Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021.

BACKGROUND: Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020. METHODS: We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990-2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data. FINDINGS: We estimated 9·40 million (95% uncertainty interval [UI] 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5-14 years, 6·29% (5·05 to 7·70) in those aged 15-49 years, 5·72% (4·02 to 7·39) in those aged 50-69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5-14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15-49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50-69 years, and a 3·29% (-5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis for 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (-713 to 2180) fewer deaths. INTERPRETATION: Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups. FUNDING: Bill & Melinda Gates Foundation.

National estimates of case-mix, mortality, and economic outcomes among inpatient HIV/AIDS mono-infection and hepatitis C co-infection cases in the US.

RATIONALE, AIMS, AND OBJECTIVES: To assess inpatient clinical and economic outcomes for AIDS/HIV and Hepatitis C (HCV) co-infection in the United States from 2003 to 2014. METHOD: This historical cohort study utilized nationally representative hospital discharge data to investigate inpatient mortality, length of stay (LoS), and inflation-adjusted charges among adults (≥18 years). Outcomes were analysed via multivariable generalized linear models according to demographics, hospital and clinical characteristics, and AIDS/HIV or HCV sequelae. RESULTS: Overall, 17.8% of the 2.75 million estimated AIDS/HIV inpatient cases involved HCV from 2003 to 2014, averaging 48.5 ± 9.0 years of age and 68.0% being male. Advanced sequalae of AIDS and HCV incurred a LoS of 10.3 ± 11.9 days, charges of $88 789 ± 131 787, and a 16.9% mortality. Many cases involved noncompliance, tobacco use disorders, and substance abuse. Although mortality decreased over time, multivariable analyses indicated that poorer outcomes were generally associated with more advanced clinical conditions and AIDS-associated sequalae, although mixed results were observed for specific manifestations of HCV. Rural residence was independently associated with a 3.26 times higher adjusted odds of mortality from 2009 to 2014 for HIV/HCV co-infection (P < 0.001), although not for AIDS/HCV (OR = 1.38, P = 0.166). CONCLUSION: Given the systemic nature and modifiable risks inherent within coinfection, more proactive screening and intervention appear warranted, particularly within rural areas.

Assessment of cytomegalovirus and cell-mediated immunity for predicting outcomes in non-HIV-infected patients with Pneumocystis jirovecii pneumonia.

The clinical importance of pulmonary cytomegalovirus (CMV) co-infection in patients with Pneumocystis jirovecii pneumonia (PCP) is uncertain. We therefore determined the association of CMV infection with outcomes in non-HIV-infected patients with PCP by assessing CMV viral load and CMV-specific T-cell response.We prospectively enrolled all non-HIV-infected patients with confirmed PCP, over a 2-year period. Real-time polymerase chain reaction from bronchoalveolar lavage was performed to measure CMV viral load, and CMV enzyme-linked immunospot assays of peripheral blood were used to measure CMV-specific T-cell responses. The primary outcome was 30-day mortality.A total of 76 patients were finally analyzed. The mortality in patients with high BAL CMV viral load (>2.52 log copies/mL, 6/32 [18%]) showed a nonsignificant trend to be higher than in those with low CMV viral load (2/44 [5%], P = .13). However, the mortality in patients with low CMV-specific T-cell responses (<5 spots/2.0 × 10 PBMC, 6/29 [21%]) was significantly higher than in patients with high CMV-specific T-cell response (2/47 [4%], P = .048). Moreover, the 2 strata with high CMV viral load and low CMV-specific T-cell responses (4/14 [29%]) and low CMV viral load and low CMV-specific T-cell responses (2/15 [13%]) had poorer outcomes than the 2 strata with high CMV viral load and high CMV-specific T-cell responses (2/18 [11%]) and low CMV viral load and high CMV-specific T-cell responses (0/29 [0%]).These data suggest that the CMV replication and impaired CMV-specific T-cell responses adversely affect the outcomes in non-HIV-infected patients with PCP.

The burden of mucormycosis in HIV-infected patients: A systematic review.

OBJECTIVES: Mucormycosis is an invasive fungal infection afflicting immunocompromised patients, causing a significant degree of morbidity and mortality. The purpose of the study was to provide a comprehensive analysis describing the epidemiology and outcome of mucormycosis in the scenario of HIV infection. METHODS: We systematically searched PubMed for reports about mucormycosis associated with HIV. Eligible studies describe the predisposing factor, clinical form, treatment, and survival outcome. RESULTS: We included 61 articles from 212 reviewed abstracts, corresponding to 67 cases. Patients were mostly men (68.2%) with a median CD4(+) count of 47 [IQR 17-100] cells/mm(3). Intravenous drug use (50%), neutropenia (29.7%) and corticosteroid use (25%) were the predominant associated factors. The main clinical forms were disseminated (20.9%), renal (19.4%), and rhino-cerebral (17.9%). Rhizopus (45.5%) and Lichtheimia spp (30.3%) were the main fungal isolates. Treatment consisted of antifungal therapy and surgery in 38.8%. Overall mortality rate was 52.2%, and varied with the site of infection: 92.9% for disseminated disease, 62.5% for cerebral disease, 60% for pulmonary infection, and 36.4% for cutaneous infection. Survival was worse for those who did not initiate antifungals (p = .04), who were antiretroviral naïve (p = .01), who were admitted to ICU (p = .003) or had disseminated disease (p = .007). CONCLUSIONS: Mucormycosis is a life-threatening infection in HIV patients and clinician should be aware of this co-infection in the differential diagnosis of HIV opportunistic infections.

Labour productivity losses caused by premature death associated with hepatitis C in Spain.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) infection places a huge burden on healthcare systems. There is no study assessing the impact of HCV infection on premature deaths in Spain. The aim of this study was to estimate productivity losses because of premature deaths attributable to hepatitis C occurring in Spain during 2007-2011. MATERIALS AND METHODS: We use data from several sources (Registry of Deaths, Labour Force Survey and Wage Structure Survey) to develop a simulation model based on the human capital approach and to estimate the flows in labour productivity losses in the period considered. The attributable fraction method was used to estimate the numbers of deaths associated with HCV infection. Two sensitivity analyses were developed to test the robustness of the results. RESULTS: Our model shows total productivity losses attributable to HCV infection of 1054.7 million euros over the period analysed. The trend in productivity losses is decreasing over the period. This result is because of improvements in health outcomes, reflected in the reduction of the number of years of potential productive life lost. Of the total estimated losses, 18.6% were because of hepatitis C, 24.6% because of hepatocellular carcinoma, 30.1% because of cirrhosis, 15.9% because of other liver diseases and 10.7% because of HIV-HCV coinfection. CONCLUSION: The results show that premature mortality attributable to hepatitis C involves significant productivity losses. This highlights the need to extend the analysis to consider other social costs and obtain a more complete picture of the actual economic impact of hepatitis C infection.

Tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review.

Pneumonia is a major cause of morbidity and mortality in infants and children worldwide, with most cases occurring in tuberculosis-endemic settings. Studies have emphasised the potential importance of Mycobacterium tuberculosis in acute severe pneumonia in children as a primary cause or underlying comorbidity, further emphasised by the changing aetiological range with rollout of bacterial conjugate vaccines in high mortality settings. We systematically reviewed clinical and autopsy studies done in tuberculosis-endemic settings that enrolled at least 100 children aged younger than 5 years with severe pneumonia, and that prospectively included a diagnostic approach to tuberculosis in all study participants. We noted substantial heterogeneity between studies in terms of study population and diagnostic methods. Of the 3644 patients who had culture of respiratory specimens for M tuberculosis undertaken, 275 (7·5%) were culture positive, and an acute presentation was common. Inpatient case-fatality rate for pneumonia associated with tuberculosis ranged from 4% to 21% in the four clinical studies that reported pathogen-related outcomes. Prospective studies are needed in high tuberculosis-burden settings to address whether tuberculosis is a cause or comorbidity of childhood acute severe pneumonia.

HIV and hepatitis C virus coinfection in Canada: challenges and opportunities for reducing preventable morbidity and mortality.

OBJECTIVES: Hepatitis C virus (HCV) has emerged as an important health problem in the era of effective HIV treatment. However, very few data exist on the health status and disease burden of HIV/HCV-coinfected Canadians. METHODS: HIV/HCV-coinfected patients were enrolled prospectively in a multicentre cohort from 16 centres across Canada between 2003 and 2010 and followed every 6 months. We determined rates of a first liver fibrosis or endstage liver disease (ESLD) event and all-cause mortality since cohort enrolment and calculated standardized mortality ratios compared with the general Canadian population. RESULTS: A total of 955 participants were enrolled in the study and followed for a median of 1.4 (interquartile range 0.5-2.3) years. Most were male (73%) with a median age of 44.5 years; 13% self-identified as aboriginal. There were high levels of current injecting drug and alcohol use and poverty. Observed event rates [per 100 person-years; 95% confidence interval (CI)] were: significant fibrosis (10.21; 8.49, 12.19), ESLD (3.16; 2.32, 4.20) and death (3.72; 2.86, 4.77). The overall standardized mortality ratio was 17.08 (95% CI 12.83, 21.34); 12.80 (95% CI 9.10, 16.50) for male patients and 28.74 (95% CI 14.66, 42.83) for female patients. The primary causes of death were ESLD (29%) and overdose (24%). CONCLUSIONS: We observed excessive morbidity and mortality in this HIV/HCV-coinfected population in care. Over 50% of observed deaths may have been preventable. Interventions aimed at improving social circumstances, reducing harm from drug and alcohol use and increasing the delivery of HCV treatment in particular will be necessary to reduce adverse health outcomes among HIV/HCV-coinfected persons.

Additive benefits of pneumococcal and influenza vaccines among elderly persons aged 75 years or older in Taiwan--a representative population-based comparative study.

OBJECTIVE: It remains unclear whether pneumococcal vaccine provides additional protection to the elderly who have already vaccinated with influenza vaccine. This retrospective cohort study aimed to assess the additive effect of pneumococcal and influenza vaccines on the risk of mortality, hospitalization, and inpatient expenditure in the elderly aged 75 years or older in Taiwan. METHODS: Data were extracted from the National Health Insurance claims data of a nationally representative elderly sample. To reduce potential selection bias, we employed a propensity score matching method to classify the vaccination status into 3 groups. Multivariable logistic and linear regression models were used to compare the outcomes among different groups. RESULTS: Each group contained 8142 subjects. The results indicated that an additive effect of receiving both vaccines was associated with a significantly lower all-cause mortality (relative risk [RR]: 0.74; 95% confidence interval [CI]: 0.57-0.96), hospitalization of all diseases including pneumonia, influenza, chronic obstructive pulmonary disease, respiratory diseases, and congestive heart disease (RR: 0.77; 95% CI: 0.67-0.90), and a 13% reduction (95% CI: 0.81-0.94) in inpatient expenditures of all diseases when compared with receiving influenza vaccine alone. CONCLUSIONS: This study confirmed that vaccination of elderly individuals with pneumococcal vaccine and influenza vaccine concomitantly has substantial beneficial effects.

Risk factors for mortality among MDR- and XDR-TB patients in a high HIV prevalence setting.

SETTING: Recent studies suggest that the prevalence of drug-resistant tuberculosis (TB) in sub-Saharan Africa may be rising. This is of concern, as human immunodeficiency virus (HIV) co-infection in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has been associated with exceedingly high mortality rates. OBJECTIVE: To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa. DESIGN: Case-control study of patients who died of all causes within 2 years of diagnosis with MDR- or XDR-TB. RESULTS: Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count ≤ 50 (HR 4.64, P = 0.01) and 51-200 cells/mm(3) (HR 4.17, P = 0.008) were the strongest independent risk factors for mortality. Among 139 XDR-TB patients, 111 (80%) died. CD4 count ≤ 50 cells/mm(3) (HR 4.46, P = 0.01) and resistance to all six drugs tested (HR 2.54, P = 0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, P = 0.009). CONCLUSIONS: Mortality due to MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation.

The effect of hepatitis C treatment and human immunodeficiency virus (HIV) co-infection on the disease burden of hepatitis C among injecting drug users in Amsterdam.

AIMS: The hepatitis C virus (HCV) disease burden among injecting drug users (IDUs) is determined by HCV incidence, the long latency period of HCV, competing mortality causes, presence of co-infection and HCV treatment uptake. We examined the effect of these factors and estimated the HCV disease burden in Amsterdam. DESIGN: A Markov model was developed, incorporating HCV and human immunodeficiency virus (HIV), and parameterized with data from the Amsterdam Cohort Studies, surveillance studies and literature. SETTING: IDU population of Amsterdam. MEASUREMENTS: HCV infection simulated from its acute phase to HCV-related liver disease (i.e. decompensated cirrhosis and hepatocellular carcinoma). FINDINGS: The HCV prevalence among IDUs in Amsterdam increased to approximately 80% in the 1980s. From 2011 to 2025, the HCV-related disease prevalence will accordingly rise by 36%, from 57 cases (95% range 33-94) to 78 (95% range 43-138), respectively. In total, 945 (95% range 617-1309) individuals will develop HCV-related liver disease. This burden would have been 33% higher in the absence of HIV, resulting in 1219 cases (95% range 796-1663). In Amsterdam, 25% of HIV-negative IDUs receive successful HCV treatment, reducing the cumulative disease burden by 14% to 810 (95% range 520-1120). Further reduction of 36% can be achieved by improving treatment, resulting in 603 cases (95% range 384-851). CONCLUSIONS: The hepatitis C virus burden among injecting drug users in Amsterdam has been reduced by a high competing mortality rate, particularly caused by HIV infection, and to a smaller extent by hepatitis C virus treatment. Improved hepatitis C virus treatment is expected to contribute to reduce the future hepatitis C virus disease burden.