China's foreign aid for global poverty alleviation:artemisinin-based combination therapies against malaria in Togo

From providing funds for the global fight against infectious diseases,to actively participating in global health security actions,to strengthening mutual cooperation in the field of health,and providing medical treatment,training and scholarships to countries in need,China’s foreign aid on global poverty alleviation is increasingly diversified and expanding in scale.Indeed,China is playing an increasingly important leading role in the global health agenda.It is worth mentioning that over the years,artemisinin compound have saved millions of lives all over the world,especially in poverty-stricken areas.China’s work mode of malaria elimination has also been written into WHO’s technical documents and recommended to other countries.Since 2007,Chinese medical staff has carried out the Artemisinin Compound Malaria Control Project in Comoros,bringing Chinese prevention and treatment programs to the local area.By 2014,Comoros had achieved zero deaths from malaria,and the number of cases had dropped by 98%.Now,this program is also extended to Togo,another African country.This article preliminarily summarizes the malaria profile in Togo and introduces China-Togo Cooperative Artemisinin Malaria Control Demonstration Project to provide a reference for better anti-malaria assistance in Togo,and also shows one of the substantive actions of China’s participation in global health governance,which contributes Chinese wisdom and offers Chinese solutions to global poverty alleviation.

Protecting future antimalarials from the trap of resistance:Lessons from artemisinin-based combination therapy (ACT) failures

Having faced increased clinical treatment failures with dihydroartemisinin-piperaquine(DHA-PPQ),Cambodia swapped the first line artemisinin-based combination therapy(ACT)from DHA-PPQ to artesunate-mefloquine given that parasites resistant to piperaquine are susceptible to mefloquine.However,triple mutants have now emerged,suggesting that drug rotations may not be adequate to keep resistance at bay.There is,therefore,an urgent need for alternative treatment strategies to tackle resistance and prevent its spread.A proper understanding of all contributors to artemisinin resistance may help us identify novel strategies to keep artemisinins effective until new drugs become available for their replacement.This review highlights the role of the key players in artemisinin resistance,the current strategies to deal with it and suggests ways of protecting future antimalarial drugs from bowing to resistance as their predecessors did.

Preference for Artemisinin-based combination therapy among healthcare providers,Lokoja,North-Central Nigeria

Background:In Nigeria,Artemisinin-based Combination Therapy(ACT)is the recommended first line antimalarial medicine for uncomplicated malaria.However,health care providers still continue the use of less efficacious medicines such as Sulphadoxine-pyrimethamine and chloroquine.We therefore determined preference for ACT(PFA)and factors associated with PFA among healthcare providers(HCP)in Lokoja,North-Central Nigeria as well as assessed healthcare providers’knowledge of malaria case management.Methods:We conducted a cross-sectional study among physicians,nurses,pharmacists,community health officers(CHOs),community health extension workers(CHEWs)and,patent and proprietary medicine vendors(PPMVs).Interviewer-administered questionnaires were administered to collect data on respondents’characteristics,previously received malaria case management training and knowledge of malaria treatment.Knowledge scores≥3 were categorised as good,maximum obtainable being 5.Results:Of the 404 respondents,214(53.0%)were males.Overall,219(54.2%)respondents who received malaria case management training included PPMVs:79(65.8%),CHEWs:25(64.1%),CHOs:5(55.6%),nurses:72(48.7%),physicians:35(47.3%)and pharmacists:3(23.1%).Overall,202(50.0%)providers including physicians:69(93.2%),CHO:8(88.9%),CHEWs:33(84.6%),pharmacists:8(61.5%),nurses:64(43.2%)and PPMVs:20(16.5%),had good knowledge of malaria treatment guidelines.Overall,preference for ACT among healthcare providers was 39.6%.Physicians:50(67.6%),pharmacists:7(59.3%)CHOs:5(55.6%),CHEWS:16(41.0%),nurses:56(37.8%)and PPMV:24(19.8%)had PFA.Receiving malaria case management training(adjusted odds ratio[aOR])=2.3;CI=1.4-3.7)and having good knowledge of malaria treatment(aOR=4.0;CI=2.4-6.7)were associated with PFA.Conclusions:Overall preference for ACT use was low among health care providers in this study.Preference for ACTs and proportion of health workers with good knowledge of malaria case management were even lower among PPMVs who had highest proportion of those who received malaria case management training.We recommend evaluation of current training quality,enhanced targeted training,follow-up supportive supervision of PPMVs and behavior change communication on ACT use.

Therapeutic efficacy and effects of artemisinin-based combination treatments on uncomplicated Plasmodium falciparum malaria-associated anaemia in Nigerian children during seven years of adoption as first-line treatments

Background:Artemisinin-based combination treatments(ACTs)are the first-line treatments of uncomplicated Plasmodium falciparum malaria in many endemic areas but there are few evaluation of their efficacy in anaemic malarious children.Methods:Therapeutic efficacy of 3-day regimens of artesunate-amodiaquine and artemether-lumefantrine was evaluated in 437 anaemic and 909 non-anaemic malarious children following treatment during a seven-year period(2008-2014).Patterns of temporal changes in haematocrit were classified based on haematocrit values<30%and≥30%.Kinetics of the disposition of the deficit in haematocrit from 30%following treatment were evaluated using a non-compartment model.Results:PCR-corrected parasitological efficacy 28 days after start of treatment was significantly higher in artesunateamodiaquine-compared to artemether-lumefantrine-treated children[97%(95%CI:92.8-100)versus 96.4%(95%CI:91.3-99.4),P=0.02],but it was similar in non-anaemic and anaemic children.Fall in haematocrit/1000 asexual parasites cleared from peripheral blood was significantly greater at lower compared to higher parasitaemias(P<0.0001),and in non-anaemic compared to anaemic children(P=0.007).In anaemic children at presentation,mean anaemia recovery time(AnRT)was 15.4 days(95%CI:13.3-17.4)and it did not change over the years.Declines in haematocrit deficits from 30%were monoexponential with mean estimated half-time of 1.4 days(95%CI:1.2-1.6).Anaemia half-time(t_(1/2anaemia))correlated positively with AnRT in the same patients(r=0.69,P<0.0001).Bland-Altman analysis of 10 multiples of t_(1/2anaemia) and AnRT showed narrow limit of agreement with insignificant bias(P=0.07)suggesting both can be used interchangeably in the same patients.Conclusions:Artesunate-amodiaquine and artemether-lumefantrine remain efficacious treatments of uncomplicated P.falciparum infections in non-anaemic and anaemic Nigerian children in the last 7 years of adoption as first-line treatments.These ACTs may also conserve haematocrit at high parasitaemias and in anaemic children.Trials registration:Pan African Clinical Trial Registry PACTR201508001188143,3 July 2015;PACTR201510001189370,3 July 2015;PACTR201508001191898,7 July 2015 and PACTR201508001193368,8 July 2015.

Parasite reduction ratio one day after initiation of artemisinin-based combination therapies and its relationship with parasite clearance time in acutely malarious children

Background:In acute falciparum malaria,asexual parasite reduction ratio two days post-treatment initiation(PRRD2)≥10000 per cycle has been used as a measure of the rapid clearance of parasitaemia and efficacy of artemisinin derivatives.However,there is little evaluation of alternative measures;for example,parasite reduction ratio one day after treatment initiation(PRRD1)and its relationship with parasite clearance time(PCT)or PRRD2.This study evaluated the use of PRRD1 as a measure of responsiveness to antimalarial drugs.Methods:In acutely malarious children treated with artesunate-amodiaquine(AA),artemether-lumefantrine(AL)or dihydroartemisinin-piperaquine(DHP),the relationships between PRRD1 or PRRD2 and PCT,and between PRRD1 and PRRD2 were evaluated using linear regression.Agreement between estimates of PCT using PRRD1 and PRRD2 linear regression equations was evaluated using the Bland-Altman analysis.Predictors of PRRD1>5000 per half cycle and PRRD2≥10000 per cycle were evaluated using stepwise multiple logistic regression models.Using the linear regression equation of the relationship between PRRD1 and PCT previously generated in half of the DHP-treated children during the early study phase,PCT estimates were compared in a prospective blinded manner with PCTs determined by microscopy during the later study phase in the remaining half.Results:In 919 malarious children,PRRD1 was significantly higher in DHP-and AA-treated compared with AL-treated children(P<0.0001).PRRD1 or PRRD2 values correlated significantly negatively with PCT values(P<0.0001 for each)and significantly positively with each other(P<0.0001).PCT estimates from linear regression equations for PRRD1 and PRRD2 showed insignificant bias on the Bland-Altman plot(P=0.7)indicating the estimates can be used interchangeably.At presentation,age>15months,parasitaemia>10000/μl and DHP treatment independently predicted PRRD1>5000 per half cycle,while age>30months,haematocrit≥31%,body temperature>37.4°C,parasitaemia>100000/μl,PRRD1 value>1000 and no gametocytaemia independently predicted PRRD2≥10000 per cycle.Using the linear regression equation generated during the early phase in 166 DHP-treated children,PCT estimates and PCTs determined by microscopy in the 155 children in the later phase were similar in the same patients.Conclusions:PRRD1 and estimates of PCT using PRRD1 linear regression equation of PRRD1 and PCT can be used in therapeutic efficacy studies.Trial registration:Pan African Clinical Trial Registration PACTR201709002064150,1 March 2017,http://www.pactr.org.

Declining responsiveness of childhood Plasmodium falciparum infections to artemisinin-based combination treatments ten years following deployment as first-line antimalarials in Nigeria

Background:The development and spread of artemisinin-resistant Plasmodium falciparum malaria in Greater Mekong Subregion has created impetus for continuing global monitoring of efficacy of artemisinin-based combination therapies(ACTs). This post analyses is aimed to evaluate changes in early treatment response markers 10 years after the adoption of ACTs as first-line treatments of uncomplicated falciparum malaria in Nigeria.Methods: At 14 sentinel sites in six geographical areas of Nigeria, we evaluated treatment responses in 1341 children under 5 years and in additional 360 children under 16 years with uncomplicated malaria enrolled in randomized trials of artemether-lumefantrine versus artesunate-amodiaquine at 5-year interval in 2009-2010 and 2014-2015 and at 2-year interval in 2009-2010 and 2012-2015, respectively after deployment in 2005.Results: Asexual parasite positivity 1 day after treatment initiation (APPD1) rose from 54 to 62% and 2 days after treatment initiation from 5 to 26% in 2009-2010 to 2014-2015(P=0.002 and P<0.0001, respectively).Parasite clearance time increased significantly from 1.6 days (95% confidence interval [CI]: 1.55-1.64) to 1.9 days (95% C,1.9-2.0) and geometric mean parasite reduction ratio 2 days after treatment initiation decreased significantly from 11 000 to 4700 within the same time period (P< 00001 for each). Enrolment parasitaemia > 75 000 μl^-1, haematocrit > 27% 1 day post-treatment initiatiortreatment with artemether-lumefantrine and enrolment in 2014-2015 independently predicted APPD1. In paralle , Kaplan-Meier estimated risk of recurrent infections by day 28 rose from 8 to 14% (P=0005) and from 9 to 15%(P=0.02) with artemether-lumefantrine and artesunate-amodiaquine, respectively. Mean asexual parasitaemia half-life increased significantly from 1.1 h to 1.3h within 2 years (P<0.0001).Conclusions:These data indicate declining parasitological responses through time to the two ACTs may be due to emergence of parasites with reduced susceptibility or decrease in immunity to the infections in these children.

The Search for Antimalarial Drugs and the Discovery of Artemisinin

With its novel chemical structure, artemisinin is an antimalarial component isolated from the traditional Chinese medicine qinghao(Artemisia annua L.). Nowadays, artemisinin and its derivatives are used compatibly with new synthesized chemical antimalarial compounds to create artemisinin-based combination therapies(ACTs). These have become the first choice in treating malaria p.f. all over the world, providing an effective solution for the global challenge of curing drug-resistant malaria. Among the five ACTs recommended by the WHO, two were initiated in China and are used as the first-line treatment of falciparum malaria in all malaria endemic areas. As the use of artemisinin-based compound drugs have made such significant contributions to rolling back malaria, regarded as one of the great achievements globally in public health of the early twenty-first century, Tu Youyou, one of the most important researchers in the discovery of artemisinin, was made the first Nobel Prize laureate in Physiology or Medicine from the Chinese mainland. Artemisinin was discovered in a special social and cultural context through a combination of the exploration of traditional Chinese medical literature with the modern research approach of pharmaceutical sciences. This(Project 523) is a typical case of goal-oriented research leading to scientific advance, and the result of scientific research driven by the national needs.

Quality Assessment of Artemether/Lumefantrine Tablets Sampled from Pharmacies in Accra, Using the MVHimagePCv8.exe Color Software

Background: Widespread resistance has been recorded with the use of monotherapy in the management of malaria. In 2000, Ghana initiated the process of using Artemisinin-based combination therapy (ACT) following the World Health Organization’s (WHO) recommendation. Globally and in Ghana, there stands a high risk of development of resistance to the ACTs due to the act of counterfeiting or substandard drugs. In 2009, there was a report that fake Coartem, an ACT had been found in Ghana by the Drug Quality and Information (DQI) Program;this is a serious national problem that needs redress thus the need to conduct this study to check if there are any substandard or counterfeit Artemether/ Lumefantrine tablets on the Ghanaian market. Method: Using Representative sampling method, a total of nine different brands or samples of artemether/lumefantrine tablets were sampled from nine different Pharmacies in Accra. The samples were analyzed using a validated MVHimagePCv8.exe colour software technology. Results: The International Conference on Harmonization (ICH) and United States Pharmacopoeia (USP) recommend that for assay of tablets, the percentage concentration should fall within 80%-120%. After the analysis, seven out of the nine samples passed the test to varying degrees. Two samples (AL-S4 and AL-S6) however failed the test with AL-S4 recording artemether concentration (126.07%) above and Lumefantrine concentration (78.38%) below the recommended figure while AL-S6’s 51.53% failed to meet the minimum allowable concentration for lumefantrine in a tablet. Conclusion: The results presented show that some Artemether/Lumefantrine tablets on the Ghanaian market still have issues with regards to quality or level of active ingredients. There would therefore be the need for further studies to be conducted into these products especially those that failed the test.

Pattern of Uncomplicated Malaria Treatment and Antimalarial Prescription Practices among Health Workers in the Littoral Region of Cameroon: An Assessment of Ten Years Post-Malaria Treatment Policy Change

Following highly prevalent Plasmodium resistant strains to antimalarial monotherapies in malaria endemic countries, uncomplicated malaria treatment policy changed to artemisinine-based combination therapies (ACTs). After adoption of this new treatment policy in a country, sufficient care is needed to be taken to prevent occurrence of resistance to the latest drugs. As Cameroon shifted to ACT in 2004, this study aimed to assess knowledge and practices of health workers in government health facilities of the Littoral region regarding mild malaria management in health facilities as well as according to prescription qualities of ACTs in leaflets received in pharmacies. A total of 66 physicians and 16 nurses were questioned in 10 health facilities and 503 medical leaflets with ACTs prescriptions were viewed in 17 pharmacies. All medical workers questioned correctly were defined mild malaria and were aware of the antimalarial policy change in Cameroon. Overall ACTs prescription for mild malaria management in children and adult patients was 72.2% and 87.8% respectively. An important proportion of health workers prescribed antimalarial monotherapies and non recommended antimalarial for uncomplicated malaria treatment. 31.7% of participants did not systematically recommend laboratory diagnostic test before antimalarial prescription. Of leaflets viewed in pharmacies, ACTs were prescribed by physicians, nurses and laboratory technicians. Age was the only criteria for ACTs prescription. Appropriate ACTs quality prescription ranged between 81.2% and 94.4%. Of the ACTs prescribed, blisters had the highest (92.9%) appropriate quality prescription and solutions the lowest (83.3%). According to qualification of prescribers, physicians had the highest score (93.1%) of appropriate quality prescription and laboratory technicians the lowest score (28.1%). For all ACTs containing medical leaflets, concomitant medications were recorded namely antipyretic (73.9%), antibiotic (21.9%), non steroid anti-inflammatory (19.9%) or vitamins (18.1%). Data gathered indicated that although health workers were aware of uncomplicated malaria treatment policy change in Cameroon, mild malaria mismanagement was prevailing in health facilities of the Littoral region and ACTs quality prescription in medical leaflets was not optimal. Therefore, awareness is still needed among prescribers in order to prevent or at least slow the occurrence of Plasmodium resistant strains to ACTs in Cameroon.

Effect of Primaquine on Gametocyte Carriage in the Case-Management of Uncomplicated Falciparum Malaria with Acts: Nigerian Perspective

Background: Drugs that kill or inhibit sexual stages of Plasmodium such as Primaqiune (PQ) could potentially amplify or synergize the impact of first line antimalarials by blocking transmission to mosquitoes. This study examined the effect of Primaquine on gametocyte carriage in the case management of uncomplicated falciparum malaria with artemisinin-based combination therapy (ACT) with the overall purpose of possibly recommending it as an adjunct drug for malaria control. Methods: A total of 181 patients with uncomplicated falciparum malaria, normal glucose-6-phosphate dehydrogenase (G6PD) enzyme levels, and haemoglobin levels ≥ 8 g/dL completed this two-arm randomized blinded clinical trial to test the efficacy of a single dose PQ (0.75 mg/kg) on falciparum gametocytaemia. 88 subjects were assigned to a standard 3-day course of Dihydroartemisinin-Piperaquine (DHP) alone (n = 88) while 93 others had DHP combined with a single dose of PQ on day 3 (n = 93). A 28-day follow-up schedule carried out in the outpatient clinic of a Primary health facility in Vom, Plateau State Nigeria where study participants were seen on days 1, 3, 7 and then weekly to assess the presence of asexual parasites and gametocytes by microscopy. A Kaplan-Meier analysis was employed to determine the survival function of gametocytes on day 3. The data was analyzed using Epi info version 7.1.5. Results: With a gametocyte prevalence of 27.1%, gametocyte carriage rate was lower in the PQ group due to higher probability of clearing gametocytes (Breslow test χ2 = 8.306, df = 1, p = 0.004) and significantly less likely to harbor gametocytes by day 7 when compared to the DHP-alone group (χ2 = 6.218, df = 1, p = 0.013). Conclusion: Addition of single-dose 0.75 mg/kg PQ was associated with reduced gametocyte carriage as a result of faster gametocyte clearance and lower incidence of gametocyte development in DHP-treated patients. PQ as gametocytocidal drug may be useful in combination with artemisinin-based combination therapy (ACT) regimen to clear gametocytes and thereby interrupt malaria transmission to mosquito vector more effectively than ACT alone.

Diagnosis and management of malaria in the intensive care unit

Malaria is responsible for approximately three-quarters of a million deaths in humans globally each year.Most of the morbidity and mortality reported are from Sub-Saharan Africa and Asia,where the disease is endemic.In non-endemic areas,malaria is the most common cause of imported infection and is associated with significant mortality despite recent advancements and investments in elimination programs.Severe malaria often requires intensive care unit admission and can be complicated by cerebral malaria,respiratory distress,acute kidney injury,bleeding complications,and co-infection.Intensive care management includes prompt diagnosis and early initiation of effective antimalarial therapy,recognition of complications,and appropriate supportive care.However,the lack of diagnostic capacities due to limited advances in equipment,personnel,and infrastructure presents a challenge to the effective diagnosis and management of malaria.This article reviews the clinical classification,diagnosis,and management of malaria as relevant to critical care clinicians,highlighting the role of diagnostic capacity,treatment options,and supportive care.

Therapeutic efficacy and effects of artesunate-amodiaquine and artemetherlumefantrine on malaria-associated anaemia in Nigerian children aged two years and under

Background:Artemisinin-based combination therapies are recommended as first-line treatments for uncomplicated falciparum malaria,but there is little evaluation of their efficacy and effects on uncomplicated malaria-associated anaemia in children aged 2 years and under.Methods:Parasitological efficacy and effects on malaria-associated anaemia were evaluated in 250 malarious children aged 2 years and under,and efficacy was evaluated in 603 malarious children older than two but younger than 5 years of age following treatment with artesunate-amodiaquine(AA)or artemether-lumefantrine(AL).Kinetics of the disposition of parasitaemia following treatment were evaluated using a non-compartment model.Late-appearing anaemia(LAA)was diagnosed using the following criteria:clearance of parasitaemia,fever and other symptoms occurring within 7 days of starting treatment,adequate clinical and parasitological response on days 28–42,haematocrit(HCT)≥30%at 1 and/or 2 weeks,a fall in HCT to<30%occurring at 3–6 weeks,absence of concomitant illness at 1–6 weeks,and absence of asexual parasitaemia detected using both microscopy and polymerase chain reaction(PCR)at 1–6 weeks.Results:Overall,in children aged 2 years and under,the PCR-corrected parasitological efficacy was 97.2%(95%CI 92.8–101.6),which was similar for both treatments.In children older than 2 years,parasitological efficacy was also similar for both treatments,but parasite prevalence 1 day after treatment began was significantly higher,and fever and parasite clearance times were significantly faster in the AA-treated children compared with the AL-treated children.Declines in parasitaemia were monoexponential with an estimated elimination half-time of 1 h.Elimination half-times were similar for both treatments.In children aged 2 years and under who were anaemic at presentation,the mean anaemia recovery time was 12.1 days(95%CI 10.6–13.6,n=127),which was similar for both treatments.Relatively asymptomatic LAA occurred in 11 children(4.4%)aged 2 years and under,the recovery from which was uneventful.Conclusion:This study showed that AA and AL are efficacious treatments for uncomplicated falciparum malaria in Nigerian children aged 2 years and under,and that AA clears parasitaemia and fever significantly faster than AL in children older than 2 years.Both treatments may cause a relatively asymptomatic LAA with uneventful recovery in a small proportion of children aged 2 years and under.Trials registration:Pan African Clinical Trial Registry PACTR201508001188143,3 July 2015;PACTR201510001189370,3 July 2015;PACTR201508001191898,7 July 2015 and PACTR201508001193368,8 July 2015 http://www.pactr.org.