Treatment of uncomplicated falciparum malaria in nonpregnant adults and children

INTRODUCTION — Uncomplicated falciparum malaria consists of symptomatic Plasmodium falciparum infection with a positive parasitologic test and parasitemia <4 percent, in the absence of symptoms consistent with severe malaria (table 1).

Issues related to treatment of uncomplicated falciparum malaria in nonpregnant adults and children will be reviewed here. Issues related to treatment of severe malaria, treatment of malaria in pregnant women, and treatment of non-falciparum malaria are discussed separately. (See "Treatment of severe malaria" and "Malaria in pregnancy: Prevention and treatment" and "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae" and "Non-falciparum malaria: Plasmodium knowlesi".)

Investigational antimalarial drugs are discussed separately. (See "Antimalarial drugs: An overview".)

INDICATIONS FOR HOSPITALIZATION — Hospitalization permits clinical observation for tolerance of antimalarial therapy, monitoring for reduction in parasitemia (reflecting efficacy of therapy), and advanced management in the case of progression to severe disease. Hospitalization is appropriate for patients in the following categories, who may deteriorate rapidly [1-3]:

●Young children

●Immunocompromised patients

●Individuals with no acquired immunity (ie, individuals from nonendemic areas)

●Patients with hyperparasitemia (4 to 10 percent) but no signs of severe infection; such patients are at increased risk for progression to severe malaria and/or treatment failure

ANTIMALARIAL SELECTION

Within endemic areas

General approach

●Treatment considerations – The approach to first-line therapy should take into consideration local guidelines, drug sensitivity patterns, and drug availability. P. falciparum may or may not be sensitive to chloroquine, as determined by local antimalarial drug resistance data.

●Management approach

•Use of combination therapy – In general, treatment of uncomplicated malaria consists of oral therapy with a combination of two drugs (in the case of chloroquine resistance) or chloroquine monotherapy (in the case of chloroquine sensitivity) if artemisinin combination therapy (ACT) is not available. The goal of this strategy is to forestall development of further resistance and conserve the agents that are presently effective.

•Selection of first-line agent – We are in agreement with the World Health Organization (WHO) which recommends use of ACT for treatment of uncomplicated P. falciparum malaria (irrespective of chloroquine sensitivity) [3]. However, in the case of chloroquine-sensitive P. falciparum where ACT is not readily available, we favor treatment with chloroquine or hydroxychloroquine, in alignment with the recommendations of the United States Centers for Disease Control and Prevention (CDC) [1].

●Malaria infection in spite of prophylaxis – Patients can develop malaria despite using chemoprophylaxis; such patients should receive a different antimalarial regimen for treatment. In 2018, 43 United States residents who reported taking and fully adhering to a CDC-recommended prophylaxis regimen developed malaria [4].

Selecting an ACT — There are numerous artemisinin-based combination therapies (ACTs) available for treatment of uncomplicated P. falciparum malaria (or species not identified) in endemic areas with chloroquine resistance. We are in agreement with the WHO, which favors first-line therapy with one of the following ACTs (table 2) [2,3,5,6]:

●Artemether-lumefantrine

●Artesunate-amodiaquine

●Artesunate-mefloquine

●Artesunate-pyronaridine

●Artesunate-sulfadoxine-pyrimethamine (SP), in areas with known SP sensitivity.

●Dihydroartemisinin-piperaquine (DP), in areas with known piperaquine sensitivity; DP should not be used for treatment of malaria acquired in the greater Mekong subregion (including southwestern Vietnam, western Cambodia, and northeastern Thailand), unless combined with mefloquine.

ACTs have a low side effect profile, are potent against all blood stages (asexual forms) of malaria, and have the most rapid clearance time relative to other antimalarial drugs (figure 1) [7]. Artemisinins should be administered with a second agent that has a longer half-life than the artemisinin drug to forestall development of artemisinin resistance and to provide an extended duration of drug level to clear parasitemia [8,9]. Administration of artemisinins alone would result in recrudescence (treatment failure) [10]. Dosing of ACTs is summarized in the table (table 2) [2,5].

The efficacy of artemether-lumefantrine may be diminished as body weight increases; therefore, for patients >65 kg, close follow-up after artemether-lumefantrine treatment (or use of an alternative treatment such as atovaquone-proguanil) warrants consideration. This was illustrated in one study including more than 390 episodes of falciparum malaria, lower efficacy of artemether-lumefantrine was observed among patients >65 kg than patients ≤65 kg (90 percent [95% CI 79-96 percent] versus 100 percent [95% CI 66-100 percent]) [11]. Similarly, in another study including 165 patients, 28-day parasitologic cure rates were lower among patients >65 kg (93.4 percent [95% CI 85.3-97.8 percent] versus 100 percent [95% CI 92.5-100.0 percent]) [12]. (See "Antimalarial drugs: An overview".)

No ACT has been proven to be superior to any other; the compounds differ slightly in their stability, oral absorption, bioavailability, metabolism, and adverse event profile. Clinical studies evaluating the efficacy of these agents are summarized in the table (table 3). Local drug resistance patterns should inform treatment guidelines. (See 'Artemisinin-resistant malaria' below.)

The total artemisinin dose (10 to 12 mg/kg) is given over three days. In areas of artemisinin resistance, a six-day course of treatment is warranted [13]. A three-day regimen covers two asexual cycles such that only a small fraction of parasites remain for clearance by the partner drug, thus reducing potential for development of resistance to the partner drug. Administration of a five-day course has not been associated with clinical superiority over a three-day course [14]. (See 'Artemisinin-resistant malaria' below.)

Patients who are not able to tolerate oral medication require initial treatment with rectal or parenteral drug administration until they are able to tolerate oral medication; subsequently, a full three-day course of oral ACT should be administered. The rectal and parenteral regimens are as described separately for treatment of severe malaria. (See "Treatment of severe malaria".)

Patients with mild malaria and hyperparasitemia (4 to 10 percent) are at increased risk of treatment failure and warrant close monitoring in a hospital setting if feasible [2].

If ACT is not readily available — As noted above, we favor use of artemisinin combination therapy (ACT) for treatment of uncomplicated malaria due to P. falciparum (irrespective of chloroquine sensitivity) [3]. (See 'General approach' above.)

However, in the case of chloroquine-sensitive P. falciparum where ACT is not readily available, we favor treatment with chloroquine or hydroxychloroquine [1].

Regions with chloroquine-sensitive malaria include Haiti, the Dominican Republic, most regions of the Middle East, and Central America west of the Panama Canal (figure 2A-C). Additional information summarizing drug resistance by country is available online [15].

Dosing for administration of chloroquine is outlined in the table (table 4). (See "Antimalarial drugs: An overview".)

In the setting of exposure to a region with unknown prevalence of chloroquine resistance, or uncertain exposure history, treatment for chloroquine-resistant P. falciparum should be administered. (See 'General approach' above.)

Recurrent infection

●Recurrent falciparum malaria - Recurrence of P. falciparum malaria can result from recrudescence (treatment failure) or reinfection; these may be difficult to distinguish. Treatment failure can occur as a result of drug resistance or inadequate drug exposure (due to underdosing, poor adherence, vomiting, pharmacokinetic factors, or substandard medication).

In general, treatment failure may be assumed in the setting of lack of resolution of fever and parasitemia or recurrence of these findings within 28 days of treatment; reinfection may be assumed in the setting of fever and parasitemia >28 days following treatment [2].

For patients with recurrent infection ≤28 days following treatment for uncomplicated malaria (likely attributable to recrudescence [treatment failure]), we are in agreement with the WHO, which favors treatment with an alternative ACT known to be effective in the region [2]. Retreatment with the same ACT may be reasonable (particularly in settings where there is no second ACT available); one study noted similar retreatment outcomes between patients retreated the same ACT versus an alternative ACT [16].

For patients with recurrent infection >28 days following treatment for uncomplicated malaria (likely attributable to reinfection), we are in agreement with the WHO, which favors treatment with a first-line ACT [2]. However, reuse of mefloquine within 60 days of initial treatment has been associated with an increased risk for neuropsychiatric reactions; therefore, if mefloquine was administered during initial treatment, an alternative regimen should be used.

When possible, suspected treatment failure should be confirmed parasitologically, with microscopy or rapid diagnostic tests (RDTs). RDTs based on lactate dehydrogenase are preferred for diagnosis of treatment failure, since RDTs based on histidine-rich protein 2 may remain positive for weeks after treatment of the initial infection, in the absence of recrudescence. (See "Laboratory tools for diagnosis of malaria", section on 'Rapid diagnostic tests'.)

●Reducing risk of vivax infection following falciparum malaria (for areas co-endemic for vivax and falciparum malaria) – In some areas co-endemic for P. vivax and P. falciparum malaria, the greatest risk of recurrent parasitemia is due to P. vivax malaria rather than P. falciparum [17,18]. It has been hypothesized that acute P. falciparum infection may reactivate P. vivax hypnozoites. In these areas, it has been proposed that administering antirelapse therapy ("radical cure") with primaquine to patients with P. falciparum infection may reduce their risk of subsequent P. vivax parasitemia. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae", section on 'Preventing relapse'.)

In a randomized trial including more than 490 patients with uncomplicated P. falciparum monoinfection and glucose-6-phosphate dehydrogenase (G6PD) activity ≥70 percent in Bangladesh, Indonesia, and Ethiopia, patients were treated with artemisinin combination therapy (ACT; artemether-lumefantrine or dihydroartemisinin–piperaquine) and then randomly assigned to receive either radical cure with primaquine (total dose 7 mg/kg over 7 days) or standard care in endemic settings with low P. falciparum transmission (consisting of primaquine 0.25 mg/kg single dose) to reduce transmissibility of treated P. falciparum infection [19]. At day 63, the incidence risk of P. vivax parasitemia was lower in the intervention arm (11 versus 2.5 percent; hazard ratio 0.20, 95% CI 0.08–0.51). There were no serious adverse events related to primaquine.

The benefits of implementing these findings may vary with geographical location and risk of coinfection [20], the ACT regimen and its associated duration of post treatment prophylaxis [18], and the availability of G6PD screening and treatment adherence.

Reducing transmissibility — Gametocytes may persist in the blood after successful treatment of infection (figure 1); they are not harmful to the patient but serve as a source of ongoing transmission. Artemether-lumefantrine has been shown to be superior to non-artemisinin antimalarial drugs in reducing gametocytemia [21]. Primaquine has activity against mature gametocytes but no effect on asexual blood-stage parasites.

To further reduce transmissibility of treated P. falciparum infection in endemic areas with low transmission, we are in agreement with the WHO which favors administration of primaquine (0.25 mg/kg single dose) on the first day of malaria treatment to nonpregnant adults and children ≥6 months [2,3,6,9,22-24].

This approach is supported by the following studies:

●In a 2022 meta-analysis of primaquine efficacy for reducing transmissibility when given in combination with different ACTs for among more than 2500 participants in 14 studies (13 conducted in Africa), primaquine reduced gametocyte carriage (as assessed by polymerase chain reaction [PCR]) on days 7 and 14 (odds ratio [OR] 0.22, 95% CI 0.17-0.28 and OR 0.12, 95% CI 0.08-0.16, respectively); in addition, primaquine was associated with nearly complete prevention of transmission to mosquitoes in three of the studies [25].

●In a 2018 systematic review including 24 randomized trials, addition of primaquine (single low dose) added to ACT therapy reduced infectiousness of humans to mosquitoes on day 3 or 4 (from 14 to 2 percent) and was as effective as higher doses of primaquine [26].

Primaquine should be avoided in pregnant women and infants <6 months of age given the particular vulnerability of these patient groups; the approach to preventing relapse in such cases is discussed separately. (See "Malaria in pregnancy: Prevention and treatment", section on 'Non-falciparum malaria'.)

Primaquine can cause hemolysis in individuals with G6PD deficiency; however, G6PD testing is not required for patients receiving primaquine for reducing transmission given the relatively low dose for this indication. In one study including 274 Senegalese patients with mild malaria randomized to ACT plus primaquine (0.25 mg/kg, single dose) versus ACT alone, the mean reduction in hemoglobin at day 7 was equivalent [27]. Among 54 patients with G6PD deficiency, the drop in hemoglobin was 0.63 g/dL greater in those who received primaquine than in those who received an ACT alone. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Inciting drugs, chemicals, foods, illnesses'.)

Outside endemic areas

General approach

●Treatment considerations − Uncomplicated malaria can progress to severe illness in nonimmune individuals within hours to days, so it is important that there is no delay in diagnosis, that treatment be initiated promptly, and that patients be hospitalized if possible.

Patients on malaria prophylaxis who develop malaria infection should receive a different antimalarial regimen for treatment.

●Available regimens − There are a number of treatment regimens available. We are in agreement with the WHO which recommends ACTs for treatment of uncomplicated P. falciparum malaria [3]; however, guidelines based on local drug availability must be taken into account. Regimens include ACTs, atovaquone-proguanil, quinine-based regimens, and mefloquine (table 4 and table 2).

•ACTs − Issues related to ACTs are discussed above. (See 'Selecting an ACT' above.)

•Atovaquone-proguanil − Atovaquone-proguanil is a well-tolerated and effective treatment for uncomplicated falciparum malaria in patients who were not taking this agent for prophylaxis during the period of exposure to malaria [28]. This is a good alternative to artemether-lumefantrine in patients with high body mass index for reasons noted above. The use of atovaquone-proguanil in resource-limited settings is limited by cost. Studies of atovaquone-proguanil conducted in Southeast Asia, South America, and Africa have demonstrated cure rates of >95 percent with no severe adverse side effects [29,30]. Several studies have demonstrated higher efficacy of the atovaquone-proguanil combination over chloroquine-based therapy and mefloquine [31,32].

•Quinine-based regimens − An alternative regimen consists of quinine sulfate administered in combination with doxycycline, tetracycline, or clindamycin. Quinine-based regimens are effective but are less preferable due to bitter taste, cinchonism (reversible tinnitus and reversible high-tone hearing loss), and gastrointestinal side effects [33-35]. Doxycycline and tetracycline are preferred over clindamycin as quinine partner drugs since they are associated with greater efficacy. For infections acquired in Southeast Asia, treatment consists of quinine (seven days) plus doxycycline, tetracycline, or clindamycin (seven days). For infections acquired outside Southeast Asia, treatment consists of quinine (three days) plus doxycycline, tetracycline, or clindamycin (seven days).

•Mefloquine-based regimens − Mefloquine-based regimens should be used only when the above regimens are not available; mefloquine has been associated with neuropsychiatric effects and resistance in some areas [36]. Outside the Thai-Myanmar-Cambodia area, mefloquine cures 90 to 95 percent of P. falciparum malaria. Within the Thai-Myanmar-Cambodia area, mefloquine cure rates have dropped to 60 percent due to resistance [37-39].

Recrudescence — For patients with recrudescence (treatment failure) outside endemic areas, treatment should consist of an alternative antimalarial regimen in case of drug resistance to the initial regimen (table 4 and table 2).

In addition, evaluation for coinfection with Plasmodium vivax or Plasmodium ovale should be pursued, as these species can cause relapse due to their hypnozoite stage. Identification of coinfection with these species requires treatment of the asexual stage as well as primaquine or tafenoquine for treatment of hypnozoites. (See "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae".)

Artemisinin-resistant malaria

Scope — Artemisinin resistance was initially observed in Southeast Asia and has been observed in sub-Saharan Africa and South America. Key aspects of WHO recommendations to manage artemisinin-resistant malaria include surveillance of molecular markers for drug resistance (including artemisinins and partner drugs), investigation of treatment failures, treatment scale-up, interventions for prevention and elimination, and new drug development [40].

Southeast Asia — In western Cambodia, where artemisinin monotherapy has been used, prolonged P. falciparum parasite clearance times have been observed, relative to parasites in northwestern Thailand (where artemisinins have been used in combination therapy) [13,41-43]. In a study published in 2009 including 80 patients (40 in western Cambodia and 40 in northwestern Thailand) randomly assigned to treatment with oral artesunate monotherapy or combination therapy with artesunate and mefloquine, the median parasite clearance time was longer among the Cambodian patients (84 versus 48 hours) [42].

Subsequently, in 2012, prolonged parasite clearance time in the setting of artemisinin use was described in western Thailand; this is believed to have developed locally rather than by importation of resistant parasites from Cambodia, since no genotypes in Thailand matched those in western Cambodia [44].

In 2014, P. falciparum artemisinin resistance was noted across Southeast Asia and was observed to occur in association with mutations in the kelch protein gene on chromosome 13 (kelch13) [13,45]. The prevalence of artemisinin K13 propeller mutations varies greatly by region; rates as high as 47 percent in parts of Myanmar have been observed. Spread of artemisinin-resistant parasites is due to transmission of single clones across regions; however, individual populations of parasites can develop artemisinin resistance independently, which may make containment of artemisinin-resistant parasites more challenging [46-48]. One report from China noted delayed parasite clearance following artemisinin treatment of infection due to P. falciparum caused by organisms harboring a single K13 mutation [49].

In 2016, a prospective study of dihydroartemisinin-piperaquine including 81 Cambodian patients in a region with established artemisinin resistance noted parasite recrudescence in 46 percent of cases. The parasites had the artemisinin resistance–associated kelch13 mutations but also had increased the half maximal inhibitory concentration (IC₅₀) to piperaquine, suggesting that resistance in the partner drug was also an important component of clinical resistance to ACTs [23]. Treatment of malaria in this region should consist of mefloquine plus artesunate.

In 2019, analyses were published on the spread of multidrug-resistant colineage of P. falciparum named KEL1/PLA1 (2008 to 2013), which are strains that contain the kelch13 C580Y mutation associated with artemisinin resistance and an amplification of plasmepsin 2/3 associated with piperaquine resistance. These parasites were associated with high rates of treatment failure following artemisinin-piperaquine in Southeast Asia (Thailand, Cambodia, Vietnam). Before 2009, KEL1/PLA1 was only found in western Cambodia; by 2016 to 2017, its prevalence had risen to higher than 50 percent in all of the surveyed countries except for Laos. In northeastern Thailand and Vietnam, KEL1/PLA1 exceeded 80 percent of the most recent P. falciparum parasites. Sublineages had also developed mutations in the crt gene, associated with treatment failure. These data underscore that treatment of malaria in this region should consist of mefloquine plus artesunate at present [50,51].

In areas where other ACTs are failing, use of artesunate-pyronaridine has received a positive scientific opinion from the European Medicines Agency [52]. In a study including 155 adults and children in Vietnam with uncomplicated P. falciparum malaria (including regions with high prevalence of C580Y) treated with pyronaridine-artesunate for 3 days, clinical and parasitologic response at day 42 was demonstrated in more than 96 percent of cases (95% CI 91.4-98.2) [53].

In 2019, an analysis from eastern India reported a 15 percent rate of treatment failure among patients with uncomplicated malaria treated with artesunate-sulfadoxine-pyrimethamine; treatment failure was associated with a novel G625R polymorphism in kelch13 [54]. Factors contributing to the emergence of drug failures in this region include importation of artemisinin-resistant isolates due to migration as well as high frequency of resistance to sulfadoxine-pyrimethamine (resulting in de facto monotherapy with artemisinin).

Sub-Saharan Africa — Artemisinin resistance has been reported in Uganda and Rwanda:

●Uganda – In a longitudinal study in Northern Uganda between 2017 and 2019 including 240 patients with P. falciparum infection treated with artesunate, prolonged parasite clearance (half-life >5 hours) was observed in 14 patients (5.8 percent of cases) [55]. Of these, 13 patients were infected with P. falciparum parasites with mutations in the A675V or C469Y allele of the kelch13 gene. In addition, between 2015 and 2019, the prevalence of parasites with kelch13 mutations increased from 3.9 to 19.8 percent.

In a surveillance study including more than 6500 blood samples collected from patients in Uganda with uncomplicated malaria between 2016 and 2022, the prevalence of parasites with kelch13 validated or candidate resistance markers reached more than 20 percent by 2021 to 2022 in 11 of the 16 districts [56]. Mutations in the A675V or C469Y allele of the kelch13 gene reached a combined prevalence of 10 to 54 percent across much of northern Uganda. By 2022, the R561H mutation reached a prevalence of 23 percent in one southwestern district, and the P441L mutation reached a prevalence of 12 to 23 percent in three western districts.

●Rwanda – In a 2018 study including 228 Rwandan children age 6 to 59 months with P. falciparum infection treated with artemether-lumefantrine for three days, 20 participants had detectable parasitemia by microscopy on day 3 after starting treatment (a WHO criterion for partial artemisinin resistance) [57]. Day 3 parasitemia was observed more frequently among patients with isolates containing the kelch13 R561H mutation than among patients with wildtype isolates (39 versus 5 percent). The kelch13 R561H mutation has arisen independent of the partial artemisinin resistance allele found in Thailand.

●Eritrea – In a study including 841 patients with uncomplicated malaria in Eritrea treated with ACT (artesunate–amodiaquine or artemether–lumefantrine) between 2016 and 2019, the percentage of patients with parasitemia on day 3 increased from 0.4 to 4.2 percent during the study period [58]. ACT resistance was associated with a novel mutation (R622I) in the kelch13 gene; the prevalence of this mutation increased from 8.6 to 21.0 percent during the study period. The hrp2 deletion (which impedes parasite production of histidine-rich protein [HRP], the target of widely used malaria rapid diagnostic tests [RDTs]), was observed more frequently among parasites with the R622I mutation than among parasites without it (69 versus 23 percent). The emergence of P. falciparum parasites that are both artemisinin-resistant and elude diagnosis by widely used RDTs could compromise malaria control by delaying diagnosis as well as effective treatment of malaria infection.

Issues related to RDTs are discussed further separately. (See "Laboratory tools for diagnosis of malaria", section on 'Rapid diagnostic tests'.)

South America — Independent emergence of a kelch13 mutant allele has been described in Guyana [59].

Detection — Artemisinin resistance should be considered in individuals with relevant epidemiologic exposure (residence in or travel to regions where resistance has been reported). Artemisinin resistance alone typically does not cause treatment failure, unless there is also resistance in the ACT partner drug [60].

The evaluation of a malaria blood smear on day 3 of treatment with an ACT is a useful screening tool for presence of artemisinin resistance. Artemisinin resistance is unlikely if the proportion of patients with parasite density >100,000 parasites/microL is less than 3 percent following a three-day course of ACT therapy [61].

If there is a concern for artemisinin resistance, consultation with an infectious disease physician or contacting the CDC Malaria Hotline should be considered. The CDC Malaria Hotline (770-488-7788) is available Monday to Friday, 9 a.m. to 5 p.m., Eastern time. Outside these hours, providers should call 770-488-7100 and ask to speak with a CDC malaria expert. 

Treatment — The optimal approach to treatment of artemisinin-resistant malaria is uncertain. For patients with infection acquired in Southeast Asia and initial parasite density of >100,000 parasites/microL who have >3 percent parasitemia on day three of ACT treatment, we extend the duration of treatment to six days and follow daily smears until negative; the patient should be managed with expert consultation if feasible. This approach is supported by an open-label study including more than 1200 adults and children with uncomplicated P. falciparum in 10 countries (7 in Asia and 3 in Africa) treated with oral artesunate for three days followed by a standard 3-day course of ACT [13]. In western Cambodia (where treatment success with ACTs is declining), the 6-day course of antimalarial therapy was associated with a cure rate of 98 percent (95% CI 91-99) at 42 days.

Use of a triple ACT (TACT) regimen has been proposed as an alternative approach to treatment of artemisinin-resistant malaria. In a randomized trial including 1100 patients with uncomplicated P. falciparum malaria from eight countries (Cambodia, Thailand, Laos, Vietnam, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo), the efficacy of three standard ACTs (dihydroartemisinin-piperaquine, artesunate-mefloquine, and artemether-lumefantrine) was compared with two TACT regimens containing partner drugs with opposing resistance mechanisms (dihydroartemisinin-piperaquine plus mefloquine or artemether-lumefantrine plus amodiaquine) [62]. In regions with ACT resistance (Cambodia, Thailand, and Vietnam), efficacy (defined by 42-day PCR-corrected clinical and parasitologic response) was more favorable among patients who received TACT (dihydroartemisinin-piperaquine plus mefloquine) than standard ACT (dihydroartemisinin-piperaquine; 98 versus 48 percent; risk difference 0.51, 95% CI 0.42-0.59). This result was driven by the high rate of piperaquine resistance in the region; the 42-day PCR corrected efficacy of dihydroartemisinin-piperaquine plus mefloquine was noninferior to that of artesunate-mefloquine at three sites in Cambodia (96 versus 95 percent; risk difference 1 percent, 95% CI -6 to 8).

An alternative strategy to TACT in this region consists of avoiding piperaquine combination therapy. At study sites with no established artemisinin resistance, all regimens had excellent efficacy; the tolerability and toxicity of the TACTs were similar to those of the ACTs. The study was limited by a lack of blinding and by a relative lack of pediatric participants, who are the highest risk group for malaria worldwide but who make up a small proportion of malaria cases in areas with ACT resistance. Use of TACTs in regions with artemisinin resistance requires follow-up study of safety and tolerability.

Patients with HIV infection — In general, the approach to treatment of malaria is the same in human immunodeficiency virus (HIV)-infected and HIV-uninfected patients.

Potential drug interactions between antimalarials and antiretroviral drugs should be reviewed carefully. In patients with HIV and uncomplicated malaria, artesunate-sulfadoxine-pyrimethamine should be avoided if the patient is on trimethoprim-sulfamethoxazole, and artesunate-amodiaquine should be avoided if the patient is on efavirenz or zidovudine [2,3,6].

FOLLOW-UP MONITORING — Follow-up blood smears are appropriate to document declining parasite density [63-66]. In general, parasitemia typically clears within 48 to 72 hours with appropriate therapy [64,67,68].

We are in agreement with the United States Centers for Disease Control and Prevention (CDC) which advises repeat blood smears every 12 to 24 hours to monitor parasitologic response to treatment [66]. In resource-limited settings, many clinicians perform follow-up smears only for patients who do not improve clinically (with defervescence within 72 hours). (See "Laboratory tools for diagnosis of malaria", section on 'Quantification of parasitemia'.)

In individuals who do not clinically improve and have persistent parasitemia, considerations include inadequate drug dosing, poor absorption, inadequate adherence, and/or drug resistance. Issues related to dosing and adherence should be reviewed carefully. Consideration of treatment with an alternative regimen is warranted, particularly if drug resistance is a possibility. In the United States, CDC clinicians are available through the malaria hotline: 770-488-7788 or 855-856-4713; during off-hours, call 770-488-7100 and ask to have the malaria clinician on call paged.

Malaria can recrudesce; repeat evaluation for malaria should be pursued in the event of a subsequent febrile episode. (See 'Recurrent infection' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malaria".)

SUMMARY AND RECOMMENDATIONS

●Definition – Uncomplicated falciparum malaria consists of symptomatic Plasmodium falciparum infection with a positive parasitologic test and parasitemia <4 percent, in the absence of symptoms consistent with severe malaria (table 1). (See 'Introduction' above.)

●Antimalarial selection

•General approach – For treatment of uncomplicated P. falciparum malaria, we suggest treatment with artemisinin combination therapy (ACT) (Grade 2B). For individuals >65 kg treated with an ACT, we suggest use of an agent other than artemether-lumefantrine (Grade 2C). Dosing is summarized in the table (table 2). (See 'General approach' above and 'Selecting an ACT' above.)

•Patients on malaria prophylaxis – Patients on malaria prophylaxis who develop malaria infection should receive a different medication for treatment. (See 'Antimalarial selection' above.)

•Chloroquine-sensitive malaria – For patients with chloroquine-sensitive P. falciparum in settings where ACT is not readily available, we suggest treatment with chloroquine or hydroxychloroquine (Grade 2B). Dosing is summarized in the table (table 4). (See 'General approach' above and 'If ACT is not readily available' above.)

•Reducing transmissibility – To reduce transmissibility of treated P. falciparum infection in endemic areas with low transmission, we suggest administration of primaquine (0.25 mg/kg single dose) on the first day of malaria treatment to nonpregnant adults and children ≥6 months (Grade 2B). Primaquine should be avoided in pregnant women and infants <6 months of age. (See 'Reducing transmissibility' above.)

●Artemisinin-resistant malaria – Artemisinin resistance should be considered in individuals with relevant epidemiologic exposure (residence in or travel to regions where resistance has been reported). Artemisinin resistance alone typically does not cause treatment failure unless there is also resistance in the ACT partner drug. For patients who may have artemisinin-resistant malaria, daily smears should be followed until negative. For patients with initial parasite density >100,000 parasites/microL and >3 percent parasitemia on day three of ACT treatment, we suggest extending the duration of treatment to six days (Grade 2C). (See 'Artemisinin-resistant malaria' above.)

●Follow-up monitoring – Follow-up blood smears are appropriate to document declining parasite density. In general, parasitemia typically clears within 48 to 72 hours with appropriate therapy. (See 'Follow-up monitoring' above.)

●Recurrent infection – Recurrent P. falciparum malaria infection can result from recrudescence (treatment failure) or reinfection; these may be difficult to distinguish. (See 'Recurrent infection' above.)

•In general, treatment failure may be assumed in the setting of lack of resolution of fever and parasitemia (or recurrence of these findings) within 28 days of treatment for uncomplicated malaria; for such patients, we suggest therapy with an alternative ACT known to be effective in the region (Grade 2C).

•In general, reinfection may be assumed in the setting of fever and parasitemia >28 days following treatment for uncomplicated malaria; for such patients, we suggest treatment with a first-line ACT (Grade 2C).

●Recrudescence – For patients with recrudescence outside endemic areas, treatment should consist of an alternative antimalarial regimen, in case of drug resistance to the initial regimen. In addition, evaluation for coinfection with Plasmodium vivax or Plasmodium ovale should be pursued, as these species can cause relapse due to their hypnozoite stage. Identification of coinfection with these species requires treatment of the asexual stage as well as primaquine or tafenoquine for treatment of hypnozoites. (See 'Outside endemic areas' above and "Non-falciparum malaria: P. vivax, P. ovale, and P. malariae" and "Non-falciparum malaria: Plasmodium knowlesi".)