Tuberculosis in HIV programmes in lower-income countries: practices and risk factors

BACKGROUND: Tuberculosis (TB) is a common diagnosis in human immunodeficiency virus (HIV) infected patients on antiretroviral treatment (ART). OBJECTIVE: To describe TB-related practices in ART programmes in lower-income countries and identify risk factors for TB in the first year of ART. METHODS: Programme characteristics were assessed using standardised electronic questionnaire. Patient data from 2003 to 2008 were analysed and incidence rate ratios (IRRs) calculated using Poisson regression models. RESULTS: Fifteen ART programmes in 12 countries in Africa, South America and Asia were included. Chest X-ray, sputum microscopy and culture were available free of charge in respectively 13 (86.7%), 14 (93.3%) and eight (53.3%) programmes. Eight sites (53.3%) used directly observed treatment and five (33.3%) routinely administered isoniazid preventive treatment (IPT). A total of 19 413 patients aged ≥16 years contributed 13 227 person-years of follow-up; 1081 new TB events were diagnosed. Risk factors included CD4 cell count (>350 cells/μl vs. <25 cells/μl, adjusted IRR 0.46, 95%CI 0.33–0.64, P < 0.0001), sex (women vs. men, adjusted IRR 0.77, 95%CI 0.68–0.88, P = 0.0001) and use of IPT (IRR 0.24, 95%CI 0.19–0.31, P < 0.0001). CONCLUSIONS: Diagnostic capacity and practices vary widely across ART programmes. IPT prevented TB, but was used in few programmes. More efforts are needed to reduce the burden of TB in HIV co-infected patients in lower income countries.

Correcting mortality for loss to follow-up: a nomogram applied to antiretroviral treatment programmes in sub-Saharan Africa

Background The World Health Organization estimates that in sub-Saharan Africa about 4 million HIV-infected patients had started antiretroviral therapy (ART) by the end of 2008. Loss of patients to follow-up and care is an important problem for treatment programmes in this region. As mortality is high in these patients compared to patients remaining in care, ART programmes with high rates of loss to follow-up may substantially underestimate mortality of all patients starting ART. Methods and Findings We developed a nomogram to correct mortality estimates for loss to follow-up, based on the fact that mortality of all patients starting ART in a treatment programme is a weighted average of mortality among patients lost to follow-up and patients remaining in care. The nomogram gives a correction factor based on the percentage of patients lost to follow-up at a given point in time, and the estimated ratio of mortality between patients lost and not lost to follow-up. The mortality observed among patients retained in care is then multiplied by the correction factor to obtain an estimate of programme-level mortality that takes all deaths into account. A web calculator directly calculates the corrected, programme-level mortality with 95% confidence intervals (CIs). We applied the method to 11 ART programmes in sub-Saharan Africa. Patients retained in care had a mortality at 1 year of 1.4% to 12.0%; loss to follow-up ranged from 2.8% to 28.7%; and the correction factor from 1.2 to 8.0. The absolute difference between uncorrected and corrected mortality at 1 year ranged from 1.6% to 9.8%, and was above 5% in four programmes. The largest difference in mortality was in a programme with 28.7% of patients lost to follow-up at 1 year. Conclusions The amount of bias in mortality estimates can be large in ART programmes with substantial loss to follow-up. Programmes should routinely report mortality among patients retained in care and the proportion of patients lost. A simple nomogram can then be used to estimate mortality among all patients who started ART, for a range of plausible mortality rates among patients lost to follow-up.

Estimating loss to follow-up in HIV-infected patients on antiretroviral therapy: the effect of the competing risk of death in Zambia and Switzerland

Background Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. Methods and Findings HIV-infected patients aged ≥18 years who started ART 2004–2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. Conclusions In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings.

How to counter the problem of R1 resection in duodenopancreatectomy for pancreatic cancer?

Although duodenopancreatectomy has been standardized for many years, the pathological examination of the specimen was re-described in the last years. In methodical pathological studies up to 85% had an R1 margin.1,2 These mainly involved the posterior und medial resection margin.3 As a consequence we need to optimize and standardize the pathological workup of the specimen and to extend the surgical resection, where possible without risk for the patient.

[Prevalence of heart murmurs, aortic and pulmonic stenosis in boxers presented for pre-breeding exams in Switzerland]

Boxer are predisposed to subaortic (SAS) and pulmonic stenosis (PS). To decrease the prevalence, pre-breeding cardiologic exams were performed in the last years. In our study the results of 309 pre-breeding exams of boxers presented between 1999 and 2008 were evaluated retrospectively. The overall prevalence of heart murmurs was 26.5 %. A SAS was diagnosed in 25 (8.1 %) and a PS in 10 (3.3 %) dogs. A combination of both defects was found in 7 (2.3 %) Boxers. Animals with a heart murmur of at least grade 3/6 had a significantly higher peak aortic flow velocity (VmaxAo) than animals without or only soft heart murmurs. Over the study period both the frequency of heart murmurs and diagnosis of SAS and PS decreased.

Correlates of self-reported nonadherence to antiretroviral therapy in HIV-infected patients: the Swiss HIV Cohort Study

BACKGROUND: Adherence is one of the most crucial issues in the clinical management of HIV-infected patients receiving antiretroviral therapy (ART). METHODS: A 2-item adherence questionnaire was introduced into the Swiss HIV Cohort Study in July 2003. All 3607 eligible patients were on ART for > or =6 months and their current regimen for > or =1 month. Three definitions of nonadherence were considered: missing > or =1 dose, missing > or =2 doses, and taking <95% of doses in the past 4 weeks. RESULTS: Over 30% of patients reported missing > or =1 dose, 14.9% missed > or =2 doses, and 7.1% took <95% of doses in the previous 4 weeks. The rate of drug holidays was 5.8%. Whether using more or less conservative definitions of nonadherence, younger age, living alone, number of previous regimens, and boosted protease inhibitor regimens were independent factors associated with nonadherence. There was a significant association between optimal viral suppression and nonadherence as well as a significant linear trend in optimal viral suppression by missed doses. CONCLUSIONS: Younger age, lack of social support, and complexity of therapy are important factors that are related to nonadherence with ART. Investment in behavioral dimensions of HIV is crucial to improve adherence in ART recipients.

Phosphatidylethanolamine in Trypanosoma brucei is organized in two separate pools and is synthesized exclusively by the Kennedy pathway

Phosphatidylethanolamine is a major phospholipid class of all eukaryotic cells. It can be synthesized via the CDP-ethanolamine branch of the Kennedy pathway, by decarboxylation of phosphatidylserine, or by base exchange with phosphatidylserine. The contributions of these pathways to total phosphatidylethanolamine synthesis have remained unclear. Although Trypanosoma brucei, the causative agent of human and animal trypanosomiasis, has served as a model organism to elucidate the entire reaction sequence for glycosylphosphatidylinositol biosynthesis, the pathways for the synthesis of the major phospholipid classes have received little attention. We now show that disruption of the CDP-ethanolamine branch of the Kennedy pathway using RNA interference results in dramatic changes in phosphatidylethanolamine, phosphatidylserine, and phosphatidylcholine. By targeting individual enzymes of the pathway, we demonstrate that de novo phosphatidylethanolamine synthesis in T. brucei procyclic forms is strictly dependent on the CDP-ethanolamine route. Interestingly, the last step in the Kennedy pathway can be mediated by two separate activities leading to two distinct pools of phosphatidylethanolamine, consisting of predominantly alk-1-enyl-acyl- or diacyl-type molecular species. In addition, we show that phosphatidylserine in T. brucei procyclic forms is synthesized exclusively by base exchange with phosphatidylethanolamine.

Electronic medical record systems, data quality and loss to follow-up: survey of antiretroviral therapy programmes in resource-limited settings

OBJECTIVE: To describe the electronic medical databases used in antiretroviral therapy (ART) programmes in lower-income countries and assess the measures such programmes employ to maintain and improve data quality and reduce the loss of patients to follow-up. METHODS: In 15 countries of Africa, South America and Asia, a survey was conducted from December 2006 to February 2007 on the use of electronic medical record systems in ART programmes. Patients enrolled in the sites at the time of the survey but not seen during the previous 12 months were considered lost to follow-up. The quality of the data was assessed by computing the percentage of missing key variables (age, sex, clinical stage of HIV infection, CD4+ lymphocyte count and year of ART initiation). Associations between site characteristics (such as number of staff members dedicated to data management), measures to reduce loss to follow-up (such as the presence of staff dedicated to tracing patients) and data quality and loss to follow-up were analysed using multivariate logit models. FINDINGS: Twenty-one sites that together provided ART to 50 060 patients were included (median number of patients per site: 1000; interquartile range, IQR: 72-19 320). Eighteen sites (86%) used an electronic database for medical record-keeping; 15 (83%) such sites relied on software intended for personal or small business use. The median percentage of missing data for key variables per site was 10.9% (IQR: 2.0-18.9%) and declined with training in data management (odds ratio, OR: 0.58; 95% confidence interval, CI: 0.37-0.90) and weekly hours spent by a clerk on the database per 100 patients on ART (OR: 0.95; 95% CI: 0.90-0.99). About 10 weekly hours per 100 patients on ART were required to reduce missing data for key variables to below 10%. The median percentage of patients lost to follow-up 1 year after starting ART was 8.5% (IQR: 4.2-19.7%). Strategies to reduce loss to follow-up included outreach teams, community-based organizations and checking death registry data. Implementation of all three strategies substantially reduced losses to follow-up (OR: 0.17; 95% CI: 0.15-0.20). CONCLUSION: The quality of the data collected and the retention of patients in ART treatment programmes are unsatisfactory for many sites involved in the scale-up of ART in resource-limited settings, mainly because of insufficient staff trained to manage data and trace patients lost to follow-up.

Gender and the use of antiretroviral treatment in resource-constrained settings: findings from a multicenter collaboration

AIMS: To compare the gender distribution of HIV-infected adults receiving highly active antiretroviral treatment (HAART) in resource-constrained settings with estimates of the gender distribution of HIV infection; to describe the clinical characteristics of women and men receiving HAART. METHODS: The Antiretroviral Therapy in Lower-Income Countries, ART-LINC Collaboration is a network of clinics providing HAART in Africa, Latin America, and Asia. We compared UNAIDS data on the gender distribution of HIV infection with the proportions of women and men receiving HAART in the ART-LINC Collaboration. RESULTS: Twenty-nine centers in 13 countries participated. Among 33,164 individuals, 19,989 (60.3%) were women. Proportions of women receiving HAART in ART-LINC centers were similar to, or higher than, UNAIDS estimates of the proportions of HIV-infected women in all but two centers. There were fewer women receiving HAART than expected from UNAIDS data in one center in Uganda and one center in India. Taking into account heterogeneity across cohorts, women were younger than men, less likely to have advanced HIV infection, and more likely to be anemic at HAART initiation. CONCLUSIONS: Women in resource-constrained settings are not necessarily disadvantaged in their access to HAART. More attention needs to be paid to ensuring that HIV-infected men are seeking care and starting HAART.

Mortality of patients lost to follow-up in antiretroviral treatment programmes in resource-limited settings: systematic review and meta-analysis

BACKGROUND: The retention of patients in antiretroviral therapy (ART) programmes is an important issue in resource-limited settings. Loss to follow up can be substantial, but it is unclear what the outcomes are in patients who are lost to programmes. METHODS AND FINDINGS: We searched the PubMed, EMBASE, Latin American and Caribbean Health Sciences Literature (LILACS), Indian Medlars Centre (IndMed) and African Index Medicus (AIM) databases and the abstracts of three conferences for studies that traced patients lost to follow up to ascertain their vital status. Main outcomes were the proportion of patients traced, the proportion found to be alive and the proportion that had died. Where available, we also examined the reasons why some patients could not be traced, why patients found to be alive did not return to the clinic, and the causes of death. We combined mortality data from several studies using random-effects meta-analysis. Seventeen studies were eligible. All were from sub-Saharan Africa, except one study from India, and none were conducted in children. A total of 6420 patients (range 44 to 1343 patients) were included. Patients were traced using telephone calls, home visits and through social networks. Overall the vital status of 4021 patients could be ascertained (63%, range across studies: 45% to 86%); 1602 patients had died. The combined mortality was 40% (95% confidence interval 33%-48%), with substantial heterogeneity between studies (P<0.0001). Mortality in African programmes ranged from 12% to 87% of patients lost to follow-up. Mortality was inversely associated with the rate of loss to follow up in the programme: it declined from around 60% to 20% as the percentage of patients lost to the programme increased from 5% to 50%. Among patients not found, telephone numbers and addresses were frequently incorrect or missing. Common reasons for not returning to the clinic were transfer to another programme, financial problems and improving or deteriorating health. Causes of death were available for 47 deaths: 29 (62%) died of an AIDS defining illness. CONCLUSIONS: In ART programmes in resource-limited settings a substantial minority of adults lost to follow up cannot be traced, and among those traced 20% to 60% had died. Our findings have implications both for patient care and the monitoring and evaluation of programmes.

Switching to second-line antiretroviral therapy in resource-limited settings: comparison of programmes with and without viral load monitoring

BACKGROUND: In high-income countries, viral load is routinely measured to detect failure of antiretroviral therapy (ART) and guide switching to second-line ART. Viral load monitoring is not generally available in resource-limited settings. We examined switching from nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line regimens to protease inhibitor-based regimens in Africa, South America and Asia. DESIGN AND METHODS: Multicohort study of 17 ART programmes. All sites monitored CD4 cell count and had access to second-line ART and 10 sites monitored viral load. We compared times to switching, CD4 cell counts at switching and obtained adjusted hazard ratios for switching (aHRs) with 95% confidence intervals (CIs) from random-effects Weibull models. RESULTS: A total of 20 113 patients, including 6369 (31.7%) patients from 10 programmes with access to viral load monitoring, were analysed; 576 patients (2.9%) switched. Low CD4 cell counts at ART initiation were associated with switching in all programmes. Median time to switching was 16.3 months [interquartile range (IQR) 10.1-26.6] in programmes with viral load monitoring and 21.8 months (IQR 14.0-21.8) in programmes without viral load monitoring (P < 0.001). Median CD4 cell counts at switching were 161 cells/microl (IQR 77-265) in programmes with viral load monitoring and 102 cells/microl (44-181) in programmes without viral load monitoring (P < 0.001). Switching was more common in programmes with viral load monitoring during months 7-18 after starting ART (aHR 1.38; 95% CI 0.97-1.98), similar during months 19-30 (aHR 0.97; 95% CI 0.58-1.60) and less common during months 31-42 (aHR 0.29; 95% CI 0.11-0.79). CONCLUSION: In resource-limited settings, switching to second-line regimens tends to occur earlier and at higher CD4 cell counts in ART programmes with viral load monitoring compared with programmes without viral load monitoring.

Spanish Supreme Court Rules in Favour of Google Search Engine... and a Flexible Reading of Copyright Statutes?

On 3 April 2012, the Spanish Supreme Court issued a major ruling in favour of the Google search engine, including its ‘cache copy’ service: Sentencia n.172/2012, of 3 April 2012, Supreme Court, Civil Chamber.* The importance of this ruling lies not so much in the circumstances of the case (the Supreme Court was clearly disgusted by the claimant’s ‘maximalist’ petitum to shut down the whole operation of the search engine), but rather on the court going beyond the text of the Copyright Act into the general principles of the law and case law, and especially on the reading of the three-step test (in Art. 40bis TRLPI) in a positive sense so as to include all these principles. After accepting that none of the limitations listed in the Spanish Copyright statute (TRLPI) exempted the unauthorized use of fragments of the contents of a personal website through the Google search engine and cache copy service, the Supreme Court concluded against infringement, based on the grounds that the three-step test (in Art. 40bis TRLPI) is to be read not only in a negative manner but also in a positive sense so as to take into account that intellectual property – as any other kind of property – is limited in nature and must endure any ius usus inocui (harmless uses by third parties) and must abide to the general principles of the law, such as good faith and prohibition of an abusive exercise of rights (Art. 7 Spanish Civil Code).The ruling is a major success in favour of a flexible interpretation and application of the copyright statutes, especially in the scenarios raised by new technologies and market agents, and in favour of using the three-step test as a key tool to allow for it.

The EU’s Trouble with Mashups: From Disabling to Enabling a Digital Art Form

New tools for editing of digital images, music and films have opened up new possibilities to enable wider circles of society to engage in ’artistic’ activities of different qualities. User-generated content has produced a plethora of new forms of artistic expression. One type of user-generated content is the mashup. Mashups are compositions that combine existing works (often) protected by copyright and transform them into new original creations. The European legislative framework has not yet reacted to the copyright problems provoked by mashups. Neither under the US fair use doctrine, nor under the strict corset of limitations and exceptions in Art 5 (2)-(3) of the Copyright Directive (2001/29/EC) have mashups found room to develop in a safe legal environment. The contribution analyzes the current European legal framework and identifies its insufficiencies with regard to enabling a legal mashup culture. By comparison with the US fair use approach, in particular the parody defense, a recent CJEU judgment serves as a comparative example. Finally, an attempt is made to suggest solutions for the European legislator, based on the policy proposals of the EU Commission’s “Digital Agenda” and more recent policy documents (e.g. “On Content in the Digital Market”, “Licenses for Europe”). In this context, a distinction is made between non-commercial mashup artists and the emerging commercial mashup scene.

Tuberculosis in antiretroviral treatment programs in lower income countries: availability and use of diagnostics and screening

OBJECTIVES In resource-constrained settings, tuberculosis (TB) is a common opportunistic infection and cause of death in HIV-infected persons. TB may be present at the start of antiretroviral therapy (ART), but it is often under-diagnosed. We describe approaches to TB diagnosis and screening of TB in ART programs in low- and middle-income countries. METHODS AND FINDINGS We surveyed ART programs treating HIV-infected adults in sub-Saharan Africa, Asia and Latin America in 2012 using online questionnaires to collect program-level and patient-level data. Forty-seven sites from 26 countries participated. Patient-level data were collected on 987 adult TB patients from 40 sites (median age 34.7 years; 54% female). Sputum smear microscopy and chest radiograph were available in 47 (100%) sites, TB culture in 44 (94%), and Xpert MTB/RIF in 23 (49%). Xpert MTB/RIF was rarely available in Central Africa and South America. In sites with access to these diagnostics, microscopy was used in 745 (76%) patients diagnosed with TB, culture in 220 (24%), and chest X-ray in 688 (70%) patients. When free of charge culture was done in 27% of patients, compared to 21% when there was a fee (p = 0.033). Corresponding percentages for Xpert MTB/RIF were 26% and 15% of patients (p = 0.001). Screening practices for active disease before starting ART included symptom screening (46 sites, 98%), chest X-ray (38, 81%), sputum microscopy (37, 79%), culture (16, 34%), and Xpert MTB/RIF (5, 11%). CONCLUSIONS Mycobacterial culture was infrequently used despite its availability at most sites, while Xpert MTB/RIF was not generally available. Use of available diagnostics was higher when offered free of charge.

Patientensicherheit in der Hausarztpraxis

Einleitung Aus der Schweizer Grundversorgung lagen bisher noch keine systematischen Daten zu kritischen Ereignissen und zum Sicherheitsklima vor. Aus diesem Grund wurde eine Befragung von Ärzten und Medizinischen Praxisassistentinnen (MPA) in Deutschschweizer Hausarztpraxen sowie ein Folgeprojekt spezifisch zur Telefon-Triage durchgeführt. Methoden Mit Hilfe eines standardisierten Fragebogens wurden Fachpersonen in Hausarztpraxen zu Sicherheitsrisiken und zum Sicherheitsklima in ihren Praxen befragt. Der Fragebogen enthielt neben Fragen zum Sicherheitsklima Beschreibungen von 23 kritischen Ereignissen in Hausarztpraxen, die bezüglich Häufigkeit des Auftretens in der Praxis in den vergangenen zwölf Monaten sowie der Schadensfolge beurteilt wurden, als das Ereignis zum letzten Mal in der Praxis aufgetreten ist. Zudem beantworteten Ärzte und MPA eine offene Frage, nach den für sie besonders relevanten Risiken für die Patientensicherheit in ihren Praxen. Im Folgeprojekt wurden Interviews und Gruppendiskussionen mit MPA und Ärzten geführt, um eine Prozessanalyse der Telefon-Triage durchzuführen und ein Hilfsmittel für Hausarztpraxen zur Stärkung einer sicheren Telefon-Triage zu entwickeln. Ergebnisse 630 Ärzte und MPA (50,2% Ärzte, 49,8% MPA) haben an der Studie teilgenommen. 30% der Ärzte und 17% der MPA gaben an, mindestens einen der untersuchten Ereignisse täglich oder wöchentlich in ihrer Praxis zu beobachten. Fehler bei der Dokumentation wurden am häufigsten beobachtet. Ereignisse, die sich aufgrund der Schadensfolge als besonders relevant erwiesen, waren Fehleinschätzungen bei Kontaktaufnahmen der Patienten mit der Praxis, Diagnosefehler, mangelnde Überwachung von Patienten nach therapeutischen Massnahmen und Fehler in Zusammenhang mit der Medikation. Die Medikation (28% der Nennungen), medizinische Verrichtungen in der Praxis (11%) und die Telefon-Triage (7%) wurden am häufigsten als die Risiken genannt, die die Studienteilnehmer in ihren Praxen gerne eliminieren würden. In Bezug auf das Sicherheitsklima erwiesen sich insbesondere Teamsitzungen und regelmässige Qualitätszirkel-Teilnahme als relevante Prädiktoren für die Dimension „Teambasierte Aktivitäten und Strategien zur Fehlerprävention“. Berufsgruppenunterschiede zwischen Ärzten und MPA konnten sowohl hinsichtlich der berichteten Sicherheitsrisiken, als auch beim Sicherheitsklima beobachtet werden. Fazit Die Ergebnisse der Studie legen die Telefon-Triage als bislang wenig beachteten jedoch sehr relevanten Sicherheitsbereich in der Grundversorgung dar. Um die Sicherheit der Telefon-Triage zu stärken, wurde ein Anschlussprojekt durchgeführt, aus dem heraus ein Leitfaden für Hausarztpraxen entwickelt wurde. Dieser Leitfaden soll Ärzte und MPA in einer gemeinsamen und kritischen Auseinandersetzung von Strukturen und Prozessen rund um die Telefon-Triage sowie der Entwicklung von Verbesserungsschritten unterstützen. Die systematisch beobachteten Berufsgruppenunterschiede sind ein wichtiger Hinweis dafür, dass das gesamte Praxisteam in die Analyse von Sicherheitsrisiken und die Entwicklung von Massnahmen einbezogen werden sollte. Nur so können Risiken umfassend erfasst und für alle Fachpersonen relevante und getragene Verbesserungen initiiert werden. Dieser Ansatz der Team-Involvierung bildet die Basis für den Praxisleitfaden zur Telefon-Triage.