chapter 1 chapter 2.1 chapter 2.2 Chapter 3 chapter 3.1

Transcription

1 CHAPTER 7 SUMMARY

2 Anaemia is an inevitable consequence of Plasmodium falciparum malaria infection, especially in areas of high malaria transmission. In these settings, the group at highrisk for malaria-associated anaemia are infants and young children. Since the emergence of drug-resistant parasite strains, the frequency of occurrence of anaemia is rising. Simultaneously, the treatment of uncomplicated falciparum malaria is posing a formidable challenge, because malaria control programs have to move onto combination therapy, which is inevitably expensive. The purpose of treating a case of uncomplicated malaria is to cure the infection, prevent progression to complications, severity and death. Severe anaemia is a major complication of malaria in areas of intense perennial transmission, especially, among young children. Treatment decisions for severe anaemia have to be made carefully, because the common intervention, blood transfusion, has become a major risk factor for HIV transmission. This thesis describes how we identified the problem of malaria-associated anaemia in young Kenyan children and the steps we followed in finding possible solutions to this problem. In chapter 1 we introduce the problem of malaria-associated anaemia and the relationship with antimalarial drug resistance. In that chapter we also outline the major aims of the studies described in this thesis. In chapter 2, we presented two studies that show the prevalence and burden of malarial anaemia in Kenyan children. In chapter 2.1, data from 3586 children who participated in the screening phase of a randomized trial were used. We found that 80% of these children had anaemia (Hb<11.0g/dL) and 3% had severe anaemia. Risk factors for presenting to hospital with anaemia were malaria parasitaemia, young age, splenomegaly, malnutrition, previous ineffective therapy and lack of bednet use. Young children below 3 years of age were identified as the high-risk population: prevalence of anaemia was 83%, Hb < 8.0 g/dl was 34% and 4% were severely anaemic (Hb<5.0g/dL). Malaria parasitaemia was strongly associated with Hb < 8.0 g/dl. This initial study characterized the problem of anaemia and identified young children<3 years of age as the population at the highest risk for severe anaemia and malaria-associated anaemia. In chapter 2.2, we aimed to determine the burden of severe malarial anaemia on paediatric admissions and mortality. Using data from a retrospective record review, we found that severe malarial anaemia was a major cause of admission and in-hospital mortality in children below 3 years of age. In this hospital, 90% of all admissions had Hb < 11g/dL, 20% were severely anaemic and 20% of all admissions were transfused. Additionally, 12% of severely anaemic children died and 52% of the malaria-related mortality was due to severe anaemia. This audit highlights the magnitude of burden that severe malarial anaemia poses on the paediatric healthcare system in this area of intense malaria transmission and identifies children < 3 years as the target group for any interventions aimed at reducing the burden of malarial anaemia. These initial studies identified that malaria, a treatable and preventable infection, was an important risk factor for severe paediatric anaemia. We therefore set out to evaluate the efficacy of current antimalarial therapy and to identify alternative treatment options. Chapter 3 describes 2 studies evaluating the role of artemisinin-based combination therapy in the treatment of uncomplicated falciparum malaria in African children. In chapter 3.1, we used the methods of meta-analysis to identify possible antimalarial 156

3 drug treatment options. Due to the problem of antimalarial drug resistance, combination therapy is widely advocated for treatment of uncomplicated falciparum malaria. In these decisions, cost and availability are major issues. We therefore compared the efficacy of one non-artemisinin-based combination (amodiaquine plus sulfadoxine-pyrimethamine [SP]) with 3 sets of artemisinin-based combinations (ACT) using data from 4472 African children with uncomplicated malaria. Besides reduction of gametocyte carriage, we found no clear advantage of ACT over amodiaquine plus SP. In some settings, amodiaquine plus SP had inferior (to artemether-lumefantrine), similar (to artesunate plus amodiaquine) or superior (to artesunate plus SP) efficacy compared to ACT. The most efficacious ACT in our study was artemether-lumefantrine, consistent with the current recommendations. We conclude that alternative options to ACT, including amodiaquine plus SP, do exist and should be considered when malaria control programmes make treatment policy decisions. Although, artesunate plus SP was inferior to amodiaquine plus SP in the meta-analysis, in some situations it may be the most feasible treatment option. We had such a situation in Kenya where the antimalarial drug of choice at the time of the study was SP, which was failing at a rapid rate. Due to limited experience with ACTs, it was considered the best option to retard the progression of SP resistance by adding artesunate. In chapter 3.2, we described a randomized, double blind, placebocontrolled trial in 600 children with uncomplicated falciparum malaria who were treated with either one [AS1] or 3 days of Artesunate plus SP [AS3] and compared with SP alone. By day 14, it was already clear that SP failure rate was unacceptably high. Adding artesunate to SP did not markedly improve the efficacy of the combination and by day 28, the parasitological failure rates when corrected by parasite genotyping were 33.1%, 20.7%, and 42.5%, for those treated with AS1, AS3 and SP alone, respectively. Both AS3 and AS1 regimens significantly reduced gametocyte carriage, fever and parasite clearance. However, the high failure rate of SP compromised the efficacy of the artesunate combination, making it an unsuitable choice for widespread use in Kenya. We concluded that ACT probably works best when the artemisinin-derivative is introduced earlier on before resistance develops to the standard companion drug. For malaria control in Kenya, alternative antimalarial drug (combination) was urgently required. Paediatric anaemia is an inevitable consequence of any significant malaria infection. Survival and improvement of haemoglobin are important clinical outcomes of antimalarial drug therapy. Chapter 4 describes two studies of the outcome of treatment for uncomplicated falciparum malaria. In chapter 4.1, the impact of introducing effective antimalarial therapy on case fatality is described. We used data from the prospective in-hospital surveillance system collected over 4 years. During the 4 years an increasing proportion of hospitalized children received an effective antimalarial therapy and there was a significant reduction in case fatality rates (from 13% at baseline to 3.5%). These results support the introduction of effective malaria therapy and we conclude that the current debate about delaying the introduction of effective, though expensive second-line (combination) therapies is not simply the debate about money, but about the cost of life. In chapter 4.2, we describe the effect of therapy on haematological recovery and anaemia prevalence within 28 days of initiating treatment. We used data from the randomized trial described in chapter

4 At enrolment 91% of the children were anaemic and only 18% achieved haematological recovery by 28 days after treatment, with only a modest reduction in the prevalence of anaemia in all treatment arms. We had hypothesized that treatment with Artesunate plus SP would result in better haematological outcomes compared to SP alone. This was not the case, probably because of the high failure rates in all treatment arms, the short follow-up period and the natural history of haemoglobin fall that follows treatment due parasite clearance. Our study confirmed that parasitological cure was necessary for achieving haematological recovery. However, our results highlight a major limitation of the current malaria control policy based heavily on case management. Children with high prevalence of malaria-associated anaemia arising probably from chronic asymptomatic parasitaemia may need repeated doses of an effective preventive antimalarial therapy, combined with a vector control strategy. Treatment of severe anaemia often includes blood transfusion a costly and labour intensive intervention, which may save life but could also transmit a chronic disease [the human immunodeficiency virus (HIV)]. In chapter 5 we used the methods of decision analysis to determine the circumstances when routine blood transfusion for severe malarial anaemia provides a higher probability of survival compared to no transfusion. Three key factors were found to determine the beneficial effect of a transfusion: a high risk of mortality without a transfusion, low risk of HIV contaminating the blood supply and the likelihood of high transfusion effectiveness (in reducing mortality). We recommend that transfusions should be given early during hospitalization using blood screened for HIV. Given the huge problem of malaria and its association with anaemia in young children, we propose that the risk of severe anaemia, hospitalization, mortality or blood transfusion could be reduced by administration of intermittent preventive therapy using an effective antimalarial drug. In chapter 6, we propose that intermittent preventive therapy in the post-discharge period (IPTpd) may be a key intervention to improving the outcomes (survival, haematological recovery and the frequency of occurrence of anaemia) of children who have survived at least one episode of severe malarial anaemia. The proposed intervention will go a step beyond the scope of the currently available interventions (insecticide-treated bednets, IPT in infancy, and malaria case management) that aim to prevent the development of a new episode of severe anaemia. However, we note that the efficacy and safety of this intervention has not been evaluated in well-designed clinical trials and there are implementation problems that need to be worked out. In conclusion, malaria-associated anaemia is a potentially preventable cause of severe morbidity and mortality among children < 5years of age in western Kenya and in other parts of sub-saharan Africa. Determining which children are at highest risk for severe anaemia, defining optimal treatment and prevention regimens, and identifying opportunities for earlier intervention may reduce the burden of disease and improve child survival. Our studies were undertaken at a time when most malaria control programmes were considering a switch from the current failing monotherapies to effective (though expensive) combination therapies. In part, our results assisted in prompting a change in the Kenyan treatment policy for uncomplicated malaria. Our 158

5 meta-analysis will help policy-makers undertake evidence-based decisions on the choice of antimalarial drug for uncomplicated malaria. Our transfusion decision analysis will aid the development of transfusion guidelines, in the context of malaria and the risk of HIV transmission through the blood supply. The epidemiology of malaria-associated anaemia in western Kenya highlights that this is still a major public health problem and that current efforts are not making a significant impact. Even with the availability of proven tools like insecticide treated bed nets, and iron supplementation (and very soon, intermittent preventive treatment of infants), these interventions do not seem to reach the target groups. A better understanding of the root causes of antimalarial drug resistsance is urgently needed. The struggle continues. 159