Intermittent preventive treatment for malaria in children to reduce deaths in Senegal

 

  1. Executive Summary

Problem:

Malaria has been a one of the main causes of child mortality in many parts of the world.  IPTc presents a possible health strategy that can be supported with conclusive evidence that it is an efficient method in tackling the risk of malaria, with places such as Senegal showing an 86% reduction in the number of recorded children cases.

Effects:

Benefits of the combination of Amodiaquine and Sulphadoxine-pyrimethamine

  • Prevents approximately ¾ of all clinical malaria episodes (high quality evidence)
  • Prevents similar proportion of all severe malaria episodes (high quality evidence)
  • Effects remain prominent even where insecticide treated net (ITN) usage is high (high quality evidence)
  • IPTc may cause a slight reduction in all-cause mortality consistent with the effect on severe malaria, but the inconclusive due to underpowered staff to provide a statistical significance (moderate quality evidence)

Harms of the combination of Amodiaquine and Sulphadoxine-pyrimethamine

  • Causes increased vomiting in this age-group (high quality evidence)

 

Reliability: For the best results to be achieved the drug should be administered daily or weekly depending on the length of seasonal transmission

Applicability: The risk of adverse effects (increased vomiting) to the patients might pause a challenge when it comes to application of the results.

Recommendation: Studies show that giving anti-malarial drugs in combination to preschool children during transmission season significantly reduces the occurrence of both clinical and severe malaria. The policy makers should take up the drugs and use them for children below six years to prevent further mortality deaths among children.

  1. Context

The problem

Most child mortality cases are caused by malaria in Senegal. In order to treat and prevent the spread of malaria in children of below six years adoption of IPTc is recommended. By following a treatment of IPTc, children will be monitored at regular intervals during the transmission season.  Senegal still uses Chloroquine as a method to treat malaria. The parasites have however become resistant towards the drug. This means that they are no longer able to control the spread of the disease. If the current policy will not change, there will be increase mortality. The World Health Organisation recommended a control approach that combines multiple anti-malarial prevention drugs (WHO 2000) to help with immunisation of children who were most vulnerable to malaria related deaths.

The Intervention

  1. Q) Is IPTc the correct treatment in the prevention of malaria related cases?

Malaria is a common disease found in the sub-Saharan (WHO reported 265,624 cases in Senegal in 2013) caused by Plasmodium parasites that is transmitted to humans via the bite of infected anopheline mosquitoes. Preschool children have virtually no immunity to Plasmodium Falciparum (the main contributor to severe malaria). They therefore become the most susceptible to the disease (Gilles 2000). Introducing immunity before the age of 10 (Branch 1998) provides an increased chance of not becoming infected.

Compared to Chloroquine this form of treatment is more widely accepted as the chances of the parasites building up a resistance is minimal due to the combination of drugs that are required. For Chloroquine, the parasites acquired a natural resistance that made it ineffective in trying to control the spread of malaria. Sulphadoxine-pyrimethamine and Amodiaquine are the drugs used and work by accumulating in the parasites food vacuole, binding to heme and forming a complex that thwarts the crystallisation in the plasmodium food vacuole causing the parasites death and destruction.

  1. Effects of treatment or intervention

What question does the review address?

The research aimed to summarise the benefits and harms of using a combination of drugs via IPTc for treating both clinical and severe malaria and preventing it from reoccurring in the future.  Reviews and write-ups were found for many trials that have taken place from 2006 (Cisse 2006)  involving 1088 children from two to 59 months and reviews from later trials, in 2011 (Dicko 2011)  involving 3017 children of the ages 3 to 59 months. Both used a combination of drugs with the latter one operating with Sulphadoxine-pyrimethamine and Amodiaquine. The results showed positive results in terms of treating and prevention of malaria.

. Out of the seven randomised controlled trials, 12,589 children were enrolled. The results found out that there were more benefits than harms when there is a combination of drugs. The benefits of using a combination of Amodiaquine and Sulphadoxine-pyrimethamine according to the reviews are:

  • Of all clinical malaria cases ¾ were prevented (rate ratio 0.26; 95% CI 0.17 to 0.38; 9321 participants, six trials, high quality evidence)
  • A similar proportion of all severe malaria cases were avoided (rate ratio 0.27, 95% CI 0.10 to 0.76; 5964 participants, two trials, high quality evidence).
  • Effects continue to be prominent even where insecticide treated net (ITN) practice is high (two trials, 5964 participants, high quality evidence)
  • IPTc may cause a slight decrease in mortality consistent with the effect on severe malaria, but is inconclusive due to it being understaffed therefore produce a statistical significance (risk ratio 0.66, 95% CI 0.31 to 1.39, moderate quality evidence).

The harms of using a combination of Amodiaquine and Sulphadoxine-pyrimethamine according to the research are:

  • Causes increased vomiting in this age group (risk ratio 2.78, 95% CI 2.31 to 3.35; 2 trials, 3544 participants, high quality evidence).

The results of the review show that combination of drugs to treat malaria in infants has more benefits than harms. Ninety five percent of the participants in all the trials showed that cases of severe malaria could be prevented when the drugs were combined. The drug can therefore be used in prevention of malaria among the children without having many side effects apart from the increased vomiting that was noted. The authors of the review were confident that this is the best drug to reduce mortality rates by preventing the spread of clinical and severe malaria.

  1. Reliability of the results

Appraise the methods of the review:

The trials assessed were using the Cochrane tool for assessing the risk of bias and there were no limitations present. An extensive search conducted was using the MEDLINE, LILACS and EMBASE databases. It is highly unlikely that the published trials assessing this question would have been missed. Unpublished trials were sought without much success.

The researchers concealed treatment allocation to reduce the risk of bias by a process of blinding where neither the person administrating the drug or the participants knew whether they were taking the drug or the placebo. The clusters were randomised with a computerised random number generator and the concealed allocation was carried out by number sealed opaque envelope. The outcomes seem appropriate and suggest that there was no/limited risk of bias during the trials.

Comment on the quality of the evidence:

Using the GRADE working methods, the quality of the evidence can be verified and the validation of the findings confirmed in each trial as they all have outcomes that are similar to other trials. The evidence in reduction of mortality is considered to be of high quality, meaning that we can be confident that the results are accurate. Further research on a larger scale is not necessary but will be useful to cement more confidence in the evidence presented so far. This means that the results are actually dependable and can be successfully used in Senegal to reduce the mortality of young children under the age of six.

  1. Applicability of the results to Senegal

The vast majority of studies conducted were in central Africa, a place that is prominent in malaria. These are some of the countries that are believed to have the most prevalent cases of child mortality caused by malaria. Some countries have adequate facilities to tackle these outbreaks, whilst some do not. Places such as Mali and Sierra Leone have such a high incidence of malaria cases among children. The research consisted of children of below six years because this group is more prone to be affected by malaria because of their low immunity against the disease. These countries normally do not have access to good healthcare and have limited knowledge on how to prevent and fight against malaria. With a greater understanding, malaria could be preventable and save thousands of lives.

The interventions that should be used for children in Senegal should follow the IPTc trials in Mali (Dicko 2011), where a dose of Amodiaquine and Sulphadoxine-pyrimethamine should be provided in three consecutive courses during peak malaria transmission. It should be carried out in a blind trial and conducted in a very specific population of infants below the age of six. This will ensure that the participants do not know if they are taking the real drug or the placebo. There are concerns however for the practicality of the trials, with the adverse effects that might occur (yet are rare), and these may limit the usefulness of the intervention. The development of anti-malarial prevention drugs has not been done before either for IPTc, so close monitoring of the process should be followed to ensure the safety of participants and future cases.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Annex 1. AMSTAR assessment of the systematic review

Review reference: Dicko 2008

 

  1. Was an ‘a priori’ design provided?

 

Yes, the research question and inclusion criterion was recognized before the conduct of the review.

 

  1. Was there duplicate study selection and data extraction?

 

Yes. There should be more than one independent data extractors and a consensus procedure for disagreements should be installed.

 

  1. Was a comprehensive literature search performed?

 

Yes.  At least two electronic sources should be searched. The report must include years and databases used (MEDLINE etc.). Key words should be stated. Easy search strategy should be in place, with contents, reviews and textbooks being supplied.

 

  1. Was the status of publication (i.e. grey literature) used as inclusion criterion?

 

No. The authors should state that they searched the reports regardless of their publication type. A statement informing us on excluded reports should be provided.

 

  1. Was a list of studies (included and excluded) provided?

 

Yes. A list of included and excluded studies were provided.

 

  1. Were the characteristics of the included studies provided?

 

Yes. In a table format that included participants, interventions and outcomes of each individual. Wide range of characteristics analysed, e.g. race, sex, socioeconomic status, disease status, severity.

 

  1. Was the scientific quality of the included studies assessed and documented?

 

Yes. ‘A priori’ methods should be provided (e.g. randomised, double-blind, placebo controlled studies used)

 

  1. Was the scientific quality of the included studies used appropriately in formulating conclusions?

Yes. The results of the methodological precision and scientific quality should be taken       into consideration in the analysis and conclusions of the review and should be stated.

 

  1. Were the methods used to combine the findings of studies appropriate?

Yes. For the pooled results a test should be taken to see if the studies are combinable, to assess their homogeneity. If heterogeneity is present, a random effects model should be used.

 

  1. Was the likelihood of publication bias assessed?

Can’t answer. An assessment of publication bias should be taken and included.

 

  1. Was the conflict of interest stated?

No. potential sources of support should be taken note of and stated. In this case, there weren’t any.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Annex 2. Assessment of the local applicability of the systematic review

Study reference: Mali (Dicko 2011)

 

  1. Were the studies included in this systematic review conducted in settings similar to Senegal, or were the findings consistent across settings and time periods?

 

Yes, the trial was conducted in a setting to Senegal (and a study has been taken there before); low socioeconomic status with a high-uncontrolled birth rate

 

 

 

  1. Are there important differences in on-the-ground realities and constraints in Ghana that might substantially alter the feasibility and acceptability of this drug/formulation?

 

The drugs have to be imported, as they are not manufactured in the country

 

 

 

 

  1. Are there important differences in health system arrangements that may mean this drug/formulation could not work in the same way?

 

None that have been recorded

 

 

 

 

  1. Are there important differences in the baseline conditions that might yield different absolute effects even if the relative effectiveness was the same?

 

Senegal sees a lower death rate suggesting that the benefits of this treatment outweigh the treatment in Mali

 

 

 

 

  1. What insights can be drawn about options, implementation, and monitoring and evaluation?

 

Its implementation would require training of more nurses and doctors along with the necessary supplementation of information to people.

 

 

 

 

References

Aregawi M, Cibulskis RE, Otten M, et al. (2009) World malaria report 2009: Geneva: World Health Organization.

Branch OH, Udhayakumar V, Hightower AW, et al. (1998) A longitudinal investigation of IgG and IgM antibody responses to the merozoite surface protein-1 19-kilodalton domain of Plasmodium falciparum in pregnant women and infants: associations with febrile illness, parasitemia, and anemia. American Journal of Tropical Medicine and Hygiene 58: 211-219.

Cissé B, Sokhna C, Boulanger D, et al. (2006) Seasonal intermittent preventive treatment with artesunate and sulfadoxine-pyrimethamine for prevention of malaria in Senegalese children: a randomised, placebo-controlled, double-blind trial. Lancet (London, England) 367: 659-667.

Gilles HM. (2000) Management of severe malaria: a practical handbook: 2nd ed. Geneva: World Health Organization. P4-15.

Greenwood B. (2010) Anti-malarial drugs and the prevention of malaria in the population of malaria endemic areas. Malaria Journal 9 Suppl 3: S2-S2.

WHO (1990) Practical chemotherapy of malaria. Technical Report Series – World Health Organization. World Health Organization (WHO), Geneva.; Switzerland.

WHO (1993) Implementation of the global malaria control strategy: report of a WHO study group on the implementation of the global plan of action for malaria control 1993-2000. WHO Technical Report Series; no 839. Geneva; Switzerland: World Health Organization, 0-57.

WHO (2000) Severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene. 94 (1), 1–90.

World Health Organization (2009). World Malaria Report 2009, Geneva.

 

 

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