Samuel Adjei

Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials

BACKGROUND Intermittent preventive treatment (IPT) is a promising strategy for malaria control in infants. We undertook a pooled analysis of the safety and efficacy of IPT in infants (IPTi) with sulfadoxine-pyrimethamine in Africa. METHODS We pooled data from six double-blind, randomised, placebo-controlled trials (undertaken one each in Tanzania, Mozambique, and Gabon, and three in Ghana) that assessed the efficacy of IPTi with sulfadoxine-pyrimethamine. In all trials, IPTi or placebo was given to infants at the time of routine vaccinations delivered by WHOs Expanded Program on Immunization. Data from the trials for incidence of clinical malaria, risk of anaemia (packed-cell volume <25% or haemoglobin <80 g/L), and incidence of hospital admissions and adverse events in infants up to 12 months of age were reanalysed by use of standard outcome definitions and time periods. Analysis was by modified intention to treat, including all infants who received at least one dose of IPTi or placebo. FINDINGS The six trials provided data for 7930 infants (IPTi, n=3958; placebo, n=3972). IPTi had a protective efficacy of 30.3% (95% CI 19.8-39.4, p<0.0001) against clinical malaria, 21.3% (8.2-32.5, p=0.002) against the risk of anaemia, 38.1% (12.5-56.2, p=0.007) against hospital admissions associated with malaria parasitaemia, and 22.9% (10.0-34.0, p=0.001) against all-cause hospital admissions. There were 56 deaths in the IPTi group compared with 53 in the placebo group (rate ratio 1.05, 95% CI 0.72-1.54, p=0.79). One death, judged as possibly related to IPTi because it occurred 19 days after a treatment dose, was subsequently attributed to probable sepsis. Four of 676 non-fatal hospital admissions in the IPTi group were deemed related to study treatment compared with five of 860 in the placebo group. None of three serious dermatological adverse events in the IPTi group were judged related to study treatment compared with one of 13 in the placebo group. INTERPRETATION IPTi with sulfadoxine-pyrimethamine was safe and efficacious across a range of malaria transmission settings, suggesting that this intervention is a useful contribution to malaria control. FUNDING Bill & Melinda Gates Foundation.

Spatial Variation of Malaria Incidence in Young Children from a Geographically Homogeneous Area with High Endemicity

BACKGROUND In sub-Saharan Africa, malaria is a leading cause of morbidity and mortality among young children. Detailed knowledge of spatial variation of malaria epidemiology and associated risk factors is important for planning and evaluating malaria-control measures. METHODS The spatial variation of malaria incidences and socioeconomic factors were assessed over 21 months, from January 2003 to September 2005, in 535 children from 9 villages of a small rural area with high Plasmodium falciparum transmission in Ghana. Household positions were mapped by use of a global positioning system, and the spatial effects on malaria rates were assessed by means of ecological analyses and bivariate Poisson regression controlling for possible confounding factors. RESULTS Malaria incidence was surprisingly heterogeneous between villages, and ecological analyses showed strong correlations with village area (R(2) = 0.74; P = .003) and population size (R(2) = 0.68; P = .006). Malaria risk was affected by a number of socioeconomic factors. Poisson regression showed an independent linear rate reduction with increasing distance between childrens households and the fringe of the forest. CONCLUSIONS The exact location of households in villages is an independent and important factor for the variation of malaria incidence in children from high-transmission areas. This fact should be considered in the planning of intervention trials and in spatial targeting of malaria interventions at a local level.

Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine

BACKGROUND The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

A Randomized Controlled Trial of Extended Intermittent Preventive Antimalarial Treatment in Infants

BACKGROUND Intermittent preventive antimalarial treatment in infants (IPTi) with sulfadoxine-pyrimethamine reduces falciparum malaria and anemia but has not been evaluated in areas with intense perennial malaria transmission. It is unknown whether an additional treatment in the second year of life prolongs protection. METHODS A randomized, double-blinded, placebo-controlled trial with administration of sulfadoxine-pyrimethamine therapy at 3, 9, and 15 months of age was conducted with 1070 children in an area in Ghana where malaria is holoendemic. Participants were monitored for 21 months after recruitment through active follow-up visits and passive case detection. The primary end point was malaria incidence, and additional outcome measures were anemia, outpatient visits, hospital admissions, and mortality. Stratified analyses for 6-month periods after each treatment were performed. RESULTS Protective efficacy against malaria episodes was 20% (95% confidence interval [CI], 11%-29%). The frequency of malaria episodes was reduced after the first 2 sulfadoxine-pyrimethamine applications (protective efficacy, 23% [95% CI, 6%-36%] after the first dose and 17% [95% CI, 1%-30%] after the second dose). After the third treatment at month 15, however, no protection was achieved. Protection against the first or single anemia episode was only significant after the first IPTi dose (protective efficacy, 30%; 95% CI, 5%-49%). The number of anemia episodes increased after the last IPTi dose (protective efficacy, -24%; 95% CI, -50% to -2%). CONCLUSION In an area of intense perennial malaria transmission, sulfadoxine-pyrimethamine-based IPTi conferred considerably lower protection than reported in areas where the disease is moderately or seasonally endemic. Protective efficacy is age-dependent, and extension of IPTi into the second year of life does not provide any benefit.

Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

Summary Background The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. Methods Using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. Findings RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. Interpretation Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. Funding UK Medical Research Council.

Economic consequences of injury and resulting family coping strategies in Ghana

The toll of human suffering from illness and injury is usually measured by mortality and disability rates. Economic consequences, such as treatment costs and lost productivity, are often considered as well. Lately, increasing attention has been paid to the economic effects of illness on a household level. In this study, we sought to assess the economic consequences of injuries in Ghana by looking at the effects on households and the coping mechanisms these households employed. Using cluster sampling and household interviews, we surveyed 21,105 persons living in 431 urban and rural sites. We sought information on any injury that occurred to a household member during the prior year and that resulted in one or more days of disability time.A total of 1609 injuries were reported for the prior year. Treatment costs and disability days were higher in the urban area than in the rural. Coping strategies were different between the two areas. Rural households were more likely to utilize intra-family labor reallocation (90%) than were urban households (75%). Rural households were also more likely to borrow money (24%) than were urban (19%). Households in both areas were equally likely to sell belongings, although the nature of the belongings sold were different. Although injuries in the urban area had more severe primary effects (treatment cost and disability time), the ultimate effect on rural households appeared more severe. A greater percentage of rural households (28%) reported a decline in food consumption than did urban households (19%). These findings result in several policy implications, including measures that could be used to assist family coping strategies and measures directed toward injuries themselves.

Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth.

The high prevalence of hemoglobin S (HbS) in Africa and hemoglobin C (HbC) in parts of West Africa is caused by the strong protection against severe falciparum malaria during childhood. Much less is known about the effect of HbS and especially HbC on Plasmodium falciparum infection, uncomplicated malaria, and anemia. A total of 1070 children from the Ashanti Region, Ghana, were enrolled at the age of 3 months and visited monthly until 2 years of age. The effects of the beta-globin genotype on the age-dependent incidence of malaria, levels of parasitemia, and hemoglobin as well as physical development were analyzed by population-averaged models. Infants with HbAS were protected from uncomplicated malaria (P < .005) and anemia (P < .001), had lower age-adjusted parasite densities (P < .001), and higher age-adjusted hemoglobin levels compared with children with the HbAA genotype (P = .004). In contrast, HbAC carriers had lower hemoglobin levels (P < .033) and were not protected against malaria or anemia. Notably, infants with HbAS were also significantly protected against stunting compared with carriers of HbAA or HbAC. This indicates differing mechanisms of protection against malaria of HbAS and HbAC and might help to understand why HbC is restricted to distinct areas of West Africa.

Long-term injury related disability in Ghana

Purpose: We sought to: (1) estimate the prevalence of longterm injury-related disability in Ghana; (2) understand the mechanisms of injury causing such disability, with implications for prevention; and (3) understand the anatomic nature of such disability, with implications for treatment. Methods: A household survey was carried out, seeking information on any injury occurring greater than one year ago, from which the injured person had not yet fully recovered. Results: Of 21 105 persons surveyed, 169 reported a long-term injury-related disability, for a prevalence of 0.83% (95% CI 0.67, 1.01%). There was no difference in the prevalence for males vs. females nor for urban vs. rural. Prevalence did increase with increased age. The injury producing events occurred a mean of 6.8 years previously. In the urban area, there was a predominance of transport-related injuries (43%). In the rural area, agricultural injuries predominated (22%), with lesser numbers of transport-related injuries (20%). The anatomic nature of the disabilities included: lower extremity (41%), upper extremity (37%), vision (12%), and miscellaneous (10%). Conclusions: In addition to mortality, long-term disability from injury is a significant problem in this African nation. Based on the mechanisms of injury priorities for injury prevention should be motor vehicle safety in both areas and agricultural safety in the rural area. In terms of injury treatment, the preponderance of injuries was to the extremities. This indicates the potential need to improve orthopaedic care and rehabilitative services. Introduction Injury has become an increasingly significant cause of mortality in developing countries, especially among older children and working aged adults. The Global Burden of Disease Study estimates that injury related causes account for three of the top six killers of children aged 5 – 14 years and for four of the top six killers of young, working aged adults, aged 15 – 44 years. To understand the total burden of any disease, we must also consider disability as well as death. In an effort to add this consideration to its estimation of disease burden, the above noted Global Burden of Disease study looked at the relative contributions of various diseases to Disability Adjusted Life Years (DALYs) lost. The DALY combines the concepts of years of life lost due to death with years of productive life lost due to varying levels of disability. The Study estimated that 12% of the DALYs lost world wide were due to injury. 3 However, the actual data that contributed to these estimates were fairly sparse, especially as regards disability and especially as regards the poorest countries. Furthermore, detailed information on the characteristics of all causes of disability, and especially of injury related disability, is very limited for most developing countries. In the current study, we sought to gain a better idea of the prevalence of long-term injury related disability in a particular African country, Ghana. Given the limited reliability of existing data sources such as hospital records and police accident reports, we undertook a community based survey. We sought to obtain a better understanding of the extent of the problem, as reflected by prevalence rates. We also sought to gain a better understanding of the mechanisms of injury contributing * Author for correspondence; Charles Mock MD PhD, Harborview Injury Prevention and Research Center, Box 359960, Harborview Medical Center, 325 Ninth Avenue, Seattle, WA 98104, USA; e-mail: cmock@u.washington.edu DISABILITY AND REHABILITATION, 2003; VOL. 25, NO. 13, 732–741 Disability and Rehabilitation ISSN 0963–8288 print/ISSN 1464–5165 online # 2003 Taylor & Francis Ltd http://www.tandf.co.uk/journals DOI: 10.1080/0963828031000090524 the most to disability, as an indication of priorities for injury prevention efforts. Finally, we sought to gain a better understanding of the anatomic nature of the disabilities, as an indication of the priorities for improvements in both acute injury treatment and rehabilitation. Several different theoretical constructs have been used for understanding functional loss from injury and other disease processes. The World Health Organization (WHO) has developed the scheme of impairment, disability and handicap. 5 Impairment indicates the dysfunction at the level of an organ or organ system, such as loss of range of motion in an extremity. Disability implies dysfunction at the level of the individual, such as loss of ability to perform the activities of daily living. Handicap indicates how impairment and disability affect an individual’s role in society. – 6 In this study, we primarily utilized and measured the concept of disability, as determined by self-report from the respondents.

Novel Human Parvovirus 4 Genotype 3 in Infants, Ghana

Human parvovirus 4 has been considered to be transmitted only parenterally. However, after novel genotype 3 of parvovirus 4 was found in 2 patients with no parenteral risks, we tested infants in Ghana. A viremia rate of 8.6% over 2 years indicates that this infection is common in children in Africa.

A randomized trial on effectiveness of artemether-lumefantrine versus artesunate plus amodiaquine for unsupervised treatment of uncomplicated Plasmodium falciparum malaria in Ghanaian children

BackgroundNumerous trials have demonstrated high efficacy and safety of artemisinin-based combination therapy (ACT) under supervised treatment. In contrast, effectiveness studies comparing different types of ACT applied unsupervised are scarce. The aim of this study was to compare effectiveness, tolerability and acceptance of artesunate plus amodiaquine (ASAQ) against that of artemether-lumefantrine (AL) in Ghanaian children with uncomplicated Plasmodium falciparum malaria.MethodsA randomized open-label trial was conducted at two district hospitals in the Ashanti region, Ghana, an area of intense malaria transmission. A total of 246 children under five years of age were randomly assigned to either ASAQ (Arsucam®) or AL (Coartem®). Study participants received their first weight-adjusted dose under supervision. After the parent/guardian was advised of times and mode of administration the respective three-day treatment course was completed unobserved at home. Follow-up visits were performed on days 3, 7, 14 and 28 to evaluate clinical and parasitological outcomes, adverse events, and haematological recovery. Length polymorphisms of variable regions of msp1 and msp2 were determined to differentiate recrudescences from reinfections. Acceptance levels of both treatment regimens were assessed by means of standardized interviews.ResultsAdequate clinical and parasitological responses after AL and ASAQ treatment were similar (88.3% and 91.7%, respectively). Interestingly, more late clinical failures until day 28 occurred in AL-treated children than in those who received ASAQ (17.5% and 7.3%, respectively; Hazard Ratio 2.41, 95% CI 1.00–5.79, p < 0.05).Haematological recovery and drug tolerability were not found to be significantly different in both study arms. The acceptance of treatment with ASAQ was higher than that with AL (rank-scores 10.6 and 10.3, respectively; p < 0.05).ConclusionUnobserved AL and ASAQ treatment showed high adequate clinical and parasitological responses, though AL was inferior in preventing late clinical failures.