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HIV infection affects the course of tuberculosis (TB), and HIV and Mycobacterium tuberculosis (Mtb) synergize in disease progression through complex immunological interplay. To gain further understanding of these mechanisms, we compared the microRNA (miRNA) and small nucleolar RNA (snoRNA) expression patterns in whole blood of individuals with active TB, with and without HIV coinfection (HIV+/TB+ and HIV-/TB+), and HIV and TB-negative individuals (HIV-/TB-). We found that 218 miRNAs were differentially expressed between HIV+/TB+ and HIV-/TB+, while no statistically significant difference in snoRNA expression was observed between these groups. In contrast, both miRNA (n = 179) and snoRNA (n = 103) expression patterns were significantly altered in HIV+/TB+ individuals compared to those of the HIV-/TB- controls. Of note, 26 of these snoRNAs were also significantly altered between the HIV-/TB+ and HIV-/TB- groups. Normalization toward the miRNA and snoRNA expression patterns of the HIV-/TB- control group was noted during anti-TB and antiretroviral treatment in HIV+/TB+ participants. In summary, these results show that HIV coinfection influences miRNA expression in active TB. In contrast, snoRNA expression patterns differ between individuals with and without active TB, independently of HIV coinfection status. Moreover, in coinfected individuals, therapy-induced control of HIV replication and clearance of Mtb appears to normalize the expression of some small non-coding RNA (sncRNA). These findings suggest that dysregulation of miRNA is a mechanism by which HIV may modify immunity against TB, while active TB alters snoRNA expression. Improved understanding of how regulation of sncRNA expression influences the disease course in coinfected individuals may have implications for diagnostics, risk stratification, and host-directed therapy. Here, we propose a novel mechanism by which HIV alters the immune response to TB. [ABSTRACT FROM AUTHOR]

Background Knowledge on tuberculosis (TB) infection epidemiology in women of reproductive age living in TB-endemic areas is limited. We used a composite definition of TB infection in a cohort of pregnant women recruited in an Ethiopian city as a model for TB exposure patterns, and to identify factors associated with TB infection. Methods Women seeking antenatal care at public health facilities underwent structured interviews, physical examination, and QuantiFERON-TB Gold-Plus (QFT) testing. Women with symptoms compatible with TB disease, and all human immunodeficiency virus (HIV)–positive women, were investigated for active TB by sputum bacteriological testing. TB infection (TB+) was defined as either positive QFT (≥ 0.35 IU/mL), self-reported previous active TB, or current active TB. Associations between TB infection and clinical, demographic, and socioeconomic characteristics were tested in multiple logistic regression analysis. Results Among 1834 participants, 679 (37.0%) met criteria for TB+ (80 [4.4%] previous active TB, 5 [0.3%] current active TB, and 594 [32.4%] QFT-positive without previous or current active TB). Age (annual adjusted odds ratio [AOR], 1.069 [95% confidence interval {CI}, 1.045–1.093]) and HIV infection (AOR, 1.43 [95% CI, 1.033–1.988]) were independently associated with TB+. The relationship with increasing age was only observed in HIV-negative women, and translated to an estimated annual risk of TB infection of 2.1% in HIV-negative women. Conclusions TB infection in women of reproductive age in Ethiopia was independently associated with HIV infection and increasing age, suggesting exposure to contagious TB and continuous acquisition of TB infection in this population. [ABSTRACT FROM AUTHOR]

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Background: The HIV-1 epidemic in Ethiopia has been shown to be dominated by two phylogenetically distinct subtype C clades, the Ethiopian (C’-ET) and East African (C-EA) clades, however, little is known about the temporal dynamics of the HIV epidemic with respect to subtypes and distinct clades. Moreover, there is only limited information concerning transmission of HIV-1 drug resistance (TDR) in the country. Methods: A cross-sectional survey was conducted among young antiretroviral therapy (ART)-naïve individuals recently diagnosed with HIV infection, in Gondar, Ethiopia, 2011–2013 using the WHO recommended threshold survey. A total of 84 study participants with a median age of 22 years were enrolled. HIV-1 genotyping was performed and investigated for drug resistance in 67 individuals. Phylogenetic analyses were performed on all available HIV sequences obtained from Gondar (n = 301) which were used to define subtype C clades, temporal trends and local transmission clusters. Dating of transmission clusters was performed using BEAST. Result: Four of 67 individuals (6.0%) carried a HIV drug resistance mutation strain, all associated with non-nucleoside reverse transcriptase inhibitors (NNRTI). Strains of the C-EA clade were most prevalent as we found no evidence of temporal changes during this time period. However, strains of the C-SA clade, prevalent in Southern Africa, have been introduced in Ethiopia, and became more abundant during the study period. The oldest Gondar transmission clusters dated back to 1980 (C-EA), 1983 (C-SA) and 1990 (C’-ET) indicating the presence of strains of different subtype C clades at about the same time point in Gondar. Moreover, some of the larger clusters dated back to the 1980s but transmissions within clusters have been ongoing up till end of the study period. Besides being associated with more sequences and larger clusters, the C-EA clade sequences were also associated with clustering of HIVDR sequences. One cluster was associated with the G190A mutation and showed onward transmissions at high rate. Conclusion: TDR was detected in 6.0% of the sequenced samples and confirmed pervious reports that the two subtype C clades, C-EA and C’-ET, are common in Ethiopia. Moreover, the findings indicated an increased diversity in the epidemic as well as differences in transmission clusters sizes of the different clades and association with resistance mutations. These findings provide epidemiological insights not directly available using standard surveillance and may inform the adjustment of public health strategies in HIV prevention in Ethiopia. [ABSTRACT FROM AUTHOR]

Introduction: Despite increasing access to antiretroviral treatment (ART) in low-income countries, HIV-related mortality is high, especially in the first months following ART initiation. We aimed to evaluate the impact of TB coinfection on early mortality and to assess gender-specific predictors of mortality in a cohort of Ethiopian adults subjected to intensified casefinding for active TB before starting ART. Material and Methods: Prospectively recruited ART-eligible adults (n = 812, 58.6% female) at five Ethiopian health centers were followed for 6 months. At inclusion sputum culture, Xpert MTB/RIF, and smear microscopy were performed (158/812 [19.5%] had TB). Primary outcome was all-cause mortality. We used multivariate Cox models to identify predictors of mortality. Results: In total, 37/812 (4.6%) participants died, 12 (32.4%) of whom had TB. Karnofsky performance score (KPS) and mid-upper arm circumference (MUAC) were associated with mortality in the whole population. However, the associations were different in men and women. In men, only MUAC remained associated with mortality (adjusted hazard ratio [aHR] 0.71 [95% CI 0.57–0.88]). In women, KPS <80% was associated with mortality (aHR 10.95 [95% CI 2.33–51.49]), as well as presence of cough (aHR 3.98 [95% CI 1.10–14.36]). Cough was also associated with mortality for TB cases (aHR 8.30 [95% CI 1.06–65.14]), but not for non-TB cases. Conclusions: In HIV-positive Ethiopian adults managed at health centers, mortality was associated with reduced performance score and malnutrition, with different distribution with regard to gender and TB coinfection. These robust variables could be used at clinic registration to identify persons at increased risk of early mortality. [ABSTRACT FROM AUTHOR]

Background: In order to increase access to antiretroviral therapy (ART) in HIV-infected children, paediatric HIV care has been introduced in health centres in Ethiopia, where patients are managed by health professionals with limited training. Objective: To compare outcomes of paediatric HIV care in hospital and health centre clinics and to determine risk factors for death and loss to follow-up (LTFU). Design: Retrospective comparison of patient characteristics and outcomes among children managed in a public hospital and all five public health centres in the uptake area. Results: Among 1,960 patients (health centres 572, hospital clinic 1,388), 34% were lost to follow-up, 2% died, 14% were transferred out, and 46% remained in care. Children initiating ART in the hospital clinic had lower median CD4 cell counts (age B1 year: 575 vs. 1,183 cells/mm3 , p0.024; age 15 years: 370 vs. 598 cells/mm3 , pB0.001; age 5 years: 186 vs. 259 cells/mm3 , pB0.001), and a higher proportion were B1 year of age (22% vs. 15%, p0.025). ART initiation rates and retention in care were similar between children managed in health centers and in the hospital clinic (36% vs. 37% and 47% vs. 46%, respectively). Among patients starting ART, mortality was associated with age B1 year [hazard ratio (HR) 12.0; 95% confidence interval (CI): 3.5, 41]. LTFU was associated with CD4 cell counts B350 cells/mm3 (HR 1.8; 95% CI: 1.2, 3.0), weight for-age z-scores below -4 (HR 2.8; 95% CI: 1.4, 5.6), and age B5 years (15 years: HR 1.6; 95% CI: 1.0, 2.5; B1 year: HR 3.3; 95% CI: 1.6, 6.6). Conclusions: Outcomes of HIV care were similar for Ethiopian children managed in a hospital clinic or in health centers. However, patients treated at the hospital clinic had characteristics of more advanced disease. Rates of LTFU were high in both types of health facility. [ABSTRACT FROM AUTHOR]

Background Diagnosis of tuberculosis (TB) in human immunodeficiency virus (HIV)-coinfected individuals is challenging. We hypothesized that combinations of inflammatory markers could facilitate identification of active TB in HIV-positive individuals. Methods Participants were HIV-positive, treatment-naive adults systematically investigated for TB at Ethiopian health centers. Plasma samples from 130 subjects with TB (HIV+/TB+) and 130 subjects without TB (HIV+/TB−) were tested for concentration of the following markers: CCL5, C-reactive protein (CRP), interleukin (IL)-6, IL12-p70, IL-18, IL-27, interferon-γ-induced protein-10 (IP-10), procalcitonin (PCT), and soluble urokinase-type plasminogen activator receptor (suPAR). Analyzed markers were then assessed, either individually or in combination, with regard to infection status, CD4 cell count, and HIV ribonucleic acid (RNA) levels. Results The HIV+/TB+ subjects had higher levels of all markers, except IL12p70, compared with HIV+/TB− subjects. The CRP showed the best performance for TB identification (median 27.9 vs 1.8 mg/L for HIV+/TB+ and HIV+/TB−, respectively; area under the curve [AUC]: 0.80). Performance was increased when CRP was combined with suPAR analysis (AUC, 0.83 [0.93 for subjects with CD4 cell count <200 cells/mm3]). Irrespective of TB status, IP-10 concentrations correlated with HIV RNA levels, and both IP-10 and IL-18 were inversely correlated to CD4 cell counts. Conclusions Although CRP showed the best single marker discriminatory potential, combining CRP and suPAR analyses increased performance for TB identification. [ABSTRACT FROM AUTHOR]

Background In order to increase treatment coverage, antiretroviral treatment (ART) is provided through primary health care in low-income high-burden countries, where tuberculosis (TB) co-infection is common. We investigated the long-term outcome of health center–based ART, with regard to concomitant TB. Methods ART-naïve adults were included in a prospective cohort at Ethiopian health centers and followed for up to 4 years after starting ART. All participants were investigated for active TB at inclusion. The primary study outcomes were the impact of concomitant TB on all-cause mortality, loss to follow-up (LTFU), and lack of virological suppression (VS). Kaplan-Meier survival estimates and Cox proportional hazards models with multivariate adjustments were used. Results In total, 141/729 (19%) subjects had concomitant TB, 85% with bacteriological confirmation (median CD4 count TB, 169 cells/mm3; IQR, 99–265; non-TB, 194 cells/mm3; IQR, 122–275). During follow-up (median, 2.5 years), 60 (8%) died and 58 (8%) were LTFU. After ≥6 months of ART, 131/630 (21%) had lack of VS. Concomitant TB did not influence the rates of death, LTFU, or VS. Male gender and malnutrition were associated with higher risk of adverse outcomes. Regardless of TB co-infection status, even after 3 years of ART, two-thirds of participants had CD4 counts below 500 cells/mm3. Conclusions Concomitant TB did not impact treatment outcomes in adults investigated for active TB before starting ART at Ethiopian health centers. However, one-third of patients had unsatisfactory long-term treatment outcomes and immunologic recovery was slow, illustrating the need for new interventions to optimize ART programs. [ABSTRACT FROM AUTHOR]