Author's response to reviews Title: Human immunodeficiency virus infection is a risk factor for cerebral malaria in children in Uganda: a case-control study Authors: Peace

Revised results section Results: HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.23-28.72, p=0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.98-15.07, p= 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54-16.07). The association was seen among HIV-positive children with a relatively normal or mild immune suppression compared to those with moderate to severe suppression. Other factors associated with cerebral malaria were age and parasite density. Background References inserted in background Malaria and Human immunodeficiency virus (HIV)-1 are two of the most common global health challenges today and the two infections commonly overlap in distribution in most countries especially in sub-Saharan Africa(1). Studies have demonstrated interaction between these two infections with the majority of studies conducted in adults (2-6). HIV-1 infection has been found to be associated with severe forms of malaria and particularly cerebral malaria in adults but there is still a paucity of information on the interaction between the two infections in children (2, 7, 8). Added reference : van Geertruyden JP, Van Eyck E, Yosaatmadja F, et al. The relationship of Plasmodium falciparum humoral immunity with HIV-1 immunosuppression and treatment efficacy in Zambia. Malar J 2009;8:258 Methods Reference for definition of cerebral malaria added: 20. Guidelines for treatment of malaria: World Health Organization2010. Because samples were sent to different laboratories for blood work up, more blood was collected from the children who had cerebral malaria. Clarified this in paragraph: “Five millilitres of blood were drawn from each child with cerebral malaria and 2-3 millilitres in children with uncomplicated malaria for a malaria smear, P. falciparum parasite density, HIV serology and CD4 cell count, blood glucose and serum electrolytes which were done in different laboratories. A finger prick was done for children with no malaria for the blood smear and rapid HIV test and a blood sample for CD4 count taken if the child was found to be HIV positive.” WHO reference for estimating parasite density added: Basic Laboratory Methods in Medical Parasitology: World Health Organization1991. Results Tables and results section were reorganized Table 4 merged with table 1 Table 2: Comparing cerebral malaria and uncomplicated malaria Table 3: Comparing cerebral malaria and no malaria groups Table 4: Association between cerebral malaria and HIV infection comparing CM group to the control groups Results section also reorganized and description of the study and description of the cases (including CD4) and controls made clearer, only important parameters indicated. Typos and minor corrections changed as suggested Multivariate analysis included in the results section Discussion In discussion, focused more on increased risk rather than prevalence. Study findings are of both clinical and public health importance and this has been mentioned in the discussion. Our findings support the hypothesis that HIV infection is a risk factor for cerebral malaria in children. The findings from this study add to the existing knowledge of interaction between HIV infection and P. falciparum malaria in children and are of both clinical and public health importance. Conclusions and recommendations HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring P.falciparum malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions.