Gijs Walraven

Artesunate Reduces but Does Not Prevent Posttreatment Transmission of Plasmodium falciparum to Anopheles gambiae

Combination therapy that includes artemisinin derivatives cures most falciparum malaria infections. Lowering transmission by reducing gametocyte infectivity would be an additional benefit. To examine the effect of such therapy on transmission, Gambian children with Plasmodium falciparum malaria were treated with standard regimens of chloroquine or pyrimethamine-sulfadoxine alone or in combination with 1 or 3 doses of artesunate. The infectivity to mosquitoes of gametocytes in peripheral blood was determined 4 or 7 days after treatment. Infection of mosquitoes was observed in all treatment groups and was positively associated with gametocyte density. The probability of transmission was lowest in those who received pyrimethamine-sulfadoxine and 3 doses of artesunate, and it was 8-fold higher in the group that received pyrimethamine-sulfadoxine alone. Artesunate reduced posttreatment infectivity dramatically but did not abolish it completely. The study raises questions about any policy to use pyrimethamine-sulfadoxine alone as the first-line treatment for malaria.

Efficacy of artesunate plus pyrimethamine-sulphadoxine for uncomplicated malaria in Gambian children: a double-blind, randomised, controlled trial

BACKGROUND Resistance to cheap effective antimalarial drugs, especially to pyrimethaminesulphadoxine (Fansidar), is likely to have a striking impact on childhood mortality in sub-Sharan Africa. The use of artesunate (artesunic acid) [corrected] in combination with pyrimethamine-sulphadoxine may delay or prevent resistance. We investigated the efficacy, safety, and tolerability of this combined treatment. METHODS We did a double-blind, randomised, placebo-controlled trial in The Gambia. 600 children with acute uncomplicated Plasmodium falciparum malaria, aged 6 months to 10 years, at five health centres were randomly assigned pyrimethaminesulphadoxine (25 mg/500 mg) with placebo; pyrimethamine-sulphadoxine plus one dose of artesunate (4mg/kg bodyweight); or pyrimethamine-sulphadoxine plus one dose 4 mg/kg bodyweight artesunate daily for 3 days. Children were visited at home each day after the start of treatment until parasitaemia had cleared. FINDINGS The combined treatment was well tolerated. No adverse reactions attributable to treatment were recorded. By day 1, only 178 (47%) of 381 children treated with artesunate were still parasitaemic, compared with 157 (81%) of 195 children in the pyrimethamine-sulphadoxine alone group (relative risk 1.7 [95% CI 1.5-2.0], p<0.001). Treatment-failure rates at day 14 were 3.1% in the pyrimethamine sulphadoxine alone group, and 3.7% in the one-dose artesunate group (risk difference -0.6% [-4.2 to 3.0]) and 1.6% in the three-dose group (1.5 [1.5-4.5], p=0.048). Symptoms resolved faster in children who received artesunate, but there was no additional benefit for three doses of artesunate over one dose. Children given artesunate were less likely to be gametocytaemic after treatment. INTERPRETATION The combined treatment was safe, well tolerated, and effective. The addition of artesunate to malaria treatment regimens in Africa results in lower gametocyte rates and may lower transmission rates.

Reduction of Malaria Transmission to Anopheles Mosquitoes with a Six-Dose Regimen of Co-Artemether

Background Resistance of malaria parasites to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) is increasing in prevalence in Africa. Combination therapy can both improve treatment and provide important public health benefits if it curbs the spread of parasites harbouring resistance genes. Thus, drug combinations must be identified which minimise gametocyte emergence in treated cases, and so prevent selective transmission of parasites resistant to any of the partner drugs. Methods and Findings In a randomised controlled trial, 497 children with uncomplicated falciparum malaria were treated with CQ and SP (three doses and one dose respectively; n = 91), or six doses of artemether in fixed combination with lumefantrine (co-artemether [Coartem, Riamet]) (n = 406). Carriage rates of Plasmodium falciparum gametocytes and trophozoites were measured 7, 14, and 28 d after treatment. The infectiousness of venous blood from 29 children carrying P. falciparum gametocytes 7 d after treatment was tested by membrane-feeding of Anopheles mosquitoes. Children treated with co-artemether were significantly less likely to carry gametocytes within the 4 weeks following treatment than those receiving CQ/SP (30 of 378 [7.94%] versus 42 of 86 [48.8%]; p < 0.0001). Carriers in the co-artemether group harboured gametocytes at significantly lower densities, for shorter periods (0.3 d versus 4.2 d; p < 0.0001) and were less infectious to mosquitoes at day 7 (p < 0.001) than carriers who had received CQ/SP. Conclusions Co-artemether is highly effective at preventing post-treatment transmission of P. falciparum. Our results suggest that co-artemether has specific activity against immature sequestered gametocytes, and has the capacity to minimise transmission of drug-resistant parasites.

Effect of pregnancy on exposure to malaria mosquitoes

Pregnant women attracted twice the number of Anopheles gambiae complex--the predominant African malaria-carrying mosquito--than did their non-pregnant counterparts. We postulate that physiological and behavioural changes that occur during pregnancy are responsible for increased attractiveness, which could be important in intervention strategies aimed at protecting this high-risk group against malaria.

A Randomised, Double-Blind, Controlled Vaccine Efficacy Trial of DNA/MVA ME-TRAP Against Malaria Infection in Gambian Adults

Background Many malaria vaccines are currently in development, although very few have been evaluated for efficacy in the field. Plasmodium falciparum multiple epitope (ME)– thrombospondin-related adhesion protein (TRAP) candidate vaccines are designed to potently induce effector T cells and so are a departure from earlier malaria vaccines evaluated in the field in terms of their mechanism of action. ME-TRAP vaccines encode a polyepitope string and the TRAP sporozoite antigen. Two vaccine vectors encoding ME-TRAP, plasmid DNA and modified vaccinia virus Ankara (MVA), when used sequentially in a prime-boost immunisation regime, induce high frequencies of effector T cells and partial protection, manifest as delay in time to parasitaemia, in a clinical challenge model. Methods and Findings A total of 372 Gambian men aged 15–45 y were randomised to receive either DNA ME-TRAP followed by MVA ME-TRAP or rabies vaccine (control). Of these men, 296 received three doses of vaccine timed to coincide with the beginning of the transmission season (141 in the DNA/MVA group and 155 in the rabies group) and were followed up. Volunteers were given sulphadoxine/pyrimethamine 2 wk before the final vaccination. Blood smears were collected weekly for 11 wk and whenever a volunteer developed symptoms compatible with malaria during the transmission season. The primary endpoint was time to first infection with asexual P. falciparum. Analysis was per protocol. DNA ME-TRAP and MVA ME-TRAP were safe and well-tolerated. Effector T cell responses to a non-vaccine strain of TRAP were 50-fold higher postvaccination in the malaria vaccine group than in the rabies vaccine group. Vaccine efficacy, adjusted for confounding factors, was 10.3% (95% confidence interval, −22% to +34%; p = 0.49). Incidence of malaria infection decreased with increasing age and was associated with ethnicity. Conclusions DNA/MVA heterologous prime-boost vaccination is safe and highly immunogenic for effector T cell induction in a malaria-endemic area. But despite having produced a substantial reduction in liver-stage parasites in challenge studies of non-immune volunteers, this first generation T cell–inducing vaccine was ineffective at reducing the natural infection rate in semi-immune African adults.

Atopy, intestinal helminth infection and total serum IgE in rural and urban adult Gambian communities

Background The rarity of atopy in traditional societies has been attributed to high parasite‐driven blocking IgE concentrations. Information is lacking on the relationship between atopy, IgE and intestinal helminth infection in African populations.

Effect of fly control on trachoma and diar rhoea

BACKGROUND Domestic flies are accepted vectors of diarrhoea, but their role in trachoma transmission has never been quantified and no study has shown that fly control decreases the prevalence of trachoma. We assessed the effect of fly control on public health in a pilot study in Gambian villages. METHODS We studied two pairs of villages--one pair in the 1997 wet season, and one pair in the 1998 dry season. For each pair, deltamethrin was sprayed for 3 months to control flies in one village whilst the other was used as a control. Fly populations were monitored with traps. We surveyed trachoma at baseline and at 3 months, and collected daily data on diarrhoea in children aged between 3 months and 5 years. FINDINGS Fly control decreased numbers of muscid flies by around 75% in the intervention villages compared with controls. Trachoma prevalence was similar at baseline (wet season, prevalence in intervention village 8.8% vs control 12.2%; dry season, 18.0% vs 16.0%), but after 3 months of fly control there were 75% fewer new cases of trachoma in the intervention villages (wet season 3.7% vs 13.7%; dry season 10.0% vs 18.9%; rate ratio and relative risk of pooled data 0.25 [adjusted 95% CI 0.09-0.64], p=0.003). There was 22% less childhood diarrhoea in the wet season (14% vs 19%, period prevalence ratio 0.78 [0.64-0.95], p=0.01), and 26% less diarrhoea in the dry season (6% vs 8%; 0.74 [0.34-1.59], p=0.60) compared with controls. INTERPRETATION Muscid flies are important vectors of trachoma and childhood diarrhoea in The Gambia. Deltamethrin spray is effective for fly control and may be useful for reducing trachoma and diarrhoea in some situations, but further research on sustainable fly-control methods is needed.

Role of flies and provision of latrines in trachoma control : cluster-randomised controlled trial.

BACKGROUND Eye-seeking flies have received much attention as possible trachoma vectors, but this remains unproved. We aimed to assess the role of eye-seeking flies as vectors of trachoma and to test provision of simple pit latrines, without additional health education, as a sustainable method of fly control. METHODS In a community-based, cluster-randomised controlled trial, we recruited seven sets of three village clusters and randomly assigned them to either an intervention group that received regular insecticide spraying or provision of pit latrines (without additional health education) to each household, or to a control group with no intervention. Our primary outcomes were fly-eye contact and prevalence of active trachoma. Frequency of child fly-eye contact was monitored fortnightly. Whole communities were screened for clinical signs of trachoma at baseline and after 6 months. Analysis was per protocol. FINDINGS Of 7080 people recruited, 6087 (86%) were screened at follow-up. Baseline community prevalence of active trachoma was 6%. The number of Musca sorbens flies caught from childrens eyes was reduced by 88% (95% CI 64-100; p<0.0001) by insecticide spraying and by 30% (7-52; p=0.04) by latrine provision by comparison with controls. Analysis of age-standardised trachoma prevalence rates at the cluster level (n=14) showed that spraying was associated with a mean reduction in trachoma prevalence of 56% (19-93; p=0.01) and 30% with latrines (-81 to 22; p=0.210) by comparison with the mean rate change in the controls. INTERPRETATION Fly control with insecticide is effective at reducing the number of flies caught from childrens eyes and is associated with substantially lower trachoma prevalence compared with controls. Such a finding is consistent with flies being important vectors of trachoma. Since latrine provision without health education was associated with a significant reduction in fly-eye contact by M sorbens, studies of their effect when combined with other trachoma control measures are warranted.

The long-term reproductive health consequences of female genital cutting in rural Gambia: a community-based survey

This paper examines the association between traditional practices of female genital cutting (FGC) and adult women’s reproductive morbidity in rural Gambia. In 1999, we conducted a cross‐sectional community survey of 1348 women aged 15–54 years, to estimate the prevalence of reproductive morbidity on the basis of women’s reports, a gynaecological examination and laboratory analysis of specimens. Descriptive statistics and logistic regression were used to compare the prevalence of each morbidity between cut and uncut women adjusting for possible confounders. A total of 1157 women consented to gynaecological examination and 58% had signs of genital cutting. There was a high level of agreement between reported circumcision status and that found on examination (97% agreement). The majority of operations consisted of clitoridectomy and excision of the labia minora (WHO classification type II) and were performed between the ages of 4 and 7 years. The practice of genital cutting was highly associated with ethnic group for two of the three main ethnic groups, making the effects of ethnic group and cutting difficult to distinguish. Women who had undergone FGC had a significantly higher prevalence of bacterial vaginosis (BV) [adjusted odds ratio (OR)=1.66; 95% confidence interval (CI) 1.25–2.18] and a substantially higher prevalence of herpes simplex virus 2 (HSV2) [adjusted OR=4.71; 95% CI 3.46–6.42]. The higher prevalence of HSV2 suggests that cut women may be at increased risk of HIV infection. Commonly cited negative consequences of FGC such as damage to the perineum or anus, vulval tumours (such as Bartholin’s cysts and excessive keloid formation), painful sex, infertility, prolapse and other reproductive tract infections (RTIs) were not significantly more common in cut women. The relationship between FGC and long‐term reproductive morbidity remains unclear, especially in settings where type II cutting predominates. Efforts to eradicate the practice should incorporate a human rights approach rather than rely solely on the damaging health consequences.

Changes in house design reduce exposure to malaria mosquitoes

House design may affect an individuals exposure to malaria parasites, and hence to disease. We conducted a randomized‐controlled study using experimental huts in rural Gambia, to determine whether installing a ceiling or closing the eaves could protect people from malaria mosquitoes. Five treatments were tested against a control hut: plywood ceiling; synthetic‐netting ceiling; insecticide‐treated synthetic‐netting ceiling (deltamethrin 12.5 mg/m2); plastic insect‐screen ceiling; or the eaves closed with mud. The acceptability of such interventions was investigated by discussions with local communities. House entry by Anopheles gambiae, the principal African malaria vector, was reduced by the presence of a ceiling: plywood (59% reduction), synthetic‐netting (79%), insecticide‐treated synthetic‐netting (78%), plastic insect‐screen (80%, P < 0.001 in all cases) and closed eaves (37%, ns). Similar reductions were also seen with Mansonia spp., vectors of lymphatic filariasis and numerous arboviruses. Netting and insect‐screen ceilings probably work as decoy traps attracting mosquitoes into the roof space, but not the room. Ceilings are likely to be well accepted and may be of greatest benefit in areas of low to moderate transmission and when used in combination with other malaria control strategies.