Leading causes of death and high mortality rates in an HIV endemic setting (Kisumu county, Kenya, 2019)

Background In resource-limited settings, underlying causes of death (UCOD) often are not ascertained systematically, leading to unreliable mortality statistics. We reviewed medical charts to establish UCOD for decedents at two high volume mortuaries in Kisumu County, Kenya, and compared ascertained UCOD to those notified to the civil registry. Methods Medical experts trained in COD certification examined medical charts and ascertained causes of death for 456 decedents admitted to the mortuaries from April 16 through July 12, 2019. Decedents with unknown HIV status or who had tested HIV-negative >90 days before the date of death were tested for HIV. We calculated annualized all-cause and cause-specific mortality rates grouped according to global burden of disease (GBD) categories and separately for deaths due to HIV/AIDS and expressed estimated deaths per 100,000 population. We compared notified to ascertained UCOD using Cohen's Kappa (κ) and assessed for the independence of proportions using Pearson's chi-squared test. Findings The four leading UCOD were HIV/AIDS (102/442 [23.1%]), hypertensive disease (41/442 [9.3%]), other cardiovascular diseases (23/442 [5.2%]), and cancer (20/442 [4.5%]). The all- cause mortality rate was 1,086/100,000 population. The highest cause-specific mortality was in GBD category II (noncommunicable diseases; 516/100,000), followed by GBD I (communicable, perinatal, maternal, and nutritional; 513/100,000), and III (injuries; 56/ 100,000). The HIV/AIDS mortality rate was 251/100,000 population. The proportion of deaths due to GBD II causes was higher among females (51.9%) than male decedents (42.1%; p = 0.039). Conversely, more men/boys (8.6%) than women/girls (2.1%) died of GBD III causes (p = 0.002). Most of the records with available recorded and ascertained UCOD (n = 236), 167 (70.8%) had incorrectly recorded UCOD, and agreement between notified and ascertained UCOD was poor (29.2%; κ = 0.26). Conclusions Mortality from infectious diseases, especially HIV/AIDS, is high in Kisumu County, but there is a shift toward higher mortality from noncommunicable diseases, possibly reflecting an epidemiologic transition and improving HIV outcomes. The epidemiologic transition suggests the need for increased focus on controlling noncommunicable conditions despite the high communicable disease burden. The weak agreement between notified and ascertained UCOD could lead to substantial inaccuracies in mortality statistics, which wholly depend on death notifications

Population-Based Biochemistry, Immunologic and Hematological Reference Values for Adolescents and Young Adults in a Rural Population in Western Kenya

BACKGROUND: There is need for locally-derived age-specific clinical laboratory reference ranges of healthy Africans in sub-Saharan Africa. Reference values from North American and European populations are being used for African subjects despite previous studies showing significant differences. Our aim was to establish clinical laboratory reference values for African adolescents and young adults that can be used in clinical trials and for patient management. METHODS AND FINDINGS: A panel of 298, HIV-seronegative individuals aged 13-34 years was randomly selected from participants in two population-based cross-sectional surveys assessing HIV prevalence and other sexually transmitted infections in western Kenya. The adolescent (/=18 years) ratio and the male-to-female ratio was 1ratio1. Median and 95% reference ranges were calculated for immunohematological and biochemistry values. Compared with U.S-derived reference ranges, we detected lower hemoglobin (HB), hematocrit (HCT), red blood cells (RBC), mean corpuscular volume (MCV), neutrophil, glucose, and blood urea nitrogen values but elevated eosinophil and total bilirubin values. Significant gender variation was observed in hematological parameters in addition to T-bilirubin and creatinine indices in all age groups, AST in the younger and neutrophil, platelet and CD4 indices among the older age group. Age variation was also observed, mainly in hematological parameters among males. Applying U.S. NIH Division of AIDS (DAIDS) toxicity grading to our results, 40% of otherwise healthy study participants were classified as having an abnormal laboratory parameter (grade 1-4) which would exclude them from participating in clinical trials. CONCLUSION: Hematological and biochemistry reference values from African population differ from those derived from a North American population, showing the need to develop region-specific reference values. Our data also show variations in hematological indices between adolescent and adult males which should be considered when developing reference ranges. This study provides the first locally-derived clinical laboratory reference ranges for adolescents and young adults in western Kenya

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

Assessing the impact of antiretroviral therapy on tuberculosis notification rates among people with HIV: a descriptive analysis of 23 countries in sub-Saharan Africa, 2010–2015

Abstract Background HIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa. Methods We estimated annual tuberculosis notification rates, stratified by HIV status during 2010–2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had ≥4 years of HIV prevalence estimates and ≥ 75% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test. Results Among 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010–2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-value = 0.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (p = 0.0106). Conclusion Tuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary