil compared to 2.9% with artesunate-amodiaquine; RR 3.19, 95% CI 0.67 to 15.22; 1 RCT, 132 participants; low-certainty evidence), although there was a similar number of PCR-unadjusted treatment failures (9 (14.1%) with atovaquone-proguanil and 8 (11.8%) with artesunate-amodiaquine; RR 1.20, 95% CI 0.49 to 2.91; 1 RCT, 132 participants; low-certainty evidence).

There were two comparisons with artesunate-mefloquine from a 2012 trial in Colombia and a 2002 trial in Thailand where there are high levels of multi-resistant malaria. There were similar numbers of PCR-adjusted treatment failures between groups at day 42 (2.7% with atovaquone-proguanil compared to 2.4% with artesunate-mefloquine; RR 1.15, 95% CI 0.57 to 2.34; 2 RCTs, 1168 participants; high-certainty evidence). There were also similar PCR-unadjusted treatment failures between groups (5.3% with atovaquone-proguanil compared to 6.6% with artesunate-mefloquine; RR 0.8, 95% CI 0.5 to 1.3; 1 RCT, 1063 participants; low-certainty evidence).

When atovaquone-proguanil was combined with artesunate, there were fewer treatment failures with and without PCR-adjustment at day 28 (PCR-adjusted treatment failures at day 28: 2.16% with atovaquone-proguanil compared to no failures with artesunate-atovaquone-proguanil; RR 5.14, 95% CI 0.61 to 43.52; 2 RCTs, 375 participants, low-certainty evidence) and day 42 (PCR-adjusted treatment failures at day 42: 3.82% with atovaquone-proguanil compared to 2.05% with artesunate-atovaquone-proguanil (RR 1.84, 95% CI 0.95 to 3.56; 2 RCTs, 1258 participants, moderate-certainty evidence). In the 2002 trial in Thailand, there were fewer treatment failures in the artesunate-atovaquone-proguanil group compared to the atovaquone-proguanil group at day 42 with PCR-adjustment.

Whilst there were some small differences in which adverse events were more frequent in the atovaquone-proguanil groups compared to comparator drugs, there were no recurrent associations to suggest that atovaquone-proguanil is strongly associated with any specific adverse event.

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