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Social contact patterns might contribute to excess burden of tuberculosis in men. We conducted a study of social contact surveys to evaluate contact patterns relevant to tuberculosis transmission. Available data describe 21 surveys in 17 countries and show profound differences in sex-based and age-based patterns of contact. Adults reported more adult contacts than children. Children preferentially mixed with women in all surveys (median sex assortativity 58%, interquartile range [IQR] 57%-59% for boys, 61% [IQR 60%-63%] for girls). Men and women reported sex-assortative mixing in 80% and 95% of surveys (median sex assortativity 56% [IQR 54%-58%] for men, 59% [IQR 57%-63%] for women). Sex-specific patterns of contact with adults were similar at home and outside the home for children; adults reported greater sex assortativity outside the home in most surveys. Sex assortativity in adult contacts likely contributes to sex disparities in adult tuberculosis burden by amplifying incidence among men. ; E.L.C. was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (WT091769). R.G.W. was supported the UK Medical Research Council and the UK Department for International Development under the Medical Research Council/Department for International Development Concordat agreement that is also part of the European and Developing Countries Clinical Trials Partnership 2 Programme supported by the European Union (MR/P002404/1); and the Bill and Melinda Gates Foundation (TB Modelling and Analysis Consortium: OPP1084276/OPP1135288, SA Modelling for Policy: OPP1110334, CORTIS: OPP1137034, Vaccines: OPP1160830) and UNITAID (4214-LSHTM-Sept15; PO 8477-0-600). ; Horton, KC (corresponding author), London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, Dept Infect Dis Epidemiol, Keppel St, London WC1E 7HT, England. katherine.horton@lshtm.ac.uk

OBJECTIVES: To mitigate the economic burden of tuberculosis (TB), it is important to fully understand the costs of TB treatment from the patient perspective. We therefore sought to quantify the patient-incurred cost of TB treatment in rural Malawi, with specific focus on costs borne by patients requiring inpatient hospitalization. METHODS: We conducted a cross-sectional survey of 197 inpatients and 156 outpatients being treated for TB in rural Malawi. We collected data on out-of-pocket costs and lost wages, including costs to guardians. Costs for inpatient TB treatment were estimated and compared to costs for outpatient TB treatment. We then explored the equity distribution of inpatient TB treatment cost using concentration curves. RESULTS: Despite free government services, inpatients were estimated to incur a mean of $137 (standard deviation: $147) per initial TB episode, corresponding to > 50% of annual household spending among patients in the lowest expenditure quintile. Non-medical hospitalization costs accounted for 88% of this total. Patients treated entirely as outpatients incurred estimated costs of $25 (standard deviation: $15) per episode. The concentration curves showed that, among individuals hospitalized for an initial TB episode, poorer patients shouldered a much greater proportion of inpatient TB treatment costs than wealthier ones (concentration index: −0.279). CONCLUSION: Patients hospitalized for TB in resource-limited rural Malawi experience devastating costs of TB treatment. Earlier diagnosis and treatment must be prioritized if we are to meet goals of effective TB control, avoidance of catastrophic costs, and provision of appropriate patient-centered care in such settings.

AbstractIntroductionHIV and tuberculosis (TB) remain leading causes of preventable death in low‐ and middle‐income countries (LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta‐analyses to estimate HIV and TB prevalence, and short‐term (two to six months) mortality, among adults with TB symptoms at community‐ and facility level.MethodsWe searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta‐analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels.ResultsSixty‐two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5% (IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short‐term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13, n = 1 study) at community level.ConclusionsAdults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom‐based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short‐term mortality are urgently needed.

IntroductionThe World Health Organization (WHO) recommends that HIV‐positive adults with CD4 count ≤500 cells/mm3initiate antiretroviral therapy (ART). In many countries of sub‐Saharan Africa, CD4 count is not widely available or consistently used and instead the WHO clinical staging system is used to determine ART eligibility. However, concerns have been raised regarding its discriminatory ability to identify patients eligible to start ART. We therefore reviewed the accuracy of WHO stage 3 or 4 assessment in identifying ART eligibility according to CD4 count thresholds for ART initiation.MethodsWe systematically searched PubMed and Global Health databases and conference abstracts using a comprehensive strategy for studies that compared the results of WHO clinical staging with CD4 count thresholds. Studies performed in sub‐Saharan Africa and published in English between 1998 and 2013 were eligible for inclusion according to our predefined study protocol. Two authors independently extracted data and assessed methodological quality and risk of bias using the Quality Assessment Tool for Diagnostic Accuracy Studies (QUADAS‐2) tool. Summary estimates of sensitivity and specificity were derived for each CD4 count threshold and hierarchical summary receiver operator characteristic curves were plotted.ResultsFifteen studies met the inclusion criteria, including 25,032 participants from 14 countries. Most studies assessed individuals attending ART clinics prior to treatment initiation. WHO clinical stage 3 or 4 disease had a sensitivity of 60% (95% CI: 45–73%,Q=914.26,p<0.001) and specificity of 73% (95% CI: 60–83%,Q=1439.43,p<0.001) for a CD4 threshold of ≤200 cells/mm3(11 studies); sensitivity and specificity for a threshold of CD4 count ≤350 cells/mm3were 45% (95% CI: 26–66%,Q=1607.31,p<0.001) and 85% (95% CI: 69–93%,Q=896.70,p<0.001), respectively (six studies). For the threshold of CD4 count ≤500 cells/mm3sensitivity was 14% (95% CI: 13–15%) and specificity was 95% (95% CI: 94–96%) (one study).ConclusionsWhen used for individual treatment decisions, WHO clinical staging misses a high proportion of individuals who are ART eligible by CD4 count, with sensitivity falling as CD4 count criteria rises. Access to accurate, accessible, robust and affordable CD4 count testing methods will be a pressing need for as long as ART initiation decisions are based on criteria other than seropositivity.

IntroductionLinkage from HIV testing and counselling (HTC) to initiation of antiretroviral therapy (ART) is suboptimal in many national programmes in sub‐Saharan Africa, leading to delayed initiation of ART and increased risk of death. Reasons for failure of linkage are poorly understood.MethodsSemi‐structured qualitative interviews were undertaken with health providers and HIV‐positive primary care patients as part of a prospective cohort study at primary health centres in Blantyre, Malawi. Patients successful and unsuccessful in linking to ART were included.ResultsProgression through the HIV care pathway was strongly influenced by socio‐cultural norms, particularly around the perceived need to regain respect lost during a period of visibly declining health. Capacity to call upon the support of networks of families, friends and employers was a key determinant of successful progression. Over‐busy clinics, non‐functioning laboratories and unsuitable tools used for ART eligibility assessment (WHO clinical staging system and centralized CD4 count measurement) were important health systems determinants of drop‐out.ConclusionsKey interventions that could rapidly improve linkage include guarantee of same‐day, same‐clinic ART eligibility assessments; utilization of the support offered by peer‐groups and community health workers; and integration of HTC and ART programmes.

AbstractBackgroundHIV and tuberculosis are frequently diagnosed concurrently. In March 2021, World Health Organization recommended that antiretroviral therapy (ART) should be started within two weeks of tuberculosis treatment start, at any CD4 count. We assessed whether earlier ART improved outcomes in people with newly diagnosed HIV and tuberculosis.MethodsWe did a systematic review by searching nine databases for trials that compared earlier ART to later ART initiation in people with HIV and tuberculosis. We included studies published from database inception to 12 March 2021. We compared ART within four weeks versus ART more than four weeks after TB treatment, and ART within two weeks versus ART between two and eight weeks, and stratified analysis by CD4 count. The main outcome was death; secondary outcomes included IRIS and AIDS‐defining events. We pooled effect estimates using random effects meta‐analysis.Results and discussionWe screened 2468 abstracts, and identified nine trials. Among people with all CD4 counts, there was no difference in mortality by earlier ART (≤4 week) versus later ART (>4 week) (risk difference [RD] 0%, 95% confidence interval [CI] −2% to +1%). Among people with CD4 count ≤50 cells/mm3, earlier ART (≤4 weeks) reduced risk of death (RD −6%, −10% to −1%). Among people with all CD4 counts earlier ART (≤4 weeks) increased the risk of IRIS (RD +6%, 95% CI +2% to +10%) and reduced the incidence of AIDS‐defining events (RD −2%, 95% CI −4% to 0%). Results were similar when trials were restricted to the four trials which permitted comparison of ART within two weeks to ART between two and eight weeks. Trials were conducted between 2004 and 2014, before recommendations to treat HIV at any CD4 count or to rapidly start ART in people without TB. No trials included children or pregnant women. No trials included integrase inhibitors in ART regimens.DiscussionEarlier ART did not alter risk of death overall among people living with HIV who had TB disease. For logistical and patient preference reasons, earlier ART initiation for everyone with TB and HIV may be preferred to later ART.

AbstractIntroductionHIV self‐testing (HIVST) is being introduced as a new way for more undiagnosed people to know their HIV status. As countries start to implement HIVST, assuring the quality and regulating in vitro diagnostics, including HIVST, are essential. We aimed to document the emerging regulatory landscape and perceptions of key stakeholders involved in HIVST policy and regulation prior to implementation in three low‐ and middle‐income countries.MethodsBetween April and August 2016, we conducted semi‐structured interviews in Malawi, Zambia and Zimbabwe to understand the relationships between different stakeholders on their perceptions of current and future HIVST regulation and the potential impact on implementation. We purposively sampled and interviewed 66 national‐level key stakeholders from the Ministry of Health and the regulatory, laboratory, logistical, donor and non‐governmental sectors. We used a thematic approach to analysis with an inductively developed common coding framework to allow inter‐country comparison of emerging themes.ResultsIn all countries, the national reference laboratory was monitoring the quality of HIVST kits entering the public sector. In Malawi, there was no legal mandate to regulate medical devices, in Zambia one regulatory body with a clear mandate had started developing regulations and in Zimbabwe the mandate to regulate was overlapping between two bodies. Stakeholders indicated that they had a poor understanding of the process and requirements for HIVST regulation, as well as lack of clarity and coordination between organizational roles. The need for good collaboration between sectors, a strong post‐market surveillance model for HIVST and technical assistance to develop regulators capacity was noted as priorities. Key informants identified technical working groups as a potential way collaboration could be improved upon to accelerate the regulation of HIVST.ConclusionRegulation of in vitro diagnostic devices, including HIVST, is now being recognized as important by regulators after a regional focus on pharmaceuticals. HIVST is providing an opportunity for each country to develop similar regulations to others in the region leading to a more coherent regulatory environment for the introduction of new devices.

INTRODUCTION: HIV self-testing (HIVST) is being introduced as a new way for more undiagnosed people to know their HIV status. As countries start to implement HIVST, assuring the quality and regulating in vitro diagnostics, including HIVST, are essential. We aimed to document the emerging regulatory landscape and perceptions of key stakeholders involved in HIVST policy and regulation prior to implementation in three low- and middle-income countries. METHODS: Between April and August 2016, we conducted semi-structured interviews in Malawi, Zambia and Zimbabwe to understand the relationships between different stakeholders on their perceptions of current and future HIVST regulation and the potential impact on implementation. We purposively sampled and interviewed 66 national-level key stakeholders from the Ministry of Health and the regulatory, laboratory, logistical, donor and non-governmental sectors. We used a thematic approach to analysis with an inductively developed common coding framework to allow inter-country comparison of emerging themes. RESULTS: In all countries, the national reference laboratory was monitoring the quality of HIVST kits entering the public sector. In Malawi, there was no legal mandate to regulate medical devices, in Zambia one regulatory body with a clear mandate had started developing regulations and in Zimbabwe the mandate to regulate was overlapping between two bodies. Stakeholders indicated that they had a poor understanding of the process and requirements for HIVST regulation, as well as lack of clarity and coordination between organizational roles. The need for good collaboration between sectors, a strong post-market surveillance model for HIVST and technical assistance to develop regulators capacity was noted as priorities. Key informants identified technical working groups as a potential way collaboration could be improved upon to accelerate the regulation of HIVST. CONCLUSION: Regulation of in vitro diagnostic devices, including HIVST, is now being recognized as important by regulators after a regional focus on pharmaceuticals. HIVST is providing an opportunity for each country to develop similar regulations to others in the region leading to a more coherent regulatory environment for the introduction of new devices.

AbstractIntroductionHIV self‐testing (HIVST) was first proposed as an additional option to standard HIV testing services in the 1980s. By 2015, two years after the first HIVST kit was approved for the American market and the year in which Unitaid invested in the "HIV Self‐Testing AfRica (STAR) Initiative," HIVST remained unexplored with negligible access in low‐ and middle‐income countries (LMIC). However, rapid progress had been made. This commentary outlines the interlinked market, regulatory and policy barriers that had inhibited product development and kept HIVST out of LMIC policy. We detail the components of STAR that enabled rapid HIVST scale‐up, including critical investments in implementation, research, market forecasting, and engagement with manufacturers and regulators.DiscussionThe STAR Initiative has generated crucial information about how to distribute HIVST products effectively, ethically and efficiently. Service delivery models range from clinic‐based distribution to workplace and partner‐delivered approaches to reach first‐time male testers, to community outreach to sex workers and general population "hotspots." These data directly informed supportive policy, notably the 2016 WHO guidelines strongly recommending HIVST as an additional testing approach, and regulatory change through support for WHO prequalification of the first HIVST kit in 2017. In July 2015, only two countries had national HIVST policies and were implementing HIVST. Three years later, 59 countries have policies, actively implemented in 28, with an additional 53 countries reporting policies under development. By end‐November 2018 several quality‐assured HIVST products had been registered, including two WHO prequalified tests. STAR Initiative countries have drafted regulations governing in vitro diagnostics, including HIVST products. With enabling policies, pre‐qualification and regulations in place, donor procurement of kits has increased rapidly, to a forecasted estimate of 16 million HIVST kits procured by 2020.ConclusionsThe STAR Initiative provided a strong foundation to introduce HIVST in LMICs and allow for rapid scale‐up based on the wealth of multi‐country evidence gathered. Together with sustained coordination and acceleration of market development work, HIVST can help address the testing gap and provide a focused and cost‐effective means to expand access to treatment and prevention services.

AbstractIntroduction: In the era of ambitious HIV targets, novel HIV testing models are required for hard‐to‐reach groups such as men, who remain underserved by existing services. Pregnancy presents a unique opportunity for partners to test for HIV, as many pregnant women will attend antenatal care (ANC). We describe the views of pregnant women and their male partners on HIV self‐test kits that are woman‐delivered, alone or with an additional intervention.Methods: A formative qualitative study to inform the design of a multi‐arm multi‐stage cluster‐randomized trial, comprised of six focus group discussions and 20 in‐depth interviews, was conducted. ANC attendees were purposively sampled on the day of initial clinic visit, while men were recruited after obtaining their contact information from their female partners. Data were analysed using content analysis, and our interpretation is hypothetical as participants were not offered self‐test kits.Results: Providing HIV self‐test kits to pregnant women to deliver to their male partners was highly acceptable to both women and men. Men preferred this approach compared with standard facility‐based testing, as self‐testing fits into their lifestyles which were characterized by extreme day‐to‐day economic pressures, including the need to raise money for food for their household daily. Men and women emphasized the need for careful communication before and after collection of the self‐test kits in order to minimize the potential for intimate partner violence although physical violence was perceived as less likely to occur. Most men stated a preference to first self‐test alone, followed by testing as a couple. Regarding interventions for optimizing linkage following self‐testing, both men and women felt that a fixed financial incentive of approximately USD$2 would increase linkage. However, there were concerns that financial incentives of greater value may lead to multiple pregnancies and lack of child spacing. In this low‐income setting, a lottery incentive was considered overly disappointing for those who receive nothing. Phone call reminders were preferred to short messaging service.Conclusions: Woman‐delivered HIV self‐testing through ANC was acceptable to pregnant women and their male partners. Feedback on additional linkage enablers will be used to alter pre‐planned trial arms.

AbstractIntroductionStrategies employing a single rapid diagnostic test (RDT) such as HIV self‐testing (HIVST) or "test for triage" (T4T) are proposed to increase HIV testing programme impact. Current guidelines recommend serial testing with two or three RDTs for HIV diagnosis, followed by retesting with the same algorithm to verify HIV‐positive status before anti‐retroviral therapy (ART) initiation. We investigated whether clients presenting to HIV testing services (HTS) following a single reactive RDT must undergo the diagnostic algorithm twice to diagnose and verify HIV‐positive status, or whether a diagnosis with the setting‐specific algorithm is adequate for ART initiation.MethodsWe calculated (1) expected number of false‐positive (FP) misclassifications per 10,000 HIV negative persons tested, (2) positive predictive value (PPV) of the overall HIV testing strategy compared to the WHO recommended PPV ≥99%, and (3) expected cost per FP misclassified person identified by additional verification testing in a typical low‐/middle‐income setting, compared to the expected lifetime ART cost of $3000. Scenarios considered were as follows: 10% prevalence using two serial RDTs for diagnosis, 1% prevalence using three serial RDTs, and calibration using programmatic data from Malawi in 2017 where the proportion of people testing HIV positive in facilities was 4%.ResultsIn the 10% HIV prevalence setting with a triage test, the expected number of FP misclassifications was 0.86 per 10,000 tested without verification testing and the PPV was 99.9%. In the 1% prevalence setting, expected FP misclassifications were 0.19 with 99.8% PPV, and in the Malawi 2017 calibrated setting the expected misclassifications were 0.08 with 99.98% PPV. The cost per FP identified by verification testing was $5879, $3770, and $24,259 respectively. Results were sensitive to assumptions about accuracy of self‐reported reactive results and whether reactive triage test results influenced biased interpretation of subsequent RDT results by the HTS provider.ConclusionsDiagnosis with the full algorithm following presentation with a reactive triage test is expected to achieve PPV above the 99% threshold. Continuing verification testing prior to ART initiation remains recommended, but HIV testing strategies involving HIVST and T4T may provide opportunities to maintain quality while increasing efficiency as part of broader restructuring of HIV testing service delivery.

BACKGROUND: A sizeable fraction of tuberculosis (TB) cases go undiagnosed. By analysing data from enhanced demographic, microbiological and geospatial surveillance of TB registrations, we aimed to identify modifiable predictors of inequitable access to diagnosis and care. METHODS: Governmental community health workers (CHW) enumerated all households in 315 catchment areas during October-December 2015. From January 2015, government TB Officers routinely implemented enhanced TB surveillance at all public and private TB treatment registration centres within Blantyre (18 clinics in total). This included collection from registering TB patients of demographic and clinical characteristics, a single sputum sample for TB microscopy and culture, and geolocation of place of residence using an electronic satellite map application. We estimated catchment area annual TB case notification rates (CNRs), stratified by microbiological status. To identify population and area-level factors predictive of CHW catchment area TB case notification rates, we constructed Bayesian spatially autocorrelated regression models with Poisson response distributions. Worldpop data were used to estimate poverty. RESULTS: In total, the 315 CHW catchment areas comprised 753,489 people (range 162 to 13,066 people/catchment area). Between 2015 and 2017, 6077 TB cases (61% male; 99% HIV tested; 67% HIV positive; 55% culture confirmed) were geolocated, with 3723 (61%) resident within a CHW catchment area. In adjusted models, greater distance to the nearest TB registration clinic was negatively correlated with TB CNRs, which halved for every 3.2-fold (95% CI 2.24-5.21) increase in distance. Poverty, which increased with distance from clinics, was negatively correlated with TB CNRs; a 23% increase (95% CI 17-34%) in the mean percentage of the population living on less than US$2 per day corresponded to a halving of the TB case notification rates. CONCLUSIONS: Using enhanced surveillance of TB cases in Blantyre, we show an ecological relationship consistent with an 'inverse care law' whereby poorer neighbourhoods and those furthest from TB clinics have lower relative CNRs. If confirmed as low case detection, then pro-poor strategies to facilitate equitable access to TB diagnosis and treatment are required.