Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial

Background Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear. Methods HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14–34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761. Findings From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference –0·2%, 95% CI –1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the cotrimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3–4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3–4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3–4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21). Interpretation Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV

Chronic and Occult Hepatitis B Virus Infection in Pregnant Women in Botswana

The hepatitis B virus (HBV) is a global problem; however, the burden of HBV infection in pregnant women in Botswana is unknown. We sought to determine the prevalence of chronic and occult HBV infection in human immunodeficiency virus (HIV)-infected and -uninfected pregnant women in Botswana. Samples from 752 pregnant women were tested for hepatitis B surface antigen (HBsAg), and HBsAg-positive samples were tested for hepatitis B e antigen (HBeAg) and HBV DNA load. Samples that were HBsAg negative were screened for occult HBV infection by determining the HBV DNA load. HBV genotypes were determined based on a 415-base-pair fragment of the surface gene. Among the 752 women tested during pregnancy or early postpartum, 16 (2.1%) (95% confidence interval (CI): 2.0–2.2) were HBsAg-positive. The prevalence of chronic HBV infection was higher (3.1%) among HIV-infected (95% CI: 3.0–3.2) compared with HIV-uninfected women (1.1%) (95% CI: 1.07–1.1, p = 0.057). Among the 622 HBsAg-negative women, the prevalence of occult HBV infection was 6.6% (95% CI: 6.5–6.7). Three of thirteen HBsAg-positive participants were HBeAg-positive, and all were HIV-negative. Of the 11 maternal samples successfully genotyped, five (45.5%) were genotype D3, five (45.5%) were genotype A1, and one was genotype E (9%). Low and similar proportions of HIV-infected and -uninfected pregnant women in Botswana had occult or chronic HBV infection. We identified a subset of HIV-negative pregnant women who had high HBV DNA levels and were HBeAg-positive, and thus likely to transmit HBV to their infants

Population uptake of HIV testing, treatment, viral suppression, and male circumcision following a community-based intervention in Botswana (Ya Tsie/BCPP): a cluster-randomised trial

BACKGROUND: In settings with high HIV prevalence and treatment coverage, such as Botswana, it is unknown whether uptake of HIV prevention and treatment interventions can be increased further. We sought to determine whether a community-based intervention to identify and rapidly treat people living with HIV, and support male circumcision could increase population levels of HIV diagnosis, treatment, viral suppression, and male circumcision in Botswana. METHODS: The Ya Tsie Botswana Combination Prevention Project study was a pair-matched cluster-randomised trial done in 30 communities across Botswana done from Oct 30, 2013, to June 30, 2018. 15 communities were randomly assigned to receive HIV prevention and treatment interventions, including enhanced HIV testing, earlier antiretroviral therapy (ART), and strengthened male circumcision services, and 15 received standard of care. The first primary endpoint of HIV incidence has already been reported. In this Article, we report findings for the second primary endpoint of population uptake of HIV prevention services, as measured by proportion of people known to be HIV-positive or tested HIV-negative in the preceding 12 months; proportion of people living with HIV diagnosed and on ART; proportion of people living with HIV on ART with viral suppression; and proportion of HIV-negative men circumcised. A longitudinal cohort of residents aged 16-64 years from a random, approximately 20% sample of households across the 15 communities was enrolled to assess baseline uptake of study outcomes; we also administered an end-of-study survey to all residents not previously enrolled in the longitudinal cohort to provide study end coverage estimates. Differences in intervention uptake over time by randomisation group were tested via paired Student's t test. The study has been completed and is registered with ClinicalTrials.gov (NCT01965470). FINDINGS: In the six communities participating in the end-of-study survey, 2625 residents (n=1304 from standard-of-care communities, n=1321 from intervention communities) were enrolled into the 20% longitudinal cohort at baseline from Oct 30, 2013, to Nov 24, 2015. In the same communities, 10 791 (86%) of 12 489 eligible enumerated residents not previously enrolled in the longitudinal cohort participated in the end-of-study survey from March 30, 2017, to Feb 25, 2018 (5896 in intervention and 4895 in standard-of-care communities). At study end, in intervention communities, 1228 people living with HIV (91% of 1353) were on ART; 1166 people living with HIV (88% of 1321 with available viral load) were virally suppressed, and 673 HIV-negative men (40% of 1673) were circumcised in intervention communities. After accounting for baseline differences, at study end the proportion of people living with HIV who were diagnosed was significantly higher in intervention communities (absolute increase of 9% to 93%) compared with standard-of-care communities (absolute increase of 2% to 88%; prevalence ratio [PR] 1·08 [95% CI 1·02-1·14], p=0·032). Population levels of ART, viral suppression, and male circumcision increased from baseline in both groups, with greater increases in intervention communities (ART PR 1·12 [95% CI 1·07-1·17], p=0·018; viral suppression 1·13 [1·09-1·17], p=0·017; male circumcision 1·26 [1·17-1·35], p=0·029). INTERPRETATION: It is possible to achieve very high population levels of HIV testing and treatment in a high-prevalence setting. Maintaining these coverage levels over the next decade could substantially reduce HIV transmission and potentially eliminate the epidemic in these areas. FUNDING: US President's Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

No Difference in Antibody Responses to Tetanus Vaccine Among HIV-Exposed and -Unexposed Infants in Botswana

Abstract Background: In Botswana, more than 10% of HIV-exposed, uninfected infants (HEU) are hospitalized or die in the first 6 months of life, largely due to infectious causes. Vaccine responses can act as a marker of the immune response to infectious antigens. Previous studies of antibody responses to vaccines in HEU have had conflicting results. We compared antibody titers to tetanus vaccine between HEU and HIV-unexposed infants (HUU), and explored whether tetanus antibody titers predicted risk of hospitalization in the first 2 years of life among HEU. Methods: 443 HIV-infected and 451 HIV-uninfected mothers and their 453 HEU / 457 HUU live-born infants were followed in a prospective observational study in Botswana (“Tshipidi”). Quantitative tetanus toxoid IgG was measured in plasma samples from 18-month-old infants. Geometric mean antibody titers (GMT) were compared between HEU and HUU infants, and between HEU infants who were or were not hospitalized by age 2. Results: Plasma was available at 18 months for 39 HEU and 42 HUU infants. Within this subset, there were 15 hospitalizations (12 in HEU) [RR of hospitalization among HEU = 1.34 (P = 0.009)]. 73% of hospitalizations overall, and 83% in HEU, were due to infection (primarily pneumonia/bronchiolitis and gastroenteritis). Among infants who had received 3 or 4 doses of tetanus vaccine by 18 months, there were no significant differences in tetanus GMT between HEU and HUU (Fig A). Among HEU who had received 3 or 4 doses of tetanus vaccine by 18 months, there were no significant differences in tetanus GMT between infants who were hospitalized and infants who were not (Fig B). Conclusion: In this small sample of infants from Botswana, we did not identify differences in antibody responses to tetanus vaccine between HEU and HUU. Although HEU demonstrated an increased risk of hospitalization, response to tetanus vaccine did not appear to be a significant predictor of morbidity. It is possible that cell-mediated immune defects play a larger role than humoral immune defects in the increased susceptibility to infection among HEU. Disclosures All authors: No reported disclosures

Decreased diarrheal and respiratory disease in HIV exposed uninfected children following vaccination with rotavirus and pneumococcal conjugate vaccines.

BackgroundRotavirus vaccine (RV) and pneumococcal vaccine (PCV) decrease diarrheal and respiratory disease incidence and severity, but there are few data about the effects of these vaccines among HIV-exposed uninfected (HEU) children.MethodsWe recorded RV and PCV vaccination history in a placebo-controlled trial that studied the need for cotrimoxazole among HEU infants in Botswana (the Mpepu Study). We categorized infants by enrollment before or after the simultaneous April 2012 introduction of RV and PCV, and compared diagnoses of diarrhea and pneumonia (grade 3/4), hospitalizations, and deaths from both disease conditions through the 12-month study visit by vaccine era/status across two sites (a city and a village) by Kaplan-Meier estimates.ResultsTwo thousand six hundred and thirty-five HEU infants were included in this secondary analysis, of these 1689 (64%) were enrolled in Gaborone (344 pre-vaccine, 1345 vaccine) and 946 (36%) in Molepolole (209 pre-vaccine, 737 vaccine). We observed substantial reduction in hazard of hospitalization or death for reason of diarrhea and pneumonia in the vaccine era versus the pre-vaccine era in Molepolole (hazard ratio, HR = 0.44, 95% confidence interval, CI = 0.28, 0.71) with smaller reduction in Gaborone (HR = 0.91, 95% CI = 0.57, 1.45). Similar downward trends were observed for diagnoses of diarrhea and pneumonia separately during the vaccine versus pre-vaccine era.ConclusionsAlthough temporal confounding cannot be excluded, significant declines in the burden of diarrheal and respiratory illness were observed among HEU children in Botswana following the introduction of RV and PCV. RV and PCV may maximally benefit HEU children in rural areas with higher disease burden

HIV-exposed children account for more than half of 24-month mortality in Botswana

Background: The contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined. Methods: From January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1–3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling. Results: Three thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58 % received three-drug ART, 23 % received zidovudine alone, 11 % received no antiretrovirals (8 % unknown); 2.1 % of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5 %) children; 106 (3.5 %) died including 12 (38 %) HIV-infected, 70 (4.7 %) HIV-exposed uninfected, and 24 (1.6 %) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95 % CI 10.7, 47.5 %), child HIV-exposure (aHR 2.7, 95 % CI 1.7, 4.5) and maternal death (aHR 8.9, 95 % CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95 % CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26 % maternal HIV prevalence), an estimated 52 % of child mortality occurs among HIV-exposed or HIV-infected children. Conclusions: In a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children