Norovirus in children 5 years and below presenting with diarrhoea in KwaZulu-Natal.

Masters Degree. University of KwaZulu-Natal, Durban.Background - NoVs are single stranded RNA viruses belonging to the family Caliciviridae. They cause gastroenteritis in all age groups but mostly in young children and the elderly. They are classified into seven genogroups (GI – GVII) and only GI, GII and GIV infect humans. They cause self-limiting infection that resolves in approximately 10 – 50 hours after exposure. Symptoms include diarrhoea, vomiting, cramps, chills and headaches. Despite a high rate of vaccine coverage in KZN through the ….., mortality among infants remains high. Therefore a study was conducted to describe the role of non-bacterial aetiologies of diarrhoea in children 5 years and under in KZN. This work investigates the contribution of NoV infection to this pathology. Methods - Stool specimens were collected between June 2014 and August 2014 from children 5 years and below presenting with diarrhoea to a regional hospital. Written informed consent was obtained from their parents or guardian. Demographic information was collected using a structured questionnaire. The specimen were tested for NoV antigen using Enzyme Linked Immunosorbent Assay (ELISA) and Realtime Polymerase Chain Reaction (RT-qPCR) was used to detect viral RNA. The two methods were than compared with each other. Results - One hundred and eighty-two stool specimens were collected and tested for NoV. The prevalence of NoV when specimens were tested by ELISA and RT-qPCR was 10.4 % and 22.5 % respectively. The sensitivity of the ELISA in comparison to RT-qPCR was 24.4 % (95 % Cl: 12.4 – 40.3 %) and the specificity was 93.6 % (95 % Cl: 88.2 – 97 %). The infection rate was highest in children within the age group of 12 – 24 months and all the NoV detected were of the GII genogroup Conclusion - NoV is a common cause of diarrhoeal illness in children presenting to the King Edward VIII Hospital. Genogroup GII dominated with 100 % of all positive NoV cases belonging to this group. Taking into consideration the low sensitivity of the ELISA test, the RT-qPCR would be more suitable for routinely testing stool specimens for NoV. An effective NoV vaccine is urgently needed

High-frequency failure of combination antiretroviral therapy in paediatric HIV infection is associated with unmet maternal needs causing maternal non-adherence

Background Early combination antiretroviral therapy (cART) reduces the size of the viral reservoir in paediatric and adult HIV infection. Very early-treated children may have higher cure/remission potential. Methods In an observational study of 151 in utero (IU)-infected infants in KwaZulu-Natal, South Africa, whose treatment adhered strictly to national guidelines, 76 infants diagnosed via point-of-care (PoC) testing initiated cART at a median of 26 h (IQR 18–38) and 75 infants diagnosed via standard-of-care (SoC) laboratory-based testing initiated cART at 10 days (IQR 8–13). We analysed mortality, time to suppression of viraemia, and maintenance of aviraemia over the first 2 years of life. Findings Baseline plasma viral loads were low (median 8000 copies per mL), with 12% of infants having undetectable viraemia pre-cART initiation. However, barely one-third (37%) of children achieved suppression of viraemia by 6 months that was maintained to >12 months. 24% had died or were lost to follow up by 6 months. Infant mortality was 9.3%. The high-frequency virological failure in IU-infected infants was associated not with transmitted or acquired drug-resistant mutations but with cART non-adherence (plasma cART undetectable/subtherapeutic, p<0.0001) and with concurrent maternal cART failure (OR 15.0, 95%CI 5.6–39.6; p<0.0001). High-frequency virological failure was observed in PoC- and SoC-tested groups of children. Interpretation The success of early infant testing and cART initiation strategies is severely limited by subsequent cART non-adherence in HIV-infected children. Although there are practical challenges to administering paediatric cART formulations, these are overcome by mothers who themselves are cART-adherent. These findings point to the ongoing obligation to address the unmet needs of the mothers. Eliminating the particular barriers preventing adequate treatment for these vulnerable women and infants need to be prioritised in order to achieve durable suppression of viraemia on cART, let alone HIV cure/remission, in HIV-infected children

Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection

Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of>170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p=0.0005) and are more type I interferon-resistant (p=0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p=0.01) and more susceptible to HIV infection in vitro (p=0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p=0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males. Sex differences in the immune response to vaccines and infections have been well described in children and adults. Here the authors describe, in a cohort of 177 HIV-infected infants, innate immune sex differences in fetal life that increase female susceptibility to intrauterine HIV infection and increase the chances of subsequent HIV remission in infected males