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The lifetime risk of tuberculosis (TB) for infected contacts is often mentioned to be 5-10%, but these estimates are based on studies conducted decades ago, and thus may not reflect current epidemiologic conditions. To estimate the risk of TB among contacts with evidence of infection and to compare this with estimates often stated in the literature. A retrospective cohort study was performed using records on contacts of pulmonary TB patients at the Public Health Service Amsterdam, 2002-2011. The Public Health Service Amsterdam TB electronic registration system identified TB cases during follow-up until October 2012; these were defined as coprevalent if diagnosed less than or equal to 180 days and incident if diagnosed greater than 180 days after TB diagnosis of index patient. Cumulative TB risk was estimated with Kaplan-Meier curves. Of 9,332 contacts of pulmonary TB patients, 4,774 were screened for latent TB infection (LTBI) of whom 739 (16%) had evidence of infection. Among these the 5-year Kaplan-Meier TB cumulative risk was 9.5% (95% confidence interval, 7.5-11.9). This varied by age: 33.3% of 36 contacts aged less than 5 years, 19.1% of 84 contacts aged 5-14 years, and 6.7% of 619 contacts aged greater than or equal to 15 years (log rank, P < 0.001). Of 739 contacts with evidence of infection, 57 had coprevalent TB and 14 developed incident TB. Of patients without coprevalent TB but with LTBI diagnosis, 45% received preventive therapy. Five-year risk of incident TB was 2.4% (95% confidence interval, 1.2-4.7) among contacts with LTBI who did not start preventive therapy. Five-year risk of TB among contacts with evidence of infection was higher compared with older estimates, and differed considerably by age. Incidence of TB among contacts with LTBI was low, suggesting limited impact may be expected of expanding preventive therapy.

Diagnosing HIV and/or TB is not sufficient; linkage to care and treatment is conditional to reduce the burden of disease. This study aimed to determine factors associated with linkage to HIV care and TB treatment at community-based services in Cape Town, South Africa. This retrospective cohort study utilized routinely collected data from clients who utilized stand-alone (fixed site not attached to a health facility) and mobile HIV testing services in eight communities in the City of Cape Town Metropolitan district, between January 2008 and June 2012. Clients were included in the analysis if they were ≥12 years and had a known HIV status. Generalized estimating equations (GEE) logistic regression models were used to assess the association between determinants (sex, age, HIV testing service and co-infection status) and self-reported linkage to HIV care and/or TB treatment. Linkage to HIV care was 3 738/5 929 (63.1%). Linkage to HIV care was associated with the type of HIV testing service. Clients diagnosed with HIV at mobile services had a significantly reduced odds of linking to HIV care (aOR 0.7 (CI 95%: 0.6-0.8), p<0.001. Linkage to TB treatment was 210/275 (76.4%). Linkage to TB treatment was not associated with sex and service type, but was associated with age. Clients in older age groups were less likely to link to TB treatment compared to clients in the age group 12-24 years (all, p-value<0.05). A large proportion of clients diagnosed with HIV at mobile services did not link to care. Almost a quarter of clients diagnosed with TB did not link to treatment. Integrated community-based HIV and TB testing services are efficient in diagnosing HIV and TB, but strategies to improve linkage to care are required to control these epidemics.

In 2014, the Joint United Nations Programme on HIV/AIDS (UNAIDS) set the 90-90-90 targets: that 90% of people living with HIV know their HIV status, that 90% of those who know their HIV-positive status are on antiretroviral therapy (ART), and that 90% of those on treatment are virally suppressed. The aim was to reach these targets by 2020. We assessed the feasibility of achieving the first two targets, and the corresponding 81% ART coverage target, as part of the HIV Prevention Trials Network (HPTN) 071 Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART) community-randomized trial. The study population was individuals aged ≥15 years living in 14 urban and peri-urban \"PopART intervention\" communities in Zambia and South Africa (SA), with a total population of approximately 600,000 and approximately 15% adult HIV prevalence. Community HIV care providers (CHiPs) delivered the PopART intervention during 2014-2017. This was a combination HIV prevention package including universal home-based HIV testing, referral of HIV-positive individuals to government HIV clinic services that offered universal ART (Arm A) or ART according to national guidelines (Arm B), and revisits to HIV-positive individuals to support linkage to HIV care and retention on ART. The intervention was delivered in 3 \"rounds,\" each about 15 months long, during which CHiPs visited all households and aimed to contact all individuals aged ≥15 years at least once. In Arm A in Round 3 (R3), 67% (41,332/61,402) of men and 86% (56,345/65,896) of women in Zambia and 56% (17,813/32,095) of men and 71% (24,461/34,514) of women in SA participated in the intervention, among 193,907 residents aged ≥15 years. Following participation, HIV status was known by 90% of men and women in Zambia and by 78% of men and 85% of women in SA. The median time from CHiP referral of HIV-positive individuals to ART initiation was approximately 3 months. By the end of R3, an estimated 95% of HIV-positive women and 85% of HIV-positive men knew their HIV status, and among these individuals, approximately 90% of women and approximately 85% of men were on ART. ART coverage among all HIV-positive individuals was approximately 85% in women and approximately 75% in men, up from about 45% at the start of the study. ART coverage was lowest among men aged 18 to 34 and women aged 15 to 24 years, and among mobile individuals/in-migrants. Findings from Arm B were similar. The main limitations to our study were that estimates of testing and treatment coverage among men relied on considerable extrapolation because, in each round, approximately one-third of men did not participate in the PopART intervention; that our findings are for a service delivery model that was relatively intensive; and that we did not have comparable data from the 7 \"standard-of-care\" (Arm C) communities. Our study showed that very high HIV testing and treatment coverage can be achieved through persistent delivery of universal testing, facilitated linkage to HIV care, and universal treatment services. The ART coverage target of 81% was achieved overall, after 4 years of delivery of the PopART intervention, though important gaps remained among men and young people. Our findings are consistent with previously reported findings from southern and east Africa, extending their generalisability to urban settings with high rates of in-migration and mobility and to Zambia and SA. ClinicalTrials.gov NCT01900977.

Background Mobile HIV testing services (HTS) are effective at reaching undiagnosed people living with HIV. However, linkage to HIV care from mobile HTS is often poor, ranging from 10 to 60%. Point-of-care (POC) CD4 testing has shown to increase retention in health facilities, but little evidence exists about their use in mobile HTS. This study assessed the feasibility of POC CD4 test implementation and investigated linkage to HIV care among clients accepting a POC test at community-based mobile HTS. Methods This retrospective study used routinely collected data from clients who utilized community-based mobile HTS in the City of Cape Town Metropolitan district, South Africa between December 2014 and September 2016. A POC CD4 test was offered to all clients with an HIV positive diagnosis during this period, and a CD4 cell count was provided to clients accepting a POC CD4 test. Random effects logistic regression was used to assess factors associated with POC CD4 test uptake and self-reported linkage to care among clients accepting a POC test. Models were adjusted for sex, age, previous HIV test done, tuberculosis status and year of HIV diagnosis. Results One thousand three hundred twenty-five of Thirty-nine thousand seven hundred ninety clients utilizing mobile HTS tested HIV positive (3%). 51% (679/1325) accepted a POC test. The age group with the highest proportion accepting a POC test was 50+ years (60%). Females were less likely to accept a POC test than males (odds ratio = 0.7, 95%CI = 0.6–0.8). Median CD4 count was 429 cells/μl (interquartile range = 290–584). Among 679 clients who accepted a POC CD4 test, 491 (72%) linked to HIV care. CD4 cell count was not associated with linkage to care. Conclusion Our findings suggest that mobile HTS can identify early HIV infection, and show that a high proportion of clients with a POC test result linked to care. Future research should assess factors associated with POC test acceptance and assess the impact of POC CD4 testing in comparison to alternative strategies to engage HIV positive people in care.

Background Tuberculosis (TB)-associated mortality in South Africa remains high. This review aimed to systematically assess risk factors associated with death during TB treatment in South African patients. Methods We conducted a systematic review of TB research articles published between 2010 and 2018. We searched BioMed Central (BMC), PubMed®, EBSCOhost, Cochrane, and SCOPUS for publications between January 2010 and December 2018. Searches were conducted between August 2019 and October 2019. We included randomised control trials (RCTs), case control, cross sectional, retrospective, and prospective cohort studies where TB mortality was a primary endpoint and effect measure estimates were provided for risk factors for TB mortality during TB treatment. Due to heterogeneity in effect measures and risk factors evaluated, a formal meta-analysis of risk factors for TB mortality was not appropriate. A random effects meta-analysis was used to estimate case fatality ratios (CFRs) for all studies and for specific subgroups so that these could be compared. Quality assessments were performed using the Newcastle-Ottawa scale or the Cochrane Risk of Bias Tool. Results We identified 1995 titles for screening, 24 publications met our inclusion criteria (one cross-sectional study, 2 RCTs, and 21 cohort studies). Twenty-two studies reported on adults ( n  = 12561) and two were restricted to children < 15 years of age ( n  = 696). The CFR estimated for all studies was 26.4% (CI 18.1–34.7, n  = 13257 ); 37.5% (CI 24.8-50.3, n  = 5149) for drug-resistant (DR) TB; 12.5% (CI 1.1–23.9, n  = 1935) for drug-susceptible (DS) TB; 15.6% (CI 8.1–23.2, n  = 6173) for studies in which drug susceptibility was mixed or not specified; 21.3% (CI 15.3-27.3, n  = 7375) for people living with HIV/AIDS (PLHIV); 19.2% (CI 7.7–30.7, n  = 1691) in HIV-negative TB patients; and 6.8% (CI 4.9–8.7, n  = 696) in paediatric studies. The main risk factors associated with TB mortality were HIV infection, prior TB treatment, DR-TB, and lower body weight at TB diagnosis. Conclusions In South Africa, overall mortality during TB treatment remains high, people with DR-TB have an elevated risk of mortality during TB treatment and interventions to mitigate high mortality are needed. In addition, better prospective data on TB mortality are needed, especially amongst vulnerable sub-populations including young children, adolescents, pregnant women, and people with co-morbidities other than HIV. Limitations included a lack of prospective studies and RCTs and a high degree of heterogeneity in risk factors and comparator variables. Systematic review registration The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018108622. This study was funded by the Bill and Melinda Gates Foundation (Investment ID OPP1173131) via the South African TB Think Tank.

Introduction In 2021, there were 38.4 million people living with HIV (PLHIV) globally, of which 20.6 million (54%) were living in Eastern and Southern Africa. Longitudinal studies, inclusive of community randomized trials (CRTs), provide critical evidence to guide a broad range of health care interventions including HIV prevention. In this study, we have used an individual-level cohort study design to evaluate the association between sex and other baseline characteristics and participant retention in the HPTN 071 (PopART) trial in Zambia and South Africa. Methods HPTN 071 (PopART) was a community randomized trial (CRT) conducted from 2013 to 2018, in 21 communities. The primary outcome was measured in a randomly selected population cohort (PC), followed up over 3 to 4 years at annual rounds. PC retention was defined as completion of an annual follow-up questionnaire. Baseline characteristics were described by study arm and Poisson regression analyses used to measure the association between baseline factors and retention. In addition, we present a description of researcher-documented reasons for study withdrawal by PC participants. Results Of the 38,474 participants enrolled during the first round of the trial (PC0), most were women (27,139, 71%) and 73% completed at least one follow-up visit. Retention was lower in men (adj RR: 0.90; 95% CI: 0.88, 0.91) and higher among older participants (adj RR: 1.23; 95% CI 1.20, 1.26) when comparing ages 35–44 to 18–24 years. Retention was higher among individuals with high socioeconomic status (SES) (adj RR 1.16; 95% CI 1.14, 1.19) and medium SES (adj RR 1.12; 95% CI 1.09, 1.14) compared to low SES. The most common reasons for study withdrawal were study refusal (23%) and relocation outside the CRT catchment area (66%). Conclusion Despite challenges, satisfactory retention outcomes were achieved in PopART with limited variability across study arms. In keeping with other studies, younger age, male sex, and lower SES were associated with lower levels of retention. Relocation outside of catchment area was the most common reason for non-retention in this CRT.

Background A more stringent QuantiFERON-TB Gold In-Tube (QFT) conversion (from negative to positive) definition has been proposed to allow more definite detection of recent tuberculosis (TB) infection. We explored alternative conversion definitions to assist the interpretation of serial QFT results and estimate incidence of TB infection in a large cohort study. Methods We used QFT serial results from TB household contacts aged ≥15 years, collected at baseline and during two follow-up visits (2006–2011) as part of a cohort study in 24 communities in Zambia and South Africa (SA). Conversion rates using the manufacturers’ definition (interferon-gamma (IFN-g) < 0.35 to ≥0.35, ‘def1’) were compared with stricter definitions (IFN-g < 0.2 to ≥0.7 IU/ml, ‘def2’; IFN-g < 0.2 to ≥1.05 IU/ml, ‘def3’; IFN-g < 0.2 to ≥1.4 IU/ml, ‘def4’). Poisson regression was used for analysis. Results One thousand three hundred sixty-five individuals in Zambia and 822 in SA had QFT results available. Among HIV-negative individuals, the QFT conversion rate was 27.4 per 100 person-years (CI:22.9–32.6) using def1, 19.0 using def2 (CI:15.2–23.7), 14.7 using def3 (CI:11.5–18.8), and 12.0 using def4 (CI:9.2–15.7). Relative differences across def1-def4 were similar in Zambia and SA. Using def1, conversion was less likely if HIV positive not on antiretroviral treatment compared to HIV negative (aRR = 0.7, 95%CI = 0.4–0.9), in analysis including both countries. The same direction of associations were found using def 2–4. Conclusion High conversion rates were found even with the strictest definition, indicating high incidence of TB infection among household contacts of TB patients in these communities. The trade-off between sensitivity and specificity using different thresholds of QFT conversion remains unknown due to the absence of a reference standard. However, we identified boundaries within which an appropriate definition might fall, and our strictest definition plausibly has high specificity.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosis infection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95% confidence interval (CI), 8.0–29.2%) among child contacts, 4.8% (95% CI, 3.0–7.7%) among adult contacts, 5.0% (95% CI, 1.6–14.5%) among migrants and 4.8% (95% CI, 1.5–14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal–external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82–0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide. The risk of developing active tuberculosis (TB) in individuals with latent TB infection is highly variable within and among different risk groups. A personalized risk predictor was developed to better target preventative treatment to individuals at greatest risk, supporting evidence-based clinical decision-making for latent TB.

Background Despite vaccination programs and available treatments, seasonal influenza carries a large mortality burden, especially in intensive care unit (ICU) settings. Understanding the influenza mortality burden in ICU settings can inform treatment planning and resource allocation. Nonetheless, surveillance data on mortality in ICU‐admitted patients are scarce and estimates vary greatly. This systematic literature review (SLR) and meta‐analysis investigated all‐cause mortality risk among ICU‐admitted patients with influenza in Europe. Methods We included observational studies conducted in Europe that reported mortality among patients ≥ 6 months of age with influenza admitted to the ICU. Studies published between January‐2009 and December‐2019 were included. Quality was assessed using a modified Newcastle‐Ottawa scale. Pooled all‐cause mortality risk was calculated as a proportion using a random‐effects model with an inverse variance method. A sensitivity analysis was also conducted, including only studies identified as having low risk of bias. Results Thirty‐seven studies, reporting on 13,616 patients, were included. All‐cause mortality ranged from 0% to 67%. The overall pooled mortality risk estimate was 0.24 (95% CI: 0.20, 0.27). Study heterogeneity was high (Cochran's Q test p < 0.01, I2 = 93%). The sensitivity analysis using only studies identified as having low risk of bias produced a pooled mortality risk of 0.25 (95%CI: 0.21, 0.29). Conclusions These results indicate that approximately a quarter of patients with influenza admitted to the ICU die, reinforcing the need for effective vaccination programs and treatment optimization.