Tuberculosis preventive treatment in people living with HIV—Is the glass half empty or half full?

Olivia Oxlade and co-authors introduce a Collection on tuberculosis preventive therapy in people with HIV infection.

The most recent World Health Organization Global Tuberculosis (TB) Report suggests that 50% of people living with HIV (PLHIV) newly enrolled in HIV care initiated tuberculosis preventive treatment (TPT) in 2019 [1]. TPT is an essential intervention to prevent TB disease among people infected with Mycobacterium tuberculosis—some 25% of the world’s population [2]. Without TPT, it is estimated that up to 10% of individuals will progress to TB disease. Among PLHIV, the prognosis is worse. Of the approximately 1.4 million annual deaths from TB, 200,000 occur among PLHIV [1], who experience TB at rates more than 30 times [3] higher than people living without HIV.In 2018, governments at the United Nations High-Level Meeting (UNHLM) on TB committed to rapid expansion of testing for TB infection and provision of TPT [4]. The goal was the provision of TPT to at least 24 million household contacts of people with TB disease and 6 million PLHIV between 2018 and 2022. However, by the end of 2019, fewer than half a million household contacts had initiated TPT, well short of the pace needed to achieve the 5-year target [1]. On the other hand, approximately 5.3 million PLHIV have initiated TPT in the past 2 years [1], with particularly dramatic increases in countries supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) [5]. Globally, among PLHIV entering HIV care programs, TPT initiation rose from 36% in 2017 to 49% in 2018 and 50% in 2019 [6,7].To provide insight into scaling up TPT for PLHIV, it is important to consider each of the many steps involved in the “cascade of care” for TPT. A previous systematic review of studies in several populations receiving TPT concluded that nearly 70% of all people who may benefit from TPT were lost to follow-up at cascade of care steps prior to treatment initiation [8]. To maximize the impact of TPT for TB prevention among PLHIV, the full TPT cascade of care must be assessed to identify problems and develop targeted solutions addressing barriers at each step. Until now, these data had not been synthesized for PLHIV.In order to address important research gaps related to TPT in PLHIV such as this one, we are now presenting a Collection in PLOS Medicine on TPT in PLHIV. In the first paper in this Collection, Bastos and colleagues performed a systematic review and meta-analysis of the TPT cascade of care in 71 cohorts with a total of 94,011 PLHIV [9]. This analysis highlights key steps in the cascade where substantial attrition occurs and identifies individual-level and programmatic barriers and facilitators at each step. In stratified analyses, they found that losses during the TPT cascade were not different in high-income compared to low- or middle-income settings, nor were losses greater in centers performing tests for TB infection (tuberculin skin test [TST] or interferon gamma release assay [IGRA]) prior to TPT initiation.The net benefits of TPT could potentially be increased through greater adoption of shorter rifamycin-based TPT regimens, for which there is increasing evidence of greater safety, improved treatment completion, and noninferior efficacy, compared to isoniazid regimens. Two reviews of rifamycin-based regimens in mostly HIV–negative adults and children concluded that they were as effective for prevention of TB as longer isoniazid-based regimens, with better treatment completion and fewer adverse events [10,11]. However, safety and tolerability of TPT regimens can differ substantially between people with and without HIV, and for rifamycin-based TPT regimens, safety outcomes were actually worse in people without HIV [12], plus there can be important drug–drug interactions between rifamycin-based regimens and antiretroviral drugs [13]. Reviews of studies focused on PLHIV concluded that TPT (regardless of regimen selected) significantly reduced TB incidence [14] and that the benefits of continuous isoniazid in high TB transmission settings outweighed the risks [15]. As part of this Collection, Yanes-Lane and colleagues conducted a systematic review and network meta-analysis of 16 randomized trials to directly and indirectly compare the risks and benefits of isoniazid and rifamycin-based TPT regimens among PLHIV [16]. Their findings highlight the better safety, improved completion, and evidence of efficacy, particularly reduced mortality, with rifamycin-based TPT regimens, while also noting improved TB prevention with extended duration mono-isoniazid regimens. Their review also revealed that few studies exist on some important at-risk populations, such was pregnant women and those with drug-resistant TB infection.In North America, recommendations changed in 2020 to favor shorter rifamycin-based regimens over isoniazid [17], but WHO still favors isoniazid [18], largely due to the lower drug costs. Although drug costs for rifamycins are typically higher than for isoniazid, their shorter duration and better safety profile mean that total costs for care (including personnel costs) may be lower for rifamycin-based regimens, even in underresourced settings [19]. The cost-effectiveness of different TPT regimens among PLHIV in underresourced settings remains uncertain, as well as the impact of antiretroviral therapy (ART), and the use of diagnostic tests for TB infection, such as TST or IGRA on cost efficiency. Uppal and colleagues, in the third paper in this Collection, performed a systematic review and meta-analysis of 61 published cost-effectiveness and transmission modeling studies of TPT among PLHIV [20]. In all studies, TPT was consistently cost-effective, if not cost saving, despite wide variation in key input parameters and settings considered.When comparing access to TPT among PLHIV to household contacts, many would consider the glass is half full, given that almost half of all PLHIV newly accessing care initiated TPT in 2018 and 2019, and the UNHLM goal of 6 million PLHIV initiating TPT was already nearly achieved by the end of 2020. This remarkable achievement is the result of strong recommendations from WHO for TPT among PLHIV for nearly a decade and strong donor support. These policies are, in turn, based on clear and consistent evidence of individual benefits from multiple randomized trials, plus consistent evidence of cost-effectiveness from many economic analyses as summarized in the papers in this Collection. These are useful lessons for scaling up TPT for other target populations, particularly household contacts, of whom less than half a million have initiated TPT, of the 24 million–person target set in 2018.However, the glass of TPT among PLHIV is also half empty. In contrast to the “90-90-90” targets, 50% of PLHIV newly enrolled in care do not initiate TPT, and PLHIV still bear a disproportionate burden of TB. Programmatic scale-up of TPT continues to encounter challenges that need to be overcome in order to translate individual-level success to population-level improvement. The study by Bastos and colleagues in this Collection has identified programmatic barriers including drug stockouts and suboptimal training for healthcare workers, but it also offers useful solutions, including integration of HIV and TPT services [9]. New evidence on the success of differentiated service delivery will also be invaluable to support programmatic scale-up in different settings [21]. Acting on this evidence will be essential to achieve the goal of full access to effective, safe, and cost-effective TPT for PLHIV.     

Scaling up target regimens for tuberculosis preventive treatment in Brazil and South Africa: An analysis of costs and cost-effectiveness

BackgroundShorter, safer, and cheaper tuberculosis (TB) preventive treatment (TPT) regimens will enhance uptake and effectiveness. WHO developed target product profiles describing minimum requirements and optimal targets for key attributes of novel TPT regimens. We performed a cost-effectiveness analysis addressing the scale-up of regimens meeting these criteria in Brazil, a setting with relatively low transmission and low HIV and rifampicin-resistant TB (RR-TB) prevalence, and South Africa, a setting with higher transmission and higher HIV and RR-TB prevalence.Methods and findingsWe used outputs from a model simulating scale-up of TPT regimens meeting minimal and optimal criteria. We assumed that drug costs for minimal and optimal regimens were identical to 6 months of daily isoniazid (6H). The minimal regimen lasted 3 months, with 70% completion and 80% efficacy; the optimal regimen lasted 1 month, with 90% completion and 100% efficacy. Target groups were people living with HIV (PLHIV) on antiretroviral treatment and household contacts (HHCs) of identified TB patients. The status quo was 6H at 2019 coverage levels for PLHIV and HHCs. We projected TB cases and deaths, TB-associated disability-adjusted life years (DALYs), and costs (in 2020 US dollars) associated with TB from a TB services perspective from 2020 to 2035, with 3% annual discounting. We estimated the expected costs and outcomes of scaling up 6H, the minimal TPT regimen, or the optimal TPT regimen to reach all eligible PLHIV and HHCs by 2023, compared to the status quo. Maintaining current 6H coverage in Brazil (0% of HHCs and 30% of PLHIV treated) would be associated with 1.1 (95% uncertainty range [UR] 1.1–1.2) million TB cases, 123,000 (115,000–132,000) deaths, and 2.5 (2.1–3.1) million DALYs and would cost $1.1 ($1.0–$1.3) billion during 2020–2035. Expanding the 6H, minimal, or optimal regimen to 100% coverage among eligible groups would reduce DALYs by 0.5% (95% UR 1.2% reduction, 0.4% increase), 2.5% (1.8%–3.0%), and 9.0% (6.5%–11.0%), respectively, with additional costs of $107 ($95–$117) million and $51 ($41–$60) million and savings of $36 ($14–$58) million, respectively. Compared to the status quo, costs per DALY averted were $7,608 and $808 for scaling up the 6H and minimal regimens, respectively, while the optimal regimen was dominant (cost savings, reduced DALYs). In South Africa, maintaining current 6H coverage (0% of HHCs and 69% of PLHIV treated) would be associated with 3.6 (95% UR 3.0–4.3) million TB cases, 843,000 (598,000–1,201,000) deaths, and 36.7 (19.5–58.0) million DALYs and would cost $2.5 ($1.8–$3.6) billion. Expanding coverage with the 6H, minimal, or optimal regimen would reduce DALYs by 6.9% (95% UR 4.3%–95%), 15.5% (11.8%–18.9%), and 38.0% (32.7%–43.0%), respectively, with additional costs of $79 (−$7, $151) million and $40 (−$52, $140) million and savings of $608 ($443–$832) million, respectively. Compared to the status quo, estimated costs per DALY averted were $31 and $7 for scaling up the 6H and minimal regimens, while the optimal regimen was dominant. Study limitations included the focus on 2 countries, and no explicit consideration of costs incurred before the decision to prescribe TPT.ConclusionsOur findings suggest that scale-up of TPT regimens meeting minimum or optimal requirements would likely have important impacts on TB-associated outcomes and would likely be cost-effective or cost saving.

Placide Nsengiyumva and colleagues analyze costs and cost-effectiveness of scaling up target regimens for Tuberculosis Preventive Treatment among persons living with HIV and household contacts of TB patients in Brazil and South Africa.     

Risk of developing active tuberculosis following tuberculosis screening and preventive therapy for Tibetan refugee children and adolescents in India: An impact assessment

BackgroundTuberculosis (TB) rates among Tibetan refugee children and adolescents attending boarding schools in India are extremely high. We undertook a comprehensive case finding and TB preventive treatment (TPT) program in 7 schools in the Zero TB Kids project. We aimed to measure the TB infection and disease burden and investigate the risk of TB disease in children and adults who did and did not receive TPT in the schools.Methods and findingsA mobile team annually screened children and staff for TB at the 7 boarding schools in Himachal Pradesh, India, using symptom criteria, radiography, molecular diagnostics, and tuberculin skin tests. TB infection (TBI) was treated with short-course regimens of isoniazid and rifampin or rifampin. TB disease was treated according to Tibetan and Indian guidelines. Between April 2017 and December 2019, 6,582 schoolchildren (median age 14 [IQR 11–16] years) and 807 staff (median age 40 [IQR 33–48] years) were enrolled. Fifty-one percent of the students and 58% of the staff were females. Over 13,161 person-years of follow-up in schoolchildren (median follow-up 2.3 years) and 1,800 person-years of follow-up in staff (median follow-up 2.5 years), 69 TB episodes occurred in schoolchildren and 4 TB episodes occurred in staff, yielding annual incidence rates of 524/100,000 (95% CI 414–663/100,000) person-years and 256/100,000 (95% CI 96–683/100,000) person-years, respectively. Of 1,412 schoolchildren diagnosed with TBI, 1,192 received TPT. Schoolchildren who received TPT had 79% lower risk of TB disease (adjusted hazard ratio [aHR] 0.21; 95% CI 0.07–0.69; p = 0.010) compared to non-recipients, the primary study outcome. Protection was greater in recent contacts (aHR 0.07; 95% CI 0.01–0.42; p = 0.004), the secondary study outcome. The prevalence of recent contacts was 28% (1,843/6,582). Two different TPT regimens were used (3HR and 4R), and both were apparently effective. No staff receiving TPT developed TB. Overall, between 2017 and 2019, TB disease incidence decreased by 87%, from 837/100,000 (95% CI 604–1,129/100,000) person-years to 110/100,000 (95% CI 36–255/100,000) person-years (p < 0.001), and TBI prevalence decreased by 42% from 19% (95% CI 18%–20%) to 11% (95% CI 10%–12%) (p < 0.001). A limitation of our study is that TB incidence could be influenced by secular trends during the study period.ConclusionsIn this study, following implementation of a school-wide TB screening and preventive treatment program, we observed a significant reduction in the burden of TB disease and TBI in children and adolescents. The benefit of TPT was particularly marked for recent TB contacts. This initiative may serve as a model for TB detection and prevention in children and adolescents in other communities affected by TB.

Kunchok Dorjee and colleagues investigate infection and disease burden following mass tuberculosis preventive treatment for Tibetan refugee children at schools in India.     

Prevalence and Risk Factors for Latent Tuberculosis Infection among Health Care Workers in China: A Cross-Sectional Study

Background

Health care workers (HCWs) are at risk of latent tuberculosis infection (LTBI). In China, tuberculosis (TB) is a major public health problem, but the prevalence of LTBI in HCWs especially in the hospital for pulmonary diseases has not been assessed enough. The aim of this study was to determine the prevalence and putative risk factors of LTBI among HCWs in a chest hospital and a TB research institute in China.

Methodology/Principal Findings

A cross-sectional study was conducted among HCWs in China in 2012. LTBI was assessed by T-SPOT.TB, and information on HCWs was collected using a standardised questionnaire. Risk factors for LTBI were analyzed by univariate and multivariate regression. The overall prevalence of LTBI among HCWs was 33.6%. Analyzed by job category, the highest prevalence was found among laboratory staff (43.4%). In the different workplaces, the proportion of LTBI was significantly higher among the high risk workplaces (37.4%) compared to the low risk workplaces. The duration of employment had a significant impact on the prevalence of LTBI. Positive T-SPOT.TB test results accounted for 17.6%, 16.8%, 23.5%, 41.8% and 41.6% in groups of ≤2, 3–5, 6–10, 11–20, and >20 working years respectively. In multivariate analysis, job categories (Laboratory staff [2.76 (95% CI: 1.36; 5.60)], technician staff [2.02 (95% CI: 1.12; 3.64)]); working duration as a HCW for 11 to 20 years [3.57 (95% CI: 1.46; 8.71)], and 20 years above [3.41 (95% CI: 1.28; 9.11)]; and the history of household TB contact [2.47 (95% CI: 1.15; 5.33)] were associated with increased risk of LTBI.

Conclusions/Significance

Prevalence of LTBI estimated by T-SPOT.TB is high among Chinese HCWs and working duration, job category and the history of household TB contact were associated with increased risk. These data highlight adequate infection control measures should be undertaken.     

Unmet need for hypercholesterolemia care in 35 low- and middle-income countries: A cross-sectional study of nationally representative surveys

BackgroundAs the prevalence of hypercholesterolemia is increasing in low- and middle-income countries (LMICs), detailed evidence is urgently needed to guide the response of health systems to this epidemic. This study sought to quantify unmet need for hypercholesterolemia care among adults in 35 LMICs.Methods and findingsWe pooled individual-level data from 129,040 respondents aged 15 years and older from 35 nationally representative surveys conducted between 2009 and 2018. Hypercholesterolemia care was quantified using cascade of care analyses in the pooled sample and by region, country income group, and country. Hypercholesterolemia was defined as (i) total cholesterol (TC) ≥240 mg/dL or self-reported lipid-lowering medication use and, alternatively, as (ii) low-density lipoprotein cholesterol (LDL-C) ≥160 mg/dL or self-reported lipid-lowering medication use. Stages of the care cascade for hypercholesterolemia were defined as follows: screened (prior to the survey), aware of diagnosis, treated (lifestyle advice and/or medication), and controlled (TC <200 mg/dL or LDL-C <130 mg/dL). We further estimated how age, sex, education, body mass index (BMI), current smoking, having diabetes, and having hypertension are associated with cascade progression using modified Poisson regression models with survey fixed effects.High TC prevalence was 7.1% (95% CI: 6.8% to 7.4%), and high LDL-C prevalence was 7.5% (95% CI: 7.1% to 7.9%). The cascade analysis showed that 43% (95% CI: 40% to 45%) of study participants with high TC and 47% (95% CI: 44% to 50%) with high LDL-C ever had their cholesterol measured prior to the survey. About 31% (95% CI: 29% to 33%) and 36% (95% CI: 33% to 38%) were aware of their diagnosis; 29% (95% CI: 28% to 31%) and 33% (95% CI: 31% to 36%) were treated; 7% (95% CI: 6% to 9%) and 19% (95% CI: 18% to 21%) were controlled. We found substantial heterogeneity in cascade performance across countries and higher performances in upper-middle-income countries and the Eastern Mediterranean, Europe, and Americas. Lipid screening was significantly associated with older age, female sex, higher education, higher BMI, comorbid diagnosis of diabetes, and comorbid diagnosis of hypertension. Awareness of diagnosis was significantly associated with older age, higher BMI, comorbid diagnosis of diabetes, and comorbid diagnosis of hypertension. Lastly, treatment of hypercholesterolemia was significantly associated with comorbid hypertension and diabetes, and control of lipid measures with comorbid diabetes. The main limitations of this study are a potential recall bias in self-reported information on received health services as well as diminished comparability due to varying survey years and varying lipid guideline application across country and clinical settings.ConclusionsCascade performance was poor across all stages, indicating large unmet need for hypercholesterolemia care in this sample of LMICs—calling for greater policy and research attention toward this cardiovascular disease (CVD) risk factor and highlighting opportunities for improved prevention of CVD.

Maja Marcus and colleagues use nationally-representative surveys conducted between 2009 and 2018 to investigate the unmet need for hypercholesterolemia care in 35 low- and middle-income countries.     

Catching the Missing Million: Experiences in Enhancing TB & DR-TB Detection by Providing Upfront Xpert MTB/RIF Testing for People Living with HIV in India

BackgroundA critical challenge in providing TB care to People Living with HIV (PLHIV) is establishing an accurate bacteriological diagnosis. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents results from PLHIV taking part in a large demonstration study across India wherein upfront Xpert MTB/RIF testing was offered to all presumptive PTB cases in public health facilities.MethodThe study covered a population of 8.8 million across 18 sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each TU. All HIV-infected patients suspected of TB (both TB and Drug Resistant TB (DR-TB)) accessing public health facilities in study area were prospectively enrolled and provided upfront Xpert MTB/RIF testing.Result2,787 HIV-infected presumptive pulmonary TB cases were enrolled and 867 (31.1%, 95% Confidence Interval (CI) 29.4‒32.8) HIV-infected TB cases were diagnosed under the study. Overall 27.6% (CI 25.9–29.3) of HIV-infected presumptive PTB cases were positive by Xpert MTB/RIF, compared with 12.9% (CI 11.6–14.1) who had positive sputum smears. Upfront Xpert MTB/RIF testing of presumptive PTB and DR-TB cases resulted in diagnosis of 73 (9.5%, CI 7.6‒11.8) and 16 (11.2%, CI 6.7‒17.1) rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high 97.7% (CI 89.3‒99.8), with no significant difference with or without prior history of TB treatment.ConclusionThe study results strongly demonstrate limitations of using smear microscopy for TB diagnosis in PLHIV, leading to low TB and DR-TB detection which can potentially lead to either delayed or sub-optimal TB treatment. Our findings demonstrate the usefulness and feasibility of addressing this diagnostic gap with upfront of Xpert MTB/RIF testing, leading to overall strengthening of care and support package for PLHIV.     

Sexual Behavior among Persons Living with HIV in Uganda: Implications for Policy and Practice

Introduction

HIV epidemics are sustained and propagated by new cases of infection which result from transmission from infected persons to uninfected susceptible individuals. People living with HIV (PLHIV) play a critical role in prevention if they adopt safer sexual behaviors. This study estimated the prevalence of and factors associated with safer sexual behaviors among PLHIV seeking care from civil society organizations (CSOs).

Methods

In a cross sectional study PLHIV were interviewed about their sexual practices, use of alcohol, HIV status of their regular sexual partners, desire for more children and about their socio-demographic characteristics. We calculated the proportion of PLHIV who abstained and consistently used condoms in the previous twelve months. Independent associations between safer sex and other variables were estimated using adjusted prevalence ratios (aPR) and their 95% confidence intervals (CI).

Results

Of the 939 PLHIV, 54% (508) were either abstaining or using condoms consistently and 291 (31%) desired more children. The prevalence of consistent condom use among the sexually active was 41.3% (300/731). Consistent condom use was higher among PLHIV who: didn''t use alcohol (aPR 1.30, CI 1.03–1.63); were educated about re-infection with a new strain of HIV (aPR 1.84, CI 1.08–3.12) and had regular sexual partner who was HIV negative (aPR 1.29, CI 1.05–1.57). Prevalence of abstinence was 22.2% (208/939). Abstinence increased with age from 9.4% among PLHIV <25 years to 40.5% among those >50 years. Abstinence was extremely low (2.5%) among PLHIV who were married.

Conclusions

Effective interventions that reduce alcohol consumption among PLHIV are needed to avert HIV transmission, prevent acquisition of new HIV strains and STIs. In addition, strategies are needed to address needs of PLHIV who desire more children.     

The global gap in treatment coverage for major depressive disorder in 84 countries from 2000–2019: A systematic review and Bayesian meta-regression analysis

BackgroundThe treatment coverage for major depressive disorder (MDD) is low in many parts of the world despite MDD being a major contributor to disability globally. Most existing reviews of MDD treatment coverage do not account for potential sources of study-level heterogeneity that contribute to variation in reported treatment rates. This study aims to provide a comprehensive review of the evidence and analytically quantify sources of heterogeneity to report updated estimates of MDD treatment coverage and gaps by location and treatment type between 2000 and 2019.Methods and findingsA systematic review of the literature was conducted to identify relevant studies that provided data on treatment rates for MDD between January 1, 2000, and November 26, 2021, from 2 online scholarly databases PubMed and Embase. Cohort and cross-sectional studies were included if treatment rates pertaining to the last 12 months or less were reported directly or if sufficient information was available to calculate this along with 95% uncertainty intervals (UIs). Studies were included if they made use of population-based surveys that were representative of communities, countries, or regions under study. Studies were included if they used established diagnostic criteria to diagnose cases of MDD. Sample and methodological characteristics were extracted from selected studies. Treatment rates were modeled using a Bayesian meta-regression approach and adjusted for select covariates that quantified heterogeneity in the data. These covariates included age, sex, treatment type, location, and choice of MDD assessment tool. A total of 149 studies were included for quantitative analysis. Treatment coverage for health service use ranged from 51% [95% UI 20%, 82%] in high-income locations to 20% [95% UI 1%, 53%] in low- and lower middle-income locations. Treatment coverage for mental health service use ranged from 33% [95% UI 8%, 66%] in high-income locations to 8% [95% UI <1%, 36%] in low- and lower middle-income countries. Minimally adequate treatment (MAT) rates ranged from 23% [95% UI 2%, 55%] in high-income countries to 3% [95% UI <1%, 25%]) in low- and lower middle-income countries. A primary methodological limitation was the lack of sufficient data from low- and lower middle-income countries, which precluded our ability to provide more detailed treatment rate estimates.ConclusionsIn this study, we observed that the treatment coverage for MDD continues to be low in many parts of the world and in particular in low- and lower middle-income countries. There is a continued need for routine data collection that will help obtain more accurate estimates of treatment coverage globally.

In a systematic review and Bayesian meta-regression analysis, Modhurima Moitra and colleagues estimate major depressive disorder treatment coverage in 84 countries.     

A Clinical Algorithm to Identify HIV Patients at High Risk for Incident Active Tuberculosis: A Prospective 5-Year Cohort Study

Background

Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided.

Materials and Methods

A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/μL). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated.

Results

Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49–15.90, P = 0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52–24.40, P = 0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587–0.798) for the study cohort and 0.792 (95% CI: 0.776–0.808) and 0.766 in the 2 validation cohorts.

Conclusions

A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system.     

Risk Factors for Severe Neonatal Hyperbilirubinemia in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis

BackgroundAvailable evidence suggests that low- and middle-income countries (LMICs) bear the greatest burden of severe neonatal hyperbilirubinemia characterized by disproportionately high rates of morbidity, mortality and neurodevelopmental disorders compared to high-income countries. We set out to identify the risk factors that contribute to the burden of severe hyperbilirubinemia in the most developmentally disadvantaged LMICs to highlight areas for action and further research.MethodsWe systematically searched PubMed, Scopus, Ovid EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), WHO Library Database (WHOLIS), African Index Medicus (AIM), African Journals Online (AJOL), LILACS, and IndMed for reports published between January 1990 and June 2014. We included only studies that controlled for the effects of confounding variables in determining maternal and infant risk factors for severe hyperbilirubinemia. We conducted meta-analysis of the eligible studies and computed the summary risk estimates with random effects models.ResultsA total of 13 studies with 1,951 subjects and 32,208 controls from India, Nigeria, Pakistan, Nepal and Egypt were identified and analyzed. The pooled data showed that primiparity (OR, 1.59; 95% CI:1.26-2.00), delivery outside public hospitals (OR, 6.42; 95% CI:1.76-23.36), ABO incompatibility (OR, 4.01; 95% CI:2.44-6.61), Rhesus hemolytic disease (OR, 20.63; 95% CI:3.95-107.65), G6PD deficiency (OR, 8.01; 95% CI:2.09-30.69), UGT1A1 polymorphisms (OR, 4.92; 95% CI:1.30-18.62), low gestational age (OR, 1.71; 95% CI:1.40-2.11), underweight/weight loss (OR, 6.26; 95% CI:1.23-31.86), sepsis (OR, 9.15; 95% CI:2.78-30.10) and high transcutaneous/total serum bilirubin levels (OR, 1.46; 95% CI:1.10-1.92) placed infants at increased risk of severe hyperbilirubinemia or bilirubin induced neurologic dysfunctions. Low social class was not associated with an increased risk of severe hyperbilirubinemia.ConclusionsInfants at risk of severe hyperbilirubinemia in LMICs are associated with maternal and neonatal factors that can be effectively addressed by available interventions to curtail the disease burden prevailing in the affected countries.     

Bridging the gaps between research,policy and practice in low- and middle-income countries: a survey of health care providers

Background

Gaps continue to exist between research-based evidence and clinical practice. We surveyed health care providers in 10 low- and middle-income countries about their use of research-based evidence and examined factors that may facilitate or impede such use.

Methods

We surveyed 1499 health care providers practising in one of four areas relevant to the Millennium Development Goals (prevention of malaria, care of women seeking contraception, care of children with diarrhea and care of patients with tuberculosis) in each of China, Ghana, India, Iran, Kazakhstan, Laos, Mexico, Pakistan, Senegal and Tanzania.

Results

The proportion of respondents who reported that research was likely to change their clinical practice if performed and published in their own country (84.6% and 86.0% respectively) was higher than the proportion who reported the same about research and publications from their region (66.4% and 63.1%) or from high-income countries (55.8% and 55.5%). Respondents who were most likely to report that the use of research-based evidence led to changes in their practice included those who reported using clinical practice guidelines in paper format (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.03–2.28), using scientific journals from their own country in paper format (OR 1.70, 95% CI 1.26–2.28), viewing the quality of research performed in their country as above average or excellent (OR 1.93, 95% CI 1.16–3.22); trusting systematic reviews of randomized controlled trials (OR 1.59, 95% CI 1.08–2.35); and having easy access to the Internet (OR 1.90, 95% CI 1.19–3.02).

Interpretation

Locally conducted or published research has played an important role in changing the professional practice of health care providers surveyed in low- and middle-income countries. Increased investments in local research, or at least in locally adapted publications of research-based evidence from other settings, are therefore needed. Although access to the Internet was viewed as a significant factor in whether research-based evidence led to concrete changes in practice, few respondents reported having easy access to the Internet. Therefore, efforts to improve Internet access in clinical settings need to be accelerated.Gaps continue to exist between evidence generated by clinical research and practice.¹ Efforts to improve access to health information in low- and middle-income countries² and a greater knowledge of how to support the use of research evidence in clinical practice have made little difference. The health consequences of these gaps can be particularly profound when highly effective interventions exist. For example, in the 42 countries in which 90% of the deaths involving children worldwide occurred in 2000, nearly 2.2 million deaths among those under five years of age could have been prevented through the universal use of oral rehydration therapy in those with diarrhea and the use of insecticide-treated materials to prevent malaria.³We conducted this study to examine the use of research-based evidence in defined clinical areas in a sample of health care providers in 10 low- and middle-income countries. We also examined factors that may facilitate or impede such use.     

Association of Respiratory Viruses with Outcomes of Severe Childhood Pneumonia in Botswana

BackgroundThe highest incidence of childhood acute lower respiratory tract infection (ALRI) is in low- and middle-income countries. Few studies examined whether detection of respiratory viruses predicts ALRI outcomes in these settings.MethodsWe conducted prospective cohort and case-control studies of children 1-23 months of age in Botswana. Cases met clinical criteria for pneumonia and were recruited within six hours of presentation to a referral hospital. Controls were children without pneumonia matched to cases by primary care clinic and date of enrollment. Nasopharyngeal specimens were tested for respiratory viruses using polymerase chain reaction. We compared detection rates of specific viruses in matched case-control pairs. We examined the effect of respiratory syncytial virus (RSV) and other respiratory viruses on pneumonia outcomes.ResultsBetween April 2012 and August 2014, we enrolled 310 cases, of which 133 had matched controls. Median ages of cases and controls were 6.1 and 6.4 months, respectively. One or more viruses were detected from 75% of cases and 34% of controls. RSV and human metapneumovirus were more frequent among cases than controls, but only enterovirus/rhinovirus was detected from asymptomatic controls. Compared with non-RSV viruses, RSV was associated with an increased risk of treatment failure at 48 hours [risk ratio (RR): 1.85; 95% confidence interval (CI): 1.20, 2.84], more days of respiratory support [mean difference (MD): 1.26 days; 95% CI: 0.30, 2.22 days], and longer duration of hospitalization [MD: 1.35 days; 95% CI: 0.20, 2.50 days], but lower in-hospital mortality [RR: 0.09; 95% CI: 0.01, 0.80] in children with pneumonia.ConclusionsRespiratory viruses were detected from most children hospitalized with ALRI in Botswana, but only RSV and human metapneumovirus were more frequent than among children without ALRI. Detection of RSV from children with ALRI predicted a protracted illness course but lower mortality compared with non-RSV viruses.     

Prevalence and Incidence of Latent Tuberculosis Infection in Georgian Healthcare Workers

Background

Tuberculosis is a major occupational hazard in low and middle-income countries. Limited data exist on serial testing of healthcare workers (HCWs) with interferon-γ release assays (IGRAs) for latent tuberculosis infection (LTBI), especially in low and middle-income countries. We sought to evaluate the rates of and risk factors for LTBI prevalence and LTBI test conversion among HCWs using the tuberculin skin test (TST) and QuantiFERON-TB Gold In-tube assay (QFT-GIT).

Methods

A prospective longitudinal study was conducted among HCWs in the country of Georgia. Subjects completed a questionnaire, and TST and QFT-GIT tests were performed. LTBI testing was repeated 6-26 months after baseline testing.

Results

Among 319 HCWs enrolled, 89% reported prior BCG vaccination, and 60% worked in TB healthcare facilities (HCFs). HCWs from TB HCFs had higher prevalence of positive QFT-GIT and TST than those from non-TB HCFs: 107/194 (55%) vs. 30/125 (31%) QFT-GIT positive (p<0.0001) and 128/189 (69%) vs. 64/119 (54%) TST positive (p = 0.01). There was fair agreement between TST and QFT-GIT (kappa = 0.42, 95% CI 0.31–0.52). In multivariate analysis, frequent contact with TB patients was associated with increased risk of positive QFT-GIT (aOR 3.04, 95% CI 1.79–5.14) but not positive TST. Increasing age was associated with increased risk of positive QFT-GIT (aOR 1.05, 95% CI 1.01–1.09) and TST (aOR 1.05, 95% CI 1.01–1.10). High rates of HCW conversion were seen: the QFT-GIT conversion rate was 22.8/100 person-years, and TST conversion rate was 17.1/100 person-years. In multivariate analysis, female HCWs had decreased risk of TST conversion (aOR 0.05, 95% CI 0.01–0.43), and older HCWs had increased risk of QFT-GIT conversion (aOR 1.07 per year, 95% CI 1.01–1.13).

Conclusion

LTBI prevalence and LTBI test conversion rates were high among Georgian HCWs, especially among those working at TB HCFs. These data highlight the need for increased implementation of TB infection control measures.     

Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis

BackgroundNeonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR.Methods and findingsAll studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria.ConclusionsGram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are associated with significant rates of resistance to WHO-recommended first- and second-line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required.

Sophie Wen and co-workers report a meta-analysis on bacterial isolates and antimicrobial resistance in neonatal sepsis in low- and lower-middle-income countries.     

The Significance of Sensitive Interferon Gamma Release Assays for Diagnosis of Latent Tuberculosis Infection in Patients Receiving Tumor Necrosis Factor-α Antagonist Therapy

Objective

We compared two interferon gamma release assays (IGRAs), QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, for diagnosis of latent tuberculosis infection (LTBI) in patients before and while receiving tumor necrosis factor (TNF)-α antagonist therapy. This study evaluated the significance of sensitive IGRAs for LTBI screening and monitoring.

Methods

Before starting TNF-α antagonist therapy, 156 consecutive patients with rheumatic diseases were screened for LTBI using QFT-GIT and T-SPOT.TB tests. According to our study protocol, QFT-GIT-positive patients received LTBI treatment. Patients positive by any IGRAs were subjected to follow-up IGRA tests after completing LTBI-treatment and/or during TNF-α antagonist therapy.

Results

At the initial LTBI screening, 45 (28.9%) and 70 (44.9%) patients were positive by QFT-GIT and T-SPOT.TB, respectively. The agreement rate between IGRA results was 78.8% (k = 0.56; 95% confidence interval [95% CI] = 0.43 to 0.68). Of 29 patients who were positive only by T-SPOT.TB in the initial screening, 83% (19/23) were persistently positive by T-SPOT.TB, while QFT-GIT testing showed that 36% (9/25) had conversion during TNF-α antagonist therapy. By the end of the follow-up period (218 to 1,264 days), four patients (4/137, 2.9%) developed active tuberculosis (TB) diseases during receiving TNF-α antagonist therapy. Among them, one was Q-T+, one was Q+T-, and the remaining two were Q-T- at the initial screening (Q, QuantiFERON-TB Gold In-Tube; T, T-SPOT.TB; +, positive; -, negative). Two (2/4, 50%) patients with TB reactivation had at least one prior risk factor consistent with previous TB infection.

Conclusion

This study demonstrated the need to capitalize on sensitive IGRAs to monitor for LTBI in at-risk patients for a more sensitive diagnosis in countries with an intermediate TB burden.     

Blood metal/metalloid concentration of male subjects undergoing IVF/ICSI treatment outcomes: A prospective cohort study

BackgroundPrevious epidemiology studies reported that heavy metal/metalloid exposure is associated with the impairment of semen quality. However, it is still not clear whether the in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment outcome will be affected after the heavy metal/metalloid exposure of the male partners.MethodsA prospective cohort study with a 2-year followed-up was conducted in a tertiary IVF center. A total of 111 couples undergoing IVF/ICSI treatment were initially recruited from November 2015 to November 2016. Male blood concentrations of heavy metal/metalloid including Ca, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Mo, Cd, Hg, and Pb were measured by inductively coupled plasma mass spectrometry, and the lab and pregnancy outcome data were followed up. The associations between male blood heavy metal/metalloid concentration and the clinical outcomes were analyzed by Poisson regression analysis.ResultsOur results showed that none of the heavy metal/metalloid of male partners we investigated are significantly associated with the oocyte fertilization and good embryo (P ≥ 0.05); however, antral follicle count (AFC) was a protective factor for the oocyte fertilization (RR: 1.07, 95 % CI: 1.04–1.10). The blood Fe concentration of the male partner was positively associated (P < 0.05) with pregnancy in the first fresh cycle (RR:170.93, 95 % CI: 4.13–7082.04), cumulative pregnancy (RR: 23.61, 95 % CI: 3.25–171.64) and cumulative live birth (RR: 36.42, 95 % CI: 1.21–1092.54). In the first frozen embryo cycles, pregnancy was significantly associated (P < 0.05) with the blood Mn (RR: 0.01, 95 % CI:0.00–0.11) and Se concentration (RR: 0.01, 95 % CI:8.25 E-5–0.47) and female age (RR: 0.86, 95 % CI:0.75–0.99); live birth was significantly associated (P < 0.05) with the blood Mn concentration (RR: 0.00, 95 % CI: 1.14E-7–0.51).ConclusionsOur results suggested that the higher male blood Fe concentration was positively associated with pregnancy in the fresh embryo transfer cycle, cumulative pregnancy, and cumulative live birth, whereas the higher male blood Mn and Se concentration were associated with lower chance of pregnancy and live birth in the frozen embryo transfer cycle. However, the underline mechanism of this finding still needs further investigation.     

A Description of Mortality Associated with IPT plus ART Compared to ART Alone among HIV-Infected Individuals in Addis Ababa,Ethiopia: A Cohort Study

Background

Tuberculosis (TB) is the most common human immunodeficiency virus (HIV) associated opportunistic infection. It is the leading cause of death in HIV-infected individuals in sub-Saharan Africa. Anti-retroviral therapy (ART) and isoniazid preventive therapy (IPT) are the two useful TB preventative strategies available to reduce TB among people living with HIV (PLHIV). Therefore, the aim of this study is to compare mortality associated with IPT taken together with ART, as well as ART alone, among PLHIV.

Methods

A retrospective cohort study was undertaken at Tikur Anbessa Specialized Hospital (TASH) and Zewditu Memorial Hospital (ZMH) on 185 patients receiving IPT (6 months) plus ART and 557 patients receiving ART alone. Mortality rates (MR) per 100 person-years (PYs) were used to compare mortality rates amongst the groups. Time-to-death and survival probabilities of the patients were determined using the Kaplan Meier Method. The Cox Proportional Hazard Model was employed to estimate the effect of IPT plus ART on survival of PLHIV.

Results

The mortality cases noted in patients treated by IPT plus ART versus ART alone were 18 (4.5 cases/100 PYs) and 116 (10 cases/100 PYs), respectively. In reference to the ART alone, the IPT plus ART reduced the likelihood of death significantly (aHR 0.48; 95% CI 0.38–0.69) and median time to death was about 26 months (IQR 19–34). Moreover, WHO stage IV (aHR 2.42: 95% CI 1.42–4.11), CD4 values ≥350cells/mm3 (aHR 0.52; 95% CI 0.28–0.94), adherence to ART (aHR 0.12; 95% CI 0.08–0.20), primary levels of education (aHR 2.20; 95% CI 1.07–4.52); and alcohol consumption (aHR 1.71; 95% CI 1.04–2.81) were factors strongly associated with mortality.

Conclusion

We found that PLHIV treated by the IPT plus ART had a lower likelihood of mortality and delayed time-to-death when compared to patients treated by ART alone.