Treatment Efficacy and Malaria TRANSmission After Artemisinin Combination Therapy (TRANSACT)
Condition: Uncomplicated Malaria
MeSH terms: Malaria
Study type: Interventional

Summary: 
      Artemisinin combination therapy (ACT) with artemether lumefantrine (AL) is currently the
      first line treatment policy in Tanzania. AL is an efficacious drug that also has the capacity
      to reduce malaria transmission to mosquitoes. Nevertheless, there is concern about the
      development of parasite resistance against AL and there have been very few clinical trials
      that compared different ACT regimens. A recent clinical trial shows that the combination of
      dihydroartemisinin-piperaquine (DP) may be more efficacious than AL and may have a more
      pronounced beneficial effect on post-treatment malaria transmission. Screening for molecular
      markers that are related to parasite susceptibility to ACT drugs and to post-ACT treatment
      malaria transmission can assist in preventing the development and spread of ACT resistance.

      In the current study, the investigators compared AL and DP for the treatment of uncomplicated
      malaria. The investigators endpoints are

        -  clinical efficacy

        -  post-treatment gametocytaemia by molecular techniques

        -  post-treatment malaria transmission.
    

Detailed description: 
      2.1 MALARIA AND ITS TRANSMISSION TO MOSQUITOES Malaria is the most important parasitic
      disease in the world. Approximately one fourth of the world population is at risk of
      contracting the disease, and every year more than 2 million people, mainly young children in
      sub-Sahara Africa, die of malaria. Malaria is caused by single-cell (protozoan) parasites of
      the genus Plasmodium. Four species can cause human disease: P. falciparum, P. vivax, P. ovale
      and P. malariae. The parasites are transmitted between humans by the bite of an infected
      female mosquito (Anopheles). Inside the human body, the malaria parasites multiply rapidly in
      the liver cells. After approximately six days, parasites leave this organ and subsequently
      infect red blood cells (erythrocytes). A next wave of Plasmodium replication takes place in
      the erythrocytes, then the red blood cell bursts, followed by infection of new red blood
      cells by the parasites. Since this part of the malaria life cycle involves asexual
      replication, parasites in this phase are referred to as asexual parasites. A small fraction
      of these asexual parasites develop into sexual stage parasites (gametocytes). Asexual
      parasites are responsible for malaria morbidity and mortality, while gametocytes ensure
      transmission of the parasite from humans to mosquitoes. Malaria transmission takes place when
      mature gametocytes are ingested by mosquitoes that are taking a blood meal. Once ingested,
      male and female gametocytes merge to form a zygote that develops though an ookinete stage
      into an oocyst that can be detected on the mosquito midgut within one week after feeding. The
      oocyst will burst and sporozoites are released that migrate to the mosquito salivary glands.
      Once the salivary glands are infected with sporozoites, the mosquito is capable of infecting
      new human beings.

      2.2 MALARIA TREATMENT WITH ARTEMISININ COMBINCATION THERAPY (ACT) Accurate diagnosis followed
      by prompt and efficacious treatment is the backbone of any malaria control programme.
      However, malaria treatment has been facing huge challenges in recent years. A number of
      affordable antimalarial drugs have been used to cure malaria since the 1940s: these include
      chloroquine (CQ), sulphadoxine-pyrimethamine (SP; Fansidar®), mefloquine, amodiaquine (AQ)
      and quinine. The emergence and spread of resistance to these commonly-used drugs has been
      largely responsible for the worsening of the malaria situation observed in the past few
      years.

      Across the African continent, guidelines have recently been changed. The World Health
      Organization (WHO) recommends for falciparum malaria the use of combination therapies,
      preferably those containing artemisinin derivatives (ACTs - artemisinin-based combination
      therapies). Artemisinin derivatives, e.g. artesunate, artemether and dihydroartemisinin,
      being extremely potent antimalarial agents are the ideal partners in combinations with other
      antimalarials. ACTs have three demonstrable advantages over conventional therapy, i) they are
      efficacious in treating malaria patients, ii) substantially reduce post-treatment gametocyte
      carriaga and iii) "protect" the partner drug from selecting resistant parasites.

      In Tanzania, both CQ and SP have lost clinical efficacy. CQ was replaced by SP in 2001 and in
      the year 2006, SP was officially replaced by Artemether-Lumefantrine (AL: Coartem®). The
      policy change to the artemisinin-based drug AL is in line with the WHO recommendations to
      shift to ACT as first line antimalarial treatment.

      2.3 RESISTANT PARASITES, MALARIA TRANSMISSION AND ACT Parasite resistance against SP has a
      genetic background in mutations in the parasite dihydrofolate reductase (dhfr) and
      dihydropteroate synthetase (dhps) genes. Single nucleotide polymorphisms (SNPs) in these
      genes are associated with clinical treatment failure. There is now also accumulating evidence
      that these mutant parasite strains also have a transmission advantage compared to wildtype
      parasites. Gametocyte carriage is higher for parasite with mutations in the dhfr and dhps
      genes, even if parasites are successfully cleared due to a longer parasite clearance time.
      Importantly, these mutant parasites are also more infectious to mosquitoes. These are
      worrying findings that may explain the rapid spread of parasite resistance in the population.
      The findings also indicate that gametocytes may be used as an early warning system to
      indicate the development of parasite resistance: parasite strains that produce most
      gametocytes are likely to have a reduced susceptibility to the drug.

      So far, ACT has proved to be an efficient tool to reduce the transmission of malaria to
      mosquitoes. Compared to monotherapy with SP, ACT reduces post-treatment gametocyte prevalence
      and density. This translates in a reduction in post-treatment malaria transmission. Compared
      to monotherapy, fewer individuals are infectious to mosquitoes after ACT treatment and the
      average number of infected mosquitoes and the oocyst burden in mosquitoes is reduced.
      Importantly, ACT does not completely prevent malaria transmission but may counteract the
      transmission of mutant parasite strains.

      2.4 ACT RESISTANCE There is a genuine fear that resistance against ACTs may develop. Although
      there is no direct evidence of full-blown clinical treatment failure of artemisinin
      derivatives, there are some worrying findings suggesting a reduced susceptibility of parasite
      isolates for ACTs. An increased resistance of parasite isolates to different artemisinin
      derivatives was observed in vitro for P. falciparum field isolates from Cambodia, French
      Guiana, and Senegal. This resistance was associated with SNPs at codon S769N of the ATPase6
      locus of P. falciparum. In addition, the lumefantrine component of AL may exert a selective
      pressure for parasites with a mutation in the parasite multi-drug resistance 1 gene (Pfmdr1).
      In general, there is fear that there may be a selection for the artemisinin partner drugs.
      Although ACTs are clearly giving hopeful results, it is not yet evident which combination of
      drugs provides the best results, especially in the light of possible artemisinin
      resistance18. Recently, the combination of dihydroartemisinin-piperaquine (DP) was found to
      be superior to AL in reducing the risk of recurrent parasitaemia and post-treatment
      gametocytaemia.

      Based on the finding that SP resistant parasite strains exhibit a higher gametocyte
      production under drug pressure, we hypothesize that gametocytaemia after treatment can be
      used to screen for parasites that are most likely to have a reduced susceptibility to ACT.

      2. JUSTIFICATION Studies on the development of resistance to ACT and the spread of ACT
      resistant parasite strains in the population are extremely relevant from a public health
      perspective. If resistance against artemether-lumefantrine or other ACTs develops, there will
      be no alternative drug available for first-line treatment. The identification of predictive
      markers for ACT resistance will be of great value for the protection of ACT. Studies on
      malaria transmission after ACT are of great importance in identifying those mutations that
      may eventually cause ACT resistance.

      The current study determines the efficacy of two different ACTs with a specific focus on
      detecting markers for resistance or reduced susceptibility of parasites to ACTs and the
      transmission potential of mutant parasites.
    

Intervention name(s): Artemether-Lumefantrine; Dihydroartemisinin-piperaquine
Intervention type(s): Drug; Drug
Intervention description(s): Treatment with artemether-lumefantrine (AL; Coartem; Novartis Pharma), administered as half a tablet (20 mg of artemether and 120 mg of lumefantrine) per 5 kg of body weight in a 6-dose regimen (at enrolment and 8, 20, 32, 44, and 56 h [+/-90 min] after the initiation of treatment). AL is currently the first line treatment in Tanzania; Dihydroartemisinin-piperaquine (DP; Artekin; Duocotexin, Holley Pharm, 40 mg dihydroartemisinin/320 mg piperaquine tablets), with a dihydroartemisinin dose of 2.5 mg per kilogram and a piperaquine phosphate dose of 20 mg per kilogram daily for 3 days. DH is registered in Tanzania as Artekin and has been tested extensively in Asia and recently in clinical trials in Uganda and Rwanda
Other intervention name(s): Coartem; Riamet; Artekin
Intervention MeSH terms: Lumefantrine; Artemether; Piperaquine; Artemether, Lumefantrine Drug Combination; Artenimol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment