Antimalarial Regimens Research Articles

Antimalarial efficacy of piperaquine-based antimalarial combination therapies: facts and uncertainties

Piperaquine is a bisquinoline antimalarial drug extensively used as monotherapy in China in the 1980s and subsequently included as one of the components of the artemisinin-based combination therapies (ACTs) in the 1990s. Among them, dihydroartemisinin-piperaquine (DHA-PQP) represents a new and extremely promising fixed combination. Several clinical trials have repeatedly shown that DHA-PQP is a safe and highly efficacious therapy against uncomplicated Plasmodium falciparum and the asexual stages of Plasmodium vivax malaria. Studies conducted with this drug have reported cure rates consistently above 95%, with the only exception being a study carried out in Papua New Guinea which reported a high rate of treatment failures. Although it has been hypothesized that such treatment failures could be related to cross-resistance mechanisms between piperaquine and other quinolines or to a reduced susceptibility of parasites to artemisinin derivatives, a critical review of the studies published so far seems to exclude both of these possibilities. Overall, there is now sufficient evidence on the safety and efficacy of the DHA-PQP therapy. Accordingly, the use of this ACT for the treatment of P.falciparum malaria has been recently approved in the EU via a centralized procedure by the European Medicines Agency. Moreover, it is now recommended globally by the World Health Organization as an option for the first-line treatment of uncomplicated malaria.

Patterns of anti-malarial drug treatment among pregnant women in Uganda

BackgroundPrompt use of an effective anti-malarial drug is essential for controlling malaria and its adverse effects in pregnancy. The World Health Organization recommends an artemisinin-based combination therapy as the first-line treatment of uncomplicated malaria in the second and third trimesters of pregnancy. The study objective was to determine the degree to which presumed episodes of uncomplicated symptomatic malaria in pregnancy were treated with a recommended anti-malarial regimen in a region of Uganda.MethodsUtilizing a population-based random sample, we interviewed women living in Jinja, Uganda who had been pregnant in the past year.ResultsSelf-reported malaria during the index pregnancy was reported among 67% (n = 334) of the 500 participants. Among the 637 self-reported episodes of malaria, an anti-malarial drug was used for treatment in 85% of the episodes. Use of a currently recommended treatment in the first trimester was uncommon (5.6%). A contraindicated anti-malarial drug (sulphadoxine-pyrimethamine and/or artemether-lumefantrine) was involved in 70% of first trimester episodes. Recommended anti-malarials were used according to the guidelines in only 30.1% of all second and third trimester episodes.ConclusionsSelf-reported malaria was extremely common in this population and adherence to treatment guidelines for the management of malaria in pregnancy was poor. Use of artemether-lumefantrine combined with non-recommended anti-malarials was common practice. Overuse of anti-malarial drugs, especially ones that are no longer recommended, undermines malaria control efforts by fueling the spread of drug resistance and delaying appropriate treatment of non-malarial febrile illnesses. Improved diagnostic capacity is essential to ultimately improving the management of malaria-like symptoms during pregnancy and appropriate use of currently available anti-malarials.

Synergy of the antiretroviral protease inhibitor indinavir and chloroquine against malaria parasites in vitro and in vivo

Many malaria-endemic areas are also associated with high rates of human immunodeficiency virus (HIV) infection. An understanding of the chemotherapeutic interactions that occur during malaria and HIV co-infections is important. Our previous studies have demonstrated that some antiretroviral protease inhibitors are effective in inhibiting Plasmodium falciparum growth in vitro. Currently, studies examining the interactions between antiretroviral protease inhibitors and antimalarial drugs are being conducted, but the data are limited. In this study, we examined the synergistic interactions between the antiretroviral protease inhibitor indinavir and chloroquine (CQ) in chloroquine-resistant and chloroquine-sensitive malaria parasites in vitro and in vivo. In vitro, by using modified fixed-ratio isobologram method, fractional inhibitory concentrations index (FICI) was calculated to indicate the interaction between the two drugs. The results demonstrated that indinavir interacted synergistically with chloroquine against both chloroquine-sensitive P. falciparum clone 3D7 (mean FICI 0.784) and multidrug-resistant P. falciparum clone Dd2 (mean FICI 0.599). In vivo drug interactions were measured using a 4-day suppressive test in a rodent malaria model infected with Plasmodium chabaudi. We observed that indinavir enhanced the antimalarial activity of chloroquine against both the chloroquine-sensitive line P. chabaudi ASS and the chloroquine-resistant line P. chabaudi ASCQ. More importantly, chloroquine had a 100% clearance of asexual parasites when used in combination with indinavir at an appropriate dose ratio (10 mg/kg CQ + 1.8 g/kg indinavir) where there was no obvious toxicity. We conclude from this study that the combination of indinavir and chloroquine may become a novel antimalarial drug regimen.

Clinical Features and Efficacy of Antimalarial Treatment for Reticular Erythematous Mucinosis

Reticular erythematous mucinosis (REM syndrome) is a rare cutaneous disease that predominantly affects the chest and upper back area of middle-aged women. Although antimalarial treatment is generally considered the most effective approach, only a few case reports exist on its use in REM syndrome. A total of 11 patients with REM syndrome (10 women and 1 man), mean age, 44 years (age range, 37-54 years), were included in this retrospective analysis. Ten of the 11 patients were cigarette smokers (91%), and 6 had concomitant autoimmune diseases (55%). Since no clinical score exists for REM syndrome, we used the validated Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) to evaluate the efficacy of antimalarial treatment. Overall, a significant decrease in the clinical score was observed from a median of 4 (range, 2-8) before initiation of treatment to 0 (range, 0-4) after 3 months of antimalarial therapy and to 0 (range, 0-4) after 12 months of therapy (P < .001). Two patients withdrew from the study owing to adverse gastrointestinal tract effects (nausea and vomiting); 2 relapsed after finishing their antimalarial regimens; 3 patients were free of disease 2 years after the end of treatment; and 4 patients were lost to follow-up. Antimalarial agents significantly improve or completely clear the skin lesions of patients with REM syndrome and should be considered as a first-line therapy for this rare disease.

Risk Behaviors and Spectrum of Diseases Among Elderly Travelers: A Comparison of Younger and Older Adults

Elderly travel to the developing world is increasing. Little information is available regarding risk behaviors and health during and after travel in this population. We compared the risk factors and occurrence of travel-related diseases in two populations of Israelis, travelers aged 60 years and older and travelers in the age group of 20 to 30 years. Only people traveling for less than a month were included. Pre-travel, each person received routine counseling regarding travel-associated health risks, was immunized, and given anti-malarial prescriptions as needed. Travelers were surveyed by telephone 6 to 12 months following travel about underlying medical conditions, current medications, and travel history. Risk and preventive behaviors, compliance with anti-malarial prophylaxis, and history of illness during and after travel were assessed. Of patients who visited the clinic from January to June 2008, 191/208 (91%) travelers aged 60 and older and 203/291 (69%) travelers aged 20 to 30 years were contacted by phone and recruited. Fewer elderly travelers drank open drinks, compared to young travelers (8% vs 35%, p < 0.01), and fewer purchased street food compared to young travelers (16.2% vs 37.9%, p < 0.01). More elderly travelers were fully compliant with their anti-malarial chemoprophylaxis regimen (60.7% vs 33.8%, p < 0.01). More elderly travelers took organized tours (61% vs 2%, p < 0.001). Young travelers more often backpacked (50.7% vs 10.4%, p < 0.001). Illness, most commonly diarrhea, was reported by 18.8% of elderly travelers compared to 34.0% of the young travelers (p = 0.001). In a logistic regression model only travel to East Asia (OR 4.66) (95%CI 1.93-11.22) and traveling under basic conditions (OR 1.94) (95% CI 1.42-3.29) remained significantly associated with illness, irrespective of age. Because elderly travelers tend to comply with health-related recommendations better and use less risky travel modes, their risk for illness during travel was lower. Traveling to East Asia and travel mode are associated with illness during travel, irrespective of age.

Low-quality evidence that atovaquone-proguanil and doxycycline are better tolerated prophylactic antimalarial regimens in travellers than mefloquine

Low-quality evidence that atovaquone-proguanil and doxycycline are better tolerated prophylactic antimalarial regimens in travellers than mefloquine

Artemisinin antimalarials: preserving the “magic bullet”

The artemisinins are the most effective antimalarial drugs known. They possess a remarkably wide therapeutic index. These agents have been used in traditional Chinese herbal medicine for more than 2,000 years but were not subjected to scientific scrutiny until the 1970s. The first formal clinical trials of the artemisinins, and the development of methods for their industrial scale production, followed rapidly. A decade later, Chinese scientists shared their findings with the rest of the world; since then, a significant body of international trial evidence has confirmed these drugs to be far superior to any available alternatives. In particular, they have the ability to rapidly kill a broad range of asexual parasite stages at safe concentrations that are consistently achievable via standard dosing regimens. As their half-life is very short, there was also thought to be a low risk of resistance. These discoveries coincided with the appearance and spread of resistance to all the other major classes of antimalarials. As a result, the artemisinins now form an essential element of recommended first-line antimalarial treatment regimens worldwide. To minimize the risk of artemisinin resistance, they are recommended to be used to treat uncomplicated malaria in combination with other antimalarials as artemisinin combination therapies (ACTs). Their rollout has resulted in documented reductions in malaria prevalence in a number of African and Asian countries. Unfortunately, there are already worrisome early signs of artemisinin resistance appearing in western Cambodia. If this resistance were to spread, it would be disastrous for malaria control efforts worldwide. The enormous challenge for the international community is how to avert this catastrophe and preserve the effectiveness of this antimalarial “magic bullet”. Drug Dev Res 71: 12–19, 2010. © 2009 Wiley-Liss, Inc.

Selection of Parasites with Diminished Drug Susceptibility by Amodiaquine‐Containing Antimalarial Regimens in Uganda

Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized for treatment with AQ-SP, AS-AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro susceptibility to monodesethylamodiaquine (MDAQ) was measured with a histidine-rich protein 2-based enzyme-linked immunosorbent assay, and potential resistance-mediating polymorphisms in pfmdr1 were evaluated. Parasites collected from patients treated with AQ-SP or AS-AQ within the prior 12 weeks were less susceptible to MDAQ (n = 18; mean of the median inhibitory concentration [IC(50)], 62.9 nmol/L; range, 12.7-158.3 nmol/L) than were parasites from those not treated within 12 weeks (n = 43; mean IC(50), 37.5 nmol/L; range, 6.3-184.7 nmol/L; P=.009) or only from those patients in the treatment arm that did not receive AQ (n = 12; mean IC(50), 28.8 nmol/L; range, 6.3-121.8 nmol/L; P = .004). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr1 86Y and 1246Y) increased after AQ therapy, although differences were not statistically significant. Prior therapy selected for diminished response to MDAQ, which suggests that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr1.

Evaluation of the pyrrole insecticide chlorfenapyr against pyrethroid resistant and susceptibleAnopheles funestus(Diptera: Culicidae)

To evaluate the pyrrole insecticide chlorfenapyr, which has a novel non-neurotoxic mode of action and is a promising alternative to conventional adulticides, against Anopheles funestus. The toxicity of a range of concentrations of chlorfenapyr against pyrethroid resistant and susceptible laboratory reared southern African An. funestus was assessed using standard WHO protocols and analysed using probit analysis. The pyrethroid resistant strain showed consistently higher LD50 and LD95 values compared to the susceptible strain, but these differences were not statistically significant and the magnitude was twofold at most. The LD50 values recorded for An. funestus are approximately three-fold higher than those reported elsewhere for other species of anopheline. Monooxygenase based pyrethroid resistance in An. funestus does not influence the toxic effect of chlorfenapyr. It is unlikely that such a small decrease in susceptibility of An. funestus to chlorfenapyr relative to other anophelines would have any operational implications. Chlorfenapyr is an important addition to insecticides available for malaria vector control, and could be used as a resistance management tool to either circumvent or slow the development of resistance.

Randomised trial of alternative malaria chemoprophylaxis strategies among pregnant women in Kigoma, Tanzania: II results from baseline studies

To determine baseline data among pregnant women consenting to participate in a randomised trial of alternative strategies of malaria chemoprophylaxis in Kigoma urban district, western Tanzania. Cross-sectional study. The study was conducted in an urban MCH clinic in Kigoma town in western Tanzania. All consenting pregnant women who fulfilled entry criteria were recruited into the study. BASELINE STUDIES: Baseline data were collected prior to randomisation of women to antimalarial prophylactic regimens. Baseline measurements included examination for blood depleting parasitic infections (stool and urine examinations), haemoglobin levels, haematocrit, sickling test, and blood slide for malaria parasites. A total of 728 pregnant women consented to participate in the interview and of these 705 participated in baseline studies constituting a participation rate of 96.8%. The age of participating women ranged from 14 to 45 years with a mean age of 23.7 years (standard deviation [SD] = 5.4) while the mean number of pregnancies ranged from 1 to 13 with a mean of 3.2 (SD = 2.2). The prevalence of malaria parasitaemia among the pregnant women examined was 9.4% (N = 705) while the prevalence of anaemia (defined as Hb < 8.5 gdl-1) was 12.4% (N = 579). No significant difference was observed in prevalence proportions of malaria parasitaemia in relation to age, parity, marital status and use of mosquito bednets. However the prevalence of anaemia among women in the age group 31-45 years was significantly lower than that observed among women in the age group 14-20 years (2.9% versus 18.9%; crude odds ratio [OR] = 0.13; 95% confidence interval [CI], 0.02-0.55). Sickle cell disease (HbAS) was found in 2.3% (N = 564) of the pregnant women examined. It is concluded that the prevalence of malaria parasitaemia and anaemia was very high in this population suggesting the need for interventions directed at controlling these major causes of maternal morbidity and mortality in Tanzania.

Protective efficacy and safety of three antimalarial regimens for intermittent preventive treatment for malaria in infants: a randomised, double-blind, placebo-controlled trial

Administration of sulfadoxine-pyrimethamine at times of vaccination-intermittent preventive treatment in infants (IPTi)-is a promising strategy to prevent malaria. However, rising resistance to this combination is a concern. We investigated a shortacting and longacting antimalarial drug as alternative regimens for IPTi. We undertook a double-blind, placebo-controlled trial of IPTi in an area of high resistance to sulfadoxine-pyrimethamine at sites of moderate (n=1280 infants enrolled) and low (n=1139) intensity of malaria transmission in Tanzania. Infants aged 8-16 weeks were randomly assigned in blocks of 16 to sulfadoxine (250 mg) plus pyrimethamine (12.5 mg; n=319 in moderate-transmission and 283 in low-transmission sites), chlorproguanil (15 mg) plus dapsone (18.75 mg; n=317 and 285), mefloquine (125 mg; n=320 and 284), or placebo (n=320 and 284), given at the second and third immunisations for diphtheria, pertussis, and tetanus, and for measles. Research team and child were masked to treatment. Recruitment was stopped early at the low-transmission site because of low malaria incidence. The primary endpoint was protective efficacy against all episodes of clinical malaria at 2-11 months of age. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00158574. All randomly assigned infants were analysed. At the moderate-transmission site, mefloquine had a protective efficacy of 38.1% (95% CI 11.8-56.5, p=0.008) against clinical malaria in infants aged 2-11 months, but neither sulfadoxine-pyrimethamine (-6.7%, -45.9 to 22.0) nor chlorproguanil-dapsone (10.8%, -24.6 to 36.1) had a protective effect. No regimen had any protective efficacy against anaemia or hospital admission. Mefloquine caused vomiting in 141 of 1731 (8%) doses given on day 1 (odds ratio vs placebo 5.50, 95% CI 3.56-8.46). More infants died in the chlorproguanil-dapsone and mefloquine groups (18 and 15, respectively) than in the sulfadoxine-pyrimethamine or placebo groups (eight deaths per group; p=0.05 for difference between chlorproguanil-dapsone and placebo). IPTi with a longacting, efficacious drug such as mefloquine can reduce episodes of malaria in infants in a moderate-transmission setting. IPTi with sulfadoxine-pyrimethamine has no benefit in areas of very high resistance to this combination. The appropriateness of IPTi should be measured by the expected incidence of malaria and the efficacy, tolerability, and safety of the drug. IPTi Consortium and the Gates Malaria Partnership.

Pattern of drug utilization for treatment of uncomplicated malaria in urban Ghana following national treatment policy change to artemisinin-combination therapy

BackgroundChange of first-line treatment of uncomplicated malaria to artemisinin-combination therapy (ACT) is widespread in Africa. To expand knowledge of safety profiles of ACT, pharmacovigilance activities are included in the implementation process of therapy changes. Ghana implemented first-line therapy of artesunate-amodiaquine in 2005. Drug utilization data is an important component of determining drug safety, and this paper describes how anti-malarials were prescribed within a prospective pharmacovigilance study in Ghana following anti-malarial treatment policy change.MethodsPatients with diagnosis of uncomplicated malaria were recruited from pharmacies of health facilities throughout Accra in a cohort-event monitoring study. The main drug utilization outcomes were the relation of patient age, gender, type of facility attended, mode of diagnosis and concomitant treatments to the anti-malarial regimen prescribed. Logistic regression was used to predict prescription of nationally recommended first-line therapy and concomitant prescription of antibiotics.ResultsThe cohort comprised 2,831 patients. Curative regimens containing an artemisinin derivative were given to 90.8% (n = 2,574) of patients, although 33% (n = 936) of patients received an artemisinin-based monotherapy. Predictors of first-line therapy were laboratory-confirmed diagnosis, age >5 years, and attending a government facility. Analgesics and antibiotics were the most commonly prescribed concomitant medications, with a median of two co-prescriptions per patient (range 1–9). Patients above 12 years were significantly less likely to have antibiotics co-prescribed than patients under five years; those prescribed non-artemisinin monotherapies were more likely to receive antibiotics. A dihydroartemisinin-amodiaquine combination was the most used therapy for children under five years of age (29.0%, n = 177).ConclusionThis study shows that though first-line therapy recommendations may change, clinical practice may still be affected by factors other than the decision or ability to diagnose malaria. Age, diagnostic confirmation and suspected concurrent conditions lead to benefit:risk assessments for individual patients by clinicians as to which anti-malarial treatment to prescribe. This has implications for adherence to policy changes aiming to implement effective use of ACT. These results should inform education of health professionals and rational drug use policies to reduce poly-pharmacy, and also suggest a potential positive impact of increased access to testing for malaria both within health facilities and in homes.

Modelling the impact of artemisinin combination therapy and long-acting treatments on malaria transmission intensity.

BackgroundArtemisinin derivatives used in recently introduced combination therapies (ACTs) for Plasmodium falciparum malaria significantly lower patient infectiousness and have the potential to reduce population-level transmission of the parasite. With the increased interest in malaria elimination, understanding the impact on transmission of ACT and other antimalarial drugs with different pharmacodynamics becomes a key issue. This study estimates the reduction in transmission that may be achieved by introducing different types of treatment for symptomatic P. falciparum malaria in endemic areas.Methods and FindingsWe developed a mathematical model to predict the potential impact on transmission outcomes of introducing ACT as first-line treatment for uncomplicated malaria in six areas of varying transmission intensity in Tanzania. We also estimated the impact that could be achieved by antimalarials with different efficacy, prophylactic time, and gametocytocidal effects. Rates of treatment, asymptomatic infection, and symptomatic infection in the six study areas were estimated using the model together with data from a cross-sectional survey of 5,667 individuals conducted prior to policy change from sulfadoxine-pyrimethamine to ACT. The effects of ACT and other drug types on gametocytaemia and infectiousness to mosquitoes were independently estimated from clinical trial data. Predicted percentage reductions in prevalence of infection and incidence of clinical episodes achieved by ACT were highest in the areas with low initial transmission. A 53% reduction in prevalence of infection was seen if 100% of current treatment was switched to ACT in the area where baseline slide-prevalence of parasitaemia was lowest (3.7%), compared to an 11% reduction in the highest-transmission setting (baseline slide prevalence = 57.1%). Estimated percentage reductions in incidence of clinical episodes were similar. The absolute size of the public health impact, however, was greater in the highest-transmission area, with 54 clinical episodes per 100 persons per year averted compared to five per 100 persons per year in the lowest-transmission area. High coverage was important. Reducing presumptive treatment through improved diagnosis substantially reduced the number of treatment courses required per clinical episode averted in the lower-transmission settings although there was some loss of overall impact on transmission. An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest-transmission setting.ConclusionsOur results suggest that ACTs have the potential for transmission reductions approaching those achieved by insecticide-treated nets in lower-transmission settings. ACT partner drugs and nonartemisinin regimens with longer prophylactic times could result in a larger impact in higher-transmission settings, although their long term benefit must be evaluated in relation to the risk of development of parasite resistance.

Early home treatment of childhood fevers with ineffective antimalarials is deleterious in the outcome of severe malaria

BackgroundEarly diagnosis and prompt treatment including appropriate home-based treatment of malaria is a major strategy for malaria control. A major determinant of clinical outcome in case management is compliance and adherence to effective antimalarial regimen. Home-based malaria treatment with inappropriate medicines is ineffective and there is insufficient evidence on how this contributes to the outcome of severe malaria. This study evaluated the effects of pre-hospital antimalarial drugs use on the presentation and outcome of severe malaria in children in Ibadan, Nigeria.MethodsTwo hundred and sixty-eight children with a median age of 30 months comprising 114 children with cerebral malaria and 154 with severe malarial anaemia (as defined by WHO) were prospectively enrolled. Data on socio-demographic data, treatments given at home, clinical course and outcome of admission were collected and analysed.ResultsA total of 168 children had treatment with an antimalarial treatment at home before presenting at the hospital when there was no improvement. There were no significant differences in the haematocrit levels, parasite counts and nutritional status of the pre-hospital treated and untreated groups. The most commonly used antimalarial medicine was chloroquine. Treatment policy was revised to Artemesinin-based Combination Therapy (ACT) in 2005 as a response to unacceptable levels of therapeutic failures with chloroquine, however chloroquine use remains high. The risk of presenting as cerebral malaria was 1.63 times higher with pre-hospital use of chloroquine for treatment of malaria, with a four-fold increase in the risk of mortality. Controlling for other confounding factors including age and clinical severity, pre-hospital treatment with chloroquine was an independent predictor of mortality.ConclusionThis study showed that, home treatment with chloroquine significantly impacts on the outcome of severe malaria. This finding underscores the need for wide-scale monitoring to withdraw chloroquine from circulation in Nigeria and efforts intensified at promoting prompt treatment with effective medicines in the community.

Malaria in pregnancy in an area of stable and intense transmission: is it asymptomatic?

To report a study of the signs and symptoms of malarial infection during pregnancy in an area of stable and intense transmission. As part of a clinical trial, to assess the efficacy and safety of four antimalarial drug regimens in pregnant women, we collected clinical and laboratory data from 900 parasitaemic pregnant women and 223 non-parasitaemic pregnant women who attended an antenatal clinic at a district hospital in Ghana. Frequencies of signs and symptoms were calculated and their association with the level of parasitaemia was assessed using multivariate logistic regression. History of fever (7.8%vs. 44.4%; P < 0.0001), headache (12.5%vs. 43.9%; P < 0.0001), vomiting (0 vs. 11.5%; P = 0.01), malaise (1.6%vs. 31.6%; P < 0.0001) dizziness (0%vs. 23%; P < 0.0001) and fatigue (0%vs. 22.5%; P < 0.0001) was substantially higher in parasitaemic primigravidae than in aparasitaemic primigravid women. Similar differences in the distribution of the symptoms and signs were observed between parasitaemic and aparasitaemic multigravid women. The proportion of women with elevated concentrations of aspartate aminotransferase, alanine aminotransferase and total bilirubin and its fractions was also higher in parasitaemic than in non-parasitaemic women. In areas of stable malarial transmission, malaria in pregnancy is often symptomatic. Although the symptoms are mostly non-specific, careful recording of history may be useful to identify women who need a confirmatory test and an effective antimalarial treatment.

Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children

BackgroundCombination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.MethodsA longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.ResultsOf 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 – 4.23; weakness: RR 2.26, 95% CI 1.01 – 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.ConclusionThis study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.Trial registrationCurrent Controlled Trials Identifier ISRCTN37517549

Monitoring antimalarial safety and tolerability in clinical trials: A case study from Uganda

BackgroundNew antimalarial regimens, including artemisinin-based combination therapies (ACTs), have been adopted widely as first-line treatment for uncomplicated malaria. Although these drugs appear to be safe and well-tolerated, experience with their use in Africa is limited and continued assessment of safety is a priority. However, no standardized guidelines for evaluating drug safety and tolerability in malaria studies exist. A system for monitoring adverse events in antimalarial trials conducted in Uganda was developed. Here the reporting system is described, and difficulties faced in analysing and interpreting the safety results are illustrated, using data from the trials.Case descriptionBetween 2002 and 2007, eleven randomized, controlled clinical trials were conducted to compare the efficacy, safety, and tolerability of different antimalarial regimens for treatment of uncomplicated malaria in Uganda. The approach to adverse event monitoring was similar in all studies. A total of 5,614 treatments were evaluated in 4,876 patients. Differences in baseline characteristics and patterns of adverse event reporting were noted between the sites, which limited the ability to pool and analyse data. Clinical failure following antimalarial treatment confounded associations between treatment and adverse events that were also common symptoms of malaria, particularly in areas of lower transmission intensity.Discussion and evaluationDespite prospectively evaluating for adverse events, limitations in the monitoring system were identified. New standardized guidelines for monitoring safety and tolerability in antimalarial trials are needed, which should address how to detect events of greatest importance, including serious events, those with a causal relationship to the treatment, those which impact on adherence, and events not previously reported.ConclusionAlthough the World Health Organization has supported the development of pharmacovigilance systems in African countries deploying ACTs, additional guidance on adverse events monitoring in antimalarial clinical trials is needed, similar to the standardized recommendations available for assessment of drug efficacy.

Effects of Plasmodium falciparum parasite population size and patient age on early and late parasitological outcomes of antimalarial treatment in children.

The design and interpretation of trials assessing the chemotherapeutic effects of antimalarial drugs depend on our understanding of how different selection criteria affect treatment outcomes. In this study, we analyzed the effects of baseline parameters on the initial parasite elimination rate and the risk of subsequent recrudescence as a marker for incompletely eliminated asexual blood-stage parasites in pediatric patients with uncomplicated Plasmodium falciparum infection treated with amodiaquine in a high-transmission area. We found that (i) parasite population size and patient age independently determine early and late parasitological treatment outcome measurements; (ii) the rate of recrudescence is higher in patients 1 to 3 years of age than in patients aged <1 or >3 years; (iii) patients aged >5 years with parasite densities between 2,000 and 10,000/microl have a lower recrudescence rate (13%; 95% confidence interval [CI], 8% to 21%) than patients aged <5 years with parasite densities of >10,000/microl (40%; 95% CI, 30% to 50%); and (iv) the sensitivity of detecting recrudescences outside this high-risk group, i.e., in patients of >5 years of age or with parasite densities of <10,000/microl, is as low as 27% or 22%, respectively. In conclusion, these findings highlight the need to use adequate selection criteria and to report parasitological outcome results adjusted for the readily available determinants of chemotherapeutic failure, i.e., patient age and baseline parasitemia. The thresholds may vary by transmission intensity and drug regimen. A better understanding of the limitations of antimalarial regimens in high-risk subgroups of patients has important implications for setting policy recommendations.

Antimalarial dosing regimens and drug resistance

The contribution of underdosing to antimalarial treatment failure has been underappreciated. Most recommended dosage regimens are based on studies in non-pregnant adult patients. Young children and pregnant women, who bear the heaviest malaria burden, have the highest treatment failure rates. This has been attributed previously to lower immunity, although blood concentrations of many antimalarial drugs are significantly lower in pregnant women and young children than in non-pregnant adults. Nevertheless, there have been no studies of higher dosages. Sub-therapeutic concentrations will certainly contribute to poorer responses to treatment and will fuel the emergence and spread of antimalarial drug resistance. There is an urgent need for studies to optimise antimalarial dosage regimens in infants, young children and pregnant women, both to improve cure rates and to prolong the useful therapeutic lives of antimalarial drugs.

Uncertainty in Malaria Control in Tanzania: Crossroads and Challenges for Future Interventions

In Tanzania malaria is the leading cause of morbidity and mortality, especially in children under 5 years. The disease ranks number one in both outpatient and inpatient statistics. The socio-economic impact of malaria is so high that it contributes highly to poverty and underdevelopment. Efforts made during the past century to combat and control malaria have not been successful. The prospects of achieving the Abuja declaration targets are uncertain within the remaining period of time. Currently, the Ministry of Health through a 5-year strategic plan advocates four main approaches in the fight against the disease. These include improved case management, vector control using insecticide treated mosquito nets, prevention and control of malaria in pregnancy and epidemic preparedness, prevention and control. However, these strategies face various challenges including inadequate human, financial, and material resources; inefficiency in the healthcare system that is incapable of providing quality health services and access to prompt diagnosis and treatment; lack of an effective disease surveillance system; and an inefficient health education communication mechanism. Tanzania is at the crossroads and is challenged with the need to introduce a new antimalarial treatment regimen and the reintroduction of DDT for indoor residual spray. Unless malaria control strategy adopts an integrated approach its success is far from being realized. This article reviews the current malaria control strategies and its challenges in Tanzania and proposes new strategies.