Sake J. de Vlas

Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa

Health policy making in developing countries requires estimates of the (global) burden of disease. At present, most of the available data on schistosomiasis is limited to numbers of individuals harbouring the infection. We explored the relationship between the presence of schistosome infection and clinical morbidity, in order to estimate numbers of individuals with disease-specific morbidity for Schistosoma haematobium and Schistosoma mansoni infection in sub-Saharan Africa. We searched the literature for cross-sectional data from field studies reporting both schistosome infection and morbidity. This was used to derive a functional relationship between morbidity and infection. After standardisation for diagnostic method, the number of individuals with specific types of clinical morbidity or pathology was predicted. As only aggregated prevalences of infection were available for countries or areas, we adjusted for heterogeneity in infection levels within communities in those countries. In total, 70 million individuals out of 682 million (2000 estimate) in sub-Saharan Africa were estimated to experience haematuria in the last 2 weeks associated with S. haematobium infection, and 32 million dysuria. Ultrasound detected serious consequences of S. haematobium, major bladder wall pathology and major hydronephrosis, were predicted at 18 and 10 million, respectively. Infection with S. mansoni was estimated to cause diarrhoea in 0.78 million individuals, blood in stool in 4.4 million and hepatomegaly in 8.5 million. As the associations between prevalence of S. mansoni infection and prevalence of diarrhoea and blood in stool were not very clear, the resulting estimates may be underestimations. Using the very limited data available, we estimated the mortality rates due to non-functioning kidney (from S. haematobium) and haematemesis (from S. mansoni) at 150000 and 130000 per year. Given the overall high number of cases with schistosomiasis-related disease and associated death, we conclude that schistosomiasis remains an important public health problem in sub-Saharan Africa.

Modelling HIV/AIDS epidemics in Botswana and India: impact of interventions to prevent transmission

OBJECTIVE To describe a dynamic compartmental simulation model for Botswana and India, developed to identify the best strategies for preventing spread of HIV/AIDS. METHODS The following interventions were considered: a behavioural intervention focused on female sex workers; a conventional programme for the treatment of sexually transmitted infections; a programme for the prevention of mother-to-child transmission; an antiretroviral treatment programme for the entire population, based on a single regimen; and an antiretroviral treatment programme for sex workers only, also based on a single regimen. FINDINGS The interventions directed at sex workers as well as those dealing with sexually transmitted infections showed promise for long-term prevention of human immunodeficiency virus (HIV) infection, although their relative ranking was uncertain. In India, a sex worker intervention would drive the epidemic to extinction. In Botswana none of the interventions alone would achieve this, although the prevalence of HIV would be reduced by almost 50%. Mother-to-child transmission programmes could reduce HIV transmission to infants, but would have no impact on the epidemic itself. In the long run, interventions targeting sexual transmission would be even more effective in reducing the number of HIV-infected children than mother-to-child transmission programmes. Antiretroviral therapy would prevent transmission in the short term, but eventually its effects would wane because of the development of drug resistance. CONCLUSION Depending on the country and how the antiretroviral therapy was targeted, 25-100% of HIV cases would be drug- resistant after 30 years of use.

Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

Background This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems. Methodology/Principal Findings After a preliminary safety evaluation of low dose AMA-1/AS01B (10 µg/0.5 mL) in 5 adults, 30 malaria-naïve adults were randomly allocated to receive full dose (50 µg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 µg/mL (103–371 µg/mL), full dose AMA-1/AS01B 279 µg/mL (210–369 µg/mL) and full dose AMA-1/AS02A 216 µg/mL (169–276 µg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-γ) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements. Significance All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naïve adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali. Trial Registration www.clinicaltrials.gov NCT00385047

Spatial and temporal variations of malaria epidemic risk in Ethiopia: factors involved and implications

The aim of this study was to describe spatial and temporal variations in malaria epidemic risk in Ethiopia and to examine factors involved in relation to their implications for early warning and interpretation of geographical risk models. Forty-eight epidemic episodes were identified in various areas between September 1986 and August 1993 and factors that might have led to the events investigated using health facility records and weather data. The study showed that epidemics in specific years were associated with specific geographical areas. A major epidemic in 1988 affected the highlands whereas epidemics in 1991 and 1992 affected highland-fringe areas on the escarpments of the Rift Valley and in southern and north-western parts of the country. Malaria epidemics were significantly more often preceded by a month of abnormally high minimum temperature in the preceding 3 months than based on random chance, whereas frequency of abnormally low minimum temperature prior to epidemics was significantly lower than expected. Abnormal increases of maximum temperature and rainfall had no positive association with the epidemics. A period of low incidence during previous transmission seasons might have aggravated the events, possibly due to low level of immunity in affected populations. Epidemic risk is a dynamic phenomenon with changing geographic pattern based on temporal variations in determinant factors including weather and other eco-epidemiological characteristics of areas at risk. Epidemic early warning systems should take account of non-uniform effects of these factors by space and time and thus temporal dimensions need to be considered in spatial models of epidemic risks.

Substantial Contribution of Submicroscopical Plasmodium falciparum Gametocyte Carriage to the Infectious Reservoir in an Area of Seasonal Transmission

Background Man to mosquito transmission of malaria depends on the presence of the sexual stage parasites, gametocytes, that often circulate at low densities. Gametocyte densities below the microscopical threshold of detection may be sufficient to infect mosquitoes but the importance of submicroscopical gametocyte carriage in different transmission settings is unknown. Methodology/Principal Findings Membrane feeding experiments were carried out on 80 children below 14 years of age at the end of the wet season in an area of seasonal malaria transmission in Burkina Faso. Gametocytes were quantified by microscopy and by Pfs25-based quantitative nucleic acid sequence-based amplification assay (QT-NASBA). The childrens infectiousness was determined by membrane feeding experiments in which a venous blood sample was offered to locally reared Anopheles mosquitoes. Gametocytes were detected in 30.0% (24/80) of the children by microscopy compared to 91.6% (65/71) by QT-NASBA (p<0.001). We observed a strong association between QT-NASBA gametocyte density and infection rates (p = 0.007). Children with microscopically detectable gametocytes were more likely to be infectious (68.2% compared to 31.7% of carriers of submicroscopical gametocytes, p = 0.001), and on average infected more mosquitoes (13.2% compared to 2.3%, p<0.001). However, because of the high prevalence of submicroscopical gametocyte carriage in the study population, carriers of sub-microscopical gametocytes were responsible for 24.2% of the malaria transmission in this population. Conclusions/Significance Submicroscopical gametocyte carriage is common in an area of seasonal transmission in Burkina Faso and contributes substantially to the human infectious reservoir. Submicroscopical gametocyte carriage should therefore be considered when implementing interventions that aim to reduce malaria transmission.

Interpreting low praziquantel cure rates of Schistosoma mansoni infections in Senegal

Praziquantel is currently the drug of choice for the treatment of schistosomiasis. Selective treatment of Schistosoma mansoni infections in various endemic countries usually present cure rates of >70% when using the standard dose of 40 mg kg(-1) body weight of praziquantel. However, unusually low cure rates (18-38%) have been reported from Senegal, raising fears for emergence of resistance (or tolerance) to praziquantel. One major problem is the precise quantitative interpretation of cure rates, which allows an unequivocal distinction between drug failure and normal drug performance. This article reviews studies on praziquantel treatment of population by standardizing the data through an innovative meta-analysis and provides empirical evidence concerning the extent to which the reported low cure rates from Senegal are atypical.

Environmental factors contributing to the spread of H5N1 avian influenza in mainland China

BACKGROUND Since late 2003, highly pathogenic avian influenza (HPAI) outbreaks caused by infection with H5N1 virus has led to the deaths of millions of poultry and more than 10 thousands of wild birds, and as of 18-March 2008, at least 373 laboratory-confirmed human infections with 236 fatalities, have occurred. The unrestrained worldwide spread of this disease has caused great anxiety about the potential of another global pandemic. However, the effect of environmental factors influencing the spread of HPAI H5N1 virus is unclear. METHODOLOGY/PRINCIPAL FINDINGS A database including incident dates and locations was developed for 128 confirmed HPAI H5N1 outbreaks in poultry and wild birds, as well as 21 human cases in mainland China during 2004-2006. These data, together with information on wild bird migration, poultry densities, and environmental variables (water bodies, wetlands, transportation routes, main cities, precipitation and elevation), were integrated into a Geographical Information System (GIS). A case-control design was used to identify the environmental factors associated with the incidence of the disease. Multivariate logistic regression analysis indicated that minimal distance to the nearest national highway, annual precipitation and the interaction between minimal distance to the nearest lake and wetland, were important predictive environmental variables for the risk of HPAI. A risk map was constructed based on these factors. CONCLUSIONS/SIGNIFICANCE Our study indicates that environmental factors contribute to the spread of the disease. The risk map can be used to target countermeasures to stop further spread of the HPAI H5N1 at its source.

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND New WHO guidelines recommend initiation of antiretroviral therapy for HIV-positive adults with CD4 counts of 500 cells per μL or less, a higher threshold than was previously recommended. Country decision makers have to decide whether to further expand eligibility for antiretroviral therapy accordingly. We aimed to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy and expanded treatment coverage. METHODS We used several independent mathematical models in four settings-South Africa (generalised epidemic, moderate antiretroviral therapy coverage), Zambia (generalised epidemic, high antiretroviral therapy coverage), India (concentrated epidemic, moderate antiretroviral therapy coverage), and Vietnam (concentrated epidemic, low antiretroviral therapy coverage)-to assess the potential health benefits, costs, and cost-effectiveness of various eligibility criteria for adult antiretroviral therapy under scenarios of existing and expanded treatment coverage, with results projected over 20 years. Analyses assessed the extension of eligibility to include individuals with CD4 counts of 500 cells per μL or less, or all HIV-positive adults, compared with the previous (2010) recommendation of initiation with CD4 counts of 350 cells per μL or less. We assessed costs from a health-system perspective, and calculated the incremental cost (in US

Malaria attributable to the HIV-1 epidemic, sub-Saharan Africa.

) per disability-adjusted life-year (DALY) averted to compare competing strategies. Strategies were regarded very cost effective if the cost per DALY averted was less than the countrys 2012 per-head gross domestic product (GDP; South Africa:

The impact of pre-exposure prophylaxis (PrEP) on HIV epidemics in Africa and India: a simulation study.

8040; Zambia: