Search

Objective:In a multicountry prospective cohort of persons with HIV from six countries between 2007 and 2015, we evaluated long-term outcomes of first-line non-nucleoside reverse-transcriptase inhibitor-based antiretroviral therapy (ART), and risk factors for loss-to-follow-up, mortality, virological failure, and incomplete CD4 +T-cell recovery.Methods:We calculated cumulative incidence of lost-to-follow-up, death, virological failure (VL ≥ 1000 cps/ml) and incomplete CD4 +T-cell recovery (+T-cell count was 135 (IQR 63-205)/μl. Total follow-up time was 7208 person-years (median 24.3 months, IQR 18.7-58.3). Deaths by any cause and loss to follow-up occurred mostly during the first year of ART (84%, 201/240 and 56%, 199/353, respectively). During their first 6 years of ART, 71% (95% confidence interval [CI] 69.0-73.7) were retained on first-line, and among those 90-93% sustained viral suppression (+T-cell recovery was incomplete in 60% (220/363) of participants. The risk factors associated with poor outcomes during long-term ART were: for loss-to-follow-up, recent VL ≥1000 cps/ml, recent CD4 +T-cell count ≤50 cells/μl, age +T-cell count ≤50 cells/μl; and, for virological failure, age +T-cell count ≤200 cells/μl, poor adherence, male sex, and low-level viremia.Conclusion:To achieve long-term ART success towards the UNAIDS targets, early ART initiation is crucial, coupled with careful monitoring and retention support, particularly in the first year of ART. Male and youth-centred care delivery models are needed to improve outcomes for those vulnerable groups.

Effective science communication is challenging when scientific messages are informed by a continually updating evidence base and must often compete against misinformation. We argue that we need a new program of science communication as collective intelligence—a collaborative approach, supported by technology. This would have four key advantages over the typical model where scientists communicate as individuals: scientific messages would be informed by (a) a wider base of aggregated knowledge, (b) contributions from a diverse scientific community, (c) participatory input from stakeholders, and (d) better responsiveness to ongoing changes in the state of knowledge.

Zusammenfassung Hintergrund Die Häufigkeit von Suizidversuchen ist ein zentraler Indikator der psychischen Gesundheit der Bevölkerung und daher Gegenstand der Mental Health Surveillance am Robert Koch-Institut. Da bisher keine Datenquellen systematisch zur kontinuierlichen Erfassung von psychiatrischen Notfällen – zu denen Suizidversuche zählen – herangezogen werden, wird die Nutzung von Routinedaten aus Notaufnahmen zu diesem Zweck geprüft. Methoden Routinedaten aus 12 Notaufnahmen wurden für den Zeitraum 01.01.2018–28.03.2021 ausgewertet. Syndromdefinitionen für Suizidversuche, psychiatrische Notfälle und psychische Symptomatik wurden als Kombinationen aus Vorstellungsgründen und Diagnosen entwickelt. Fälle wurden alters- und geschlechtsspezifisch sowie im Zeitverlauf dargestellt. Ergebnisse Von insgesamt 1.516.883 Notaufnahmevorstellungen wurden 5133 (0,3 %) als Suizidversuche, 31.085 (2,1 %) als psychiatrische Notfälle und 34.230 (2,3 %) als Fälle mit einer psychischen Symptomatik identifiziert. 16,5 % der psychiatrischen Notfälle wurden so als Suizidversuch eingeschätzt. Unter den Suizidversuchen entfallen 53,4 % auf Männer und insgesamt 20,2 % auf die Altersgruppe der 25- bis 34-Jährigen. Alle 3 Syndromdefinitionen können über den gesamten Beobachtungszeitraum Fälle sowie deren zeitliche Variation abbilden. Fazit Notaufnahmedaten zeigen Potenzial zur syndromischen Surveillance von Suizidversuchen und psychiatrischen Notfällen und bieten damit einen Ausgangspunkt für weitere Validierung und Analyse. Die Abbildung von Veränderungen in Echtzeit erweitert die bisherigen Forschungsmöglichkeiten zu psychiatrischen Notfällen in Deutschland. Eine systematische Surveillance von Suizidversuchen kann zu einer evidenzbasierten Suizidprävention beitragen.

The COVID-19 pandemic has fundamentally changed the way that public health professionals work and communicate. Over a very short time span, remote working arrangements have become the norm, and meetings have shifted online. Physical distancing measures have accelerated a trend toward digital communication and social exchange. At the same time, the work of epidemiologists has been held under a magnifying glass by journalists, governments and the general public, in a way not previously seen. With social media becoming an integral part of our society over the last decade, Twitter is now a key communication tool and platform for social networking among epidemiologists (#EpiTwitter). In this article, we reflect on the use of Twitter by field epidemiologists and public health microbiologists for rapid professional exchange, public communication of science and professional development during the pandemic and the associated risks. For those field epidemiologists new to social media, we discuss how Twitter can be used in a variety of ways, both at their home institutions and during field deployment. These include information dissemination, science communication and public health advocacy, professional development, networking and experience exchange.

BACKGROUND To respond to the need for establishing infodemic management functions at the national public health institute in Germany (Robert Koch Institute; RKI), we explored and assessed available data sources, developed a social listening and integrated analysis framework, and defined when infodemic management functions would activate during emergencies. OBJECTIVE We aimed to establish a framework for social listening and integrated analysis for public health in the German context, using international examples and technical guidance documents for infodemic management. METHODS At the RKI, we 1) identified (potentially) available data sources for social listening and integrated analysis; 2) assessed these data sources for their suitability and usefulness for integrated analysis in addition to an assessment of their risk using RKIs standardised data protection requirement; 3) developed a framework and workflow to combine social listening and integrated analysis to report back actionable infodemic insights for public health communications by the RKI and stakeholders; 4) defined criteria for activating integrated analysis structures in the context of a specific health event or health emergency. RESULTS We identified and assessed 16 different types of data sources for social listening and integrated analysis in three categories: social media and online listening data, RKI-specific data, and infodemic insights. Most data sources can be analysed on a weekly basis to detect current trends and narratives and to inform a timely response through reporting insights that include a risk assessment and scalar judgements of the different narratives and themes. CONCLUSIONS This work identified, assessed, and prioritized a wide range of data sources for social listening and integrated analysis to report actionable infodemic insights, ensuring a valuable first step to establish and operationalise infodemic management at the RKI. This case study also serves as a roadmap for others to follow. Ultimately, once operational, these activities will inform better and targeted public health communication at the RKI, and beyond. CLINICALTRIAL Not applicable.

Background The COVID-19 pandemic expanded the need for timely information on acute respiratory illness at population level. Aim We explored the potential of routine emergency department data for syndromic surveillance of acute respiratory illness in Germany. Methods We used routine attendance data from emergency departments, which continuously transferred data between week 10 2017 and 10 2021, with ICD-10 codes available for > 75% of attendances. Case definitions for acute respiratory infection (ARI), severe acute respiratory infection (SARI), influenza-like illness (ILI), respiratory syncytial virus infection (RSV) and COVID-19 were based on a combination of ICD-10 codes, and/or chief complaints, sometimes combined with information on hospitalisation and age. Results We included 1,372,958 attendances from eight emergency departments. The number of attendances dropped in March 2020 during the first COVID-19 pandemic wave, increased during summer, and declined again during the resurge of COVID-19 cases in autumn and winter of 2020/21. A pattern of seasonality of respiratory infections could be observed. By using different case definitions (i.e. for ARI, SARI, ILI, RSV) both the annual influenza seasons in the years 2017–2020 and the dynamics of the COVID-19 pandemic in 2020/21 were apparent. The absence of the 2020/21 influenza season was visible, parallel to the resurge of COVID-19 cases. SARI among ARI cases peaked in April–May 2020 (17%) and November 2020–January 2021 (14%). Conclusion Syndromic surveillance using routine emergency department data can potentially be used to monitor the trends, timing, duration, magnitude and severity of illness caused by respiratory viruses, including both influenza viruses and SARS-CoV-2.

Background: During the COVID-19 pandemic and associated public health and social measures, decreasing patient numbers have been described in various healthcare settings in Germany, including emergency care. This could be explained by changes in disease burden, e.g. due to contact restrictions, but could also be a result of changes in utilization behaviour of the population. To better understand those dynamics, we analysed routine data from emergency departments to quantify changes in consultation numbers, age distribution, disease acuity and day and hour of the day during different phases of the COVID-19 pandemic. Methods: We used interrupted time series analyses to estimate relative changes for consultation numbers of 20 emergency departments spread throughout Germany. For the study period of 06-03-2017 to 13-06-2021 four different phases of the COVID-19 pandemic were defined as interruption points. Results: The most pronounced decreases were visible in the first and second wave of the pandemic, with changes of -30.0% (95%CI: -32.2%; -27.7%) and -25.7% (95%CI: -27.4%; -23.9%) for overall consultations, respectively. The decrease was even stronger for the age group of 0-19 years, with -39.4% in the first and -35.0% in the second wave. Regarding acuity levels, consultations assessed as urgent, standard and non-urgent showed the largest decrease, while the most severe cases showed the smallest decrease.Conclusions: The number of emergency department consultations decreased rapidly during the COVID-19 pandemic, without extensive variation in the distribution of patient characteristics. Smallest changes were observed for the most severe consultations and older age groups, which is especially reassuring regarding concerns of possible long-term complications due to patients avoiding urgent emergency care during the pandemic.

Background Guillain–Barré syndrome (GBS) is a rare autoimmune disease that can follow viral infections and has in a few cases been linked to vaccinations. Pre-licensure clinical trials did not observe an association between human papillomavirus (HPV) vaccination and GBS, a post-marketing study from 2017 reported an increased relative risk. Aim We assessed the risk of GBS after HPV vaccination through a systematic literature review and meta-analysis. Methods We searched Embase, MEDLINE and Cochrane for studies reporting on the risk of GBS after HPV vaccination in individuals aged ≥ 9 years, published between 1 January 2000 and 4 April 2020, excluding studies without a comparator group. Seven studies reporting relative effect sizes were pooled using random-effects meta-analysis. We assessed quality of evidence using the GRADE approach. Study protocol was registered (PROSPERO No. #CRD42019123533). Results Of 602 identified records, we included 25 studies. Based on over 10 million reports, cases of GBS were rare. In 22 studies no increased risk was observed, while in three studies a signal of increased risk of GBS after HPV vaccination was identified. Meta-analysis yielded a pooled random-effects ratio of 1.21 (95% CI: 0.60–2.43); I2 = 72% (95% CI: 36–88). This translates to a number needed to harm of one million to be vaccinated to generate one GBS case. Quality of evidence was very low. Conclusions The absolute and relative risk of GBS after HPV vaccination is very low and lacks statistical significance. This is reassuring for the already implemented vaccination programmes and should be used in respective communication activities.

BackgroundThe Coronavirus disease 2019 (COVID-19) pandemic expanded the need for timely information on acute respiratory illness on the population level.AimWe explored the potential of routine emergency department data for syndromic surveillance of acute respiratory illness in Germany.MethodsWe included routine attendance data from emergency departments who continuously transferred data between week 10-2017 and 10-2021, with ICD-10 codes available for >75% of the attendances. Case definitions for acute respiratory illness (ARI), severe ARI (SARI), influenza-like illness (ILI), respiratory syncytial virus disease (RSV) and COVID-19 were based on a combination of ICD-10 codes, and/or chief complaints, sometimes combined with information on hospitalisation and age.ResultsWe included 1,372,958 attendances from eight emergency departments. The number of attendances dropped in March 2020, increased during summer, and declined again during the resurge of COVID-19 cases in autumn and winter of 2020/2021. A pattern of seasonality of acute respiratory infections could be observed. By using different case definitions (i.e. for ARI, SARI, ILI, RSV) both the annual influenza seasons in the years 2017-2020 and the dynamics of the COVID-19 pandemic in 2020-2021 were apparent. The absence of the 2020/2021 flu season was visible, parallel to the resurge of COVID-19 cases. The percentage SARI among ARI cases peaked in April-May 2020 (17%) and November 2020-January 2021 (14%).ConclusionSyndromic surveillance using routine emergency department data has the potential to monitor the trends, timing, duration, magnitude and severity of illness caused by respiratory viruses, including both influenza and SARS-CoV-2.

The occurrence of suicide attempts is a key indicator of the population's mental health and therefore belongs in the domain of Mental Health Surveillance at the Robert Koch Institute. No data source is currently being used systematically for the continuous observation of psychiatric emergencies (including suicide attempts) in Germany. Therefore, the use of routine data from emergency departments will be explored in this work.We included routine data from 12 emergency departments between 1 January 2018 and 28 March 2021. We developed syndrome definitions for suicide attempts, psychiatric emergencies based on combinations of chief complaints, and diagnoses from patients presenting with psychopathological symptoms. A descriptive analysis over time was presented and stratified by age and sex.In total 1,516,883 emergency department attendances were included, among which we identified 5,133 cases (0.3%) as suicide attempts, 31,085 (2.1%) as psychiatric emergencies, and 34,230 (2.3%) as cases with psychiatric symptoms. Among psychiatric emergencies, 16.5% presented because of a suicide attempt. Of cases presenting with a suicide attempt, 53.4% were male and 20.2% were aged between 25 and 34 years. Cases identified by all 3 syndrome definitions and their temporal variations could be displayed over the entire observation period.Syndromic surveillance using emergency department data indicates a potential for continuous surveillance of suicide attempts and psychiatric emergencies and provides a basis for further validation and analysis. The display of changes in real time extends the current research opportunities for psychiatric emergencies in Germany. Systematic surveillance of suicide attempts can contribute to evidence-based suicide prevention.HINTERGRUND: Die Häufigkeit von Suizidversuchen ist ein zentraler Indikator der psychischen Gesundheit der Bevölkerung und daher Gegenstand der Mental Health Surveillance am Robert Koch-Institut. Da bisher keine Datenquellen systematisch zur kontinuierlichen Erfassung von psychiatrischen Notfällen – zu denen Suizidversuche zählen – herangezogen werden, wird die Nutzung von Routinedaten aus Notaufnahmen zu diesem Zweck geprüft.Routinedaten aus 12 Notaufnahmen wurden für den Zeitraum 01.01.2018–28.03.2021 ausgewertet. Syndromdefinitionen für Suizidversuche, psychiatrische Notfälle und psychische Symptomatik wurden als Kombinationen aus Vorstellungsgründen und Diagnosen entwickelt. Fälle wurden alters- und geschlechtsspezifisch sowie im Zeitverlauf dargestellt.Von insgesamt 1.516.883 Notaufnahmevorstellungen wurden 5133 (0,3 %) als Suizidversuche, 31.085 (2,1 %) als psychiatrische Notfälle und 34.230 (2,3 %) als Fälle mit einer psychischen Symptomatik identifiziert. 16,5 % der psychiatrischen Notfälle wurden so als Suizidversuch eingeschätzt. Unter den Suizidversuchen entfallen 53,4 % auf Männer und insgesamt 20,2 % auf die Altersgruppe der 25- bis 34-Jährigen. Alle 3 Syndromdefinitionen können über den gesamten Beobachtungszeitraum Fälle sowie deren zeitliche Variation abbilden.Notaufnahmedaten zeigen Potenzial zur syndromischen Surveillance von Suizidversuchen und psychiatrischen Notfällen und bieten damit einen Ausgangspunkt für weitere Validierung und Analyse. Die Abbildung von Veränderungen in Echtzeit erweitert die bisherigen Forschungsmöglichkeiten zu psychiatrischen Notfällen in Deutschland. Eine systematische Surveillance von Suizidversuchen kann zu einer evidenzbasierten Suizidprävention beitragen.

BACKGROUND: For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS: We included individuals from the HIV-CAUSAL Collaboration who enrolled

Evidence-based guidelines in HIV care aim to improve patients’ health outcomes, quality of care, and cost-effectiveness. Laboratory monitoring plays an important role in assessing clinical status of patients and forms an integral part of HIV treatment guidelines. The Dutch HIV monitoring foundation (Stichting HIV Monitoring) previously observed variation between HIV treatment centres in the Netherlands in terms of compliance with guidelines for performing laboratory tests. Drawing on qualitative research methods, this article aimswe aimed to describe factors that influence guideline compliance for laboratory monitoring in outpatient HIV care in the Netherlands. Twelve semi-structured in-depth interviews were conducted with a convenience sample of physicians from four HIV treatment centres. In general, physicians perceived laboratory guidelines as useful. However, unclear online visual representation of the guidelines, a lack of set reminders for tests, and assessment of patients’ risk behaviour, which differs per patient, were identified as barriers to guideline compliance. The compartmentalisation of the Dutch healthcare system was viewed as hampering guideline compliance. A clinical-decision-support tool could possibly facilitate compliance with laboratory monitoring guidelines. Moreover, better alignment of HIV outpatient care, municipal health services and primary care, in terms of laboratory testing, could optimize efficiency, increase cost-effectiveness, and improve quality of HIV care.

Background: The COVID-19 pandemic and associated non-pharmaceutical interventions (NPIs) affect healthcare seeking behaviour, access to healthcare, test strategies, disease notification and workload at public health authorities, but may also lead to a true change in transmission dynamics. We aimed to assess the impact of the pandemic and NPIs on other notifiable infectious diseases under surveillance in Germany. Methods: We included 32 nationally notifiable disease categories with case numbers >100/year in 2016–2019. We used quasi-Poisson regression analysis on a weekly aggregated time-series incorporating trend and seasonality, to compute the relative change in case numbers during week 2020–10 to 2020–32 (pandemic/NPIs), in comparison to week 2016–01 to 2020–09. Findings: During week 2020–10 to 2020–32, 216,825 COVID-19 cases, and 162,942 (-35%) cases of other diseases, were notified. Case numbers decreased across all ages and notification categories (all p

Two general practitioners (GPs) with SARS-CoV-2 infection provided in-person patient care to patients of their joint medical practice before and after symptom onset, up until SARS-CoV-2 laboratory confirmation. Through active contact tracing, the local public health authorities recruited the cohort of patients that had contact with either GP in their putative infectious period. In this cohort of patient contacts, we assess the frequency and determinants of SARS-CoV-2-transmission from GPs to patients. We calculated incidence rate ratios (IRR) to explore the type of contact as an explanatory variable for COVID-19 cases. Among the cohort of 83 patient contacts, we identified 22 (27%) COVID-19 cases including 17 (21%) possible, three (4%) probable and two (2%) confirmed cases. All 22 cases had contact with a GP when the GP did not wear a mask, and/or when contact was ≥10 min. Importantly, patients who had contact

Poor access to HIV viral load (VL) testing prevents the timely monitoring of HIV treatment adherence and efficacy. Factors enabling clinical benefits of VL testing when added to local standards of care, can inform the development of more cost-effective routine VL scale-up plans. We compared antiretroviral therapy (ART) switch practices in 13 clinics across 6 countries, with full (N = 8), phasing-in (N = 3) or no onsite access (N = 2) to VL. The analysis used data from the Pan-African Studies to Evaluate Resistance (PASER), observing virological and drug resistance outcomes among adults receiving first- or second-line ART between 2008 and 2015. Study plasma viral load (sVL) determined at baseline, every 12 months thereafter and at the time of switch served for retrospectively validating switch decisions, categorized into “necessary,” “unnecessary,” and “missed.” Virological failure was defined as two consecutive sVL ≥1,000 HIV-RNA copies/mL. One thousand nine hundred ninety-five of the 2,420 (82.4%) study participants had continuous virological suppression during the median 30 months of follow-up. Among the 266 virological failures (11.0%), the proportion of necessary switches were similar in clinics with full (37%), phasing-in (25%), or no access (39%) to local VL testing. Documented utilization of local VL results for the switch decision was associated with higher percentage of necessary switch (87.6% vs. 67.9%). Shorter time to necessary switch was associated with higher rates of long-term virological suppression, regardless of access to local viral load. Availability of HIV VL testing capacity does not systematically result in adequate switch practices or better virological outcomes. Systems supporting sufficient test demand execution, and actual utilization of results for patient management need strengthening.

Summary Background In December, 2019, the newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, causing COVID-19, a respiratory disease presenting with fever, cough, and often pneumonia. WHO has set the strategic objective to interrupt spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting at the end of January, 2020, provided the opportunity to study transmission events, incubation period, and secondary attack rates. Methods A case was defined as a person with SARS-CoV-2 infection confirmed by RT-PCR. Case interviews were done to describe timing of onset and nature of symptoms and to identify and classify contacts as high risk (had cumulative face-to-face contact with a confirmed case for ≥15 min, direct contact with secretions or body fluids of a patient with confirmed COVID-19, or, in the case of health-care workers, had worked within 2 m of a patient with confirmed COVID-19 without personal protective equipment) or low risk (all other contacts). High-risk contacts were ordered to stay at home in quarantine for 14 days and were actively followed up and monitored for symptoms, and low-risk contacts were tested upon self-reporting of symptoms. We defined fever and cough as specific symptoms, and defined a prodromal phase as the presence of non-specific symptoms for at least 1 day before the onset of specific symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods. Secondary attack rates were calculated as the number of cases divided by the number of contacts, using Fisher's exact test for the 95% CIs. Findings Patient 0 was a Chinese resident who visited Germany for professional reasons. 16 subsequent cases, often with mild and non-specific symptoms, emerged in four transmission generations. Signature mutations in the viral genome occurred upon foundation of generation 2, as well as in one case pertaining to generation 4. The median incubation period was 4·0 days (IQR 2·3–4·3) and the median serial interval was 4·0 days (3·0–5·0). Transmission events were likely to have occurred presymptomatically for one case (possibly five more), at the day of symptom onset for four cases (possibly five more), and the remainder after the day of symptom onset or unknown. One or two cases resulted from contact with a case during the prodromal phase. Secondary attack rates were 75·0% (95% CI 19·0–99·0; three of four people) among members of a household cluster in common isolation, 10·0% (1·2–32·0; two of 20) among household contacts only together until isolation of the patient, and 5·1% (2·6–8·9; 11 of 217) among non-household, high-risk contacts. Interpretation Although patients in our study presented with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset was substantial. Additionally, the incubation period was often very short and false-negative tests occurred. These results suggest that although the outbreak was controlled, successful long-term and global containment of COVID-19 could be difficult to achieve. Funding All authors are employed and all expenses covered by governmental, federal state, or other publicly funded institutions.

Background With regards to the global strategy towards eliminating viral hepatitis, reliable surveillance systems are essential to assess the national response for eliminating hepatitis C virus (HCV). Aim We aimed to assess the completeness of the two national registries with data on acute HCV infection in people with HIV, and estimated the number of acute HCV infections among adults (aged ≥ 18 years) with HIV in the Netherlands. Methods In this observational study, cases of HCV infection and reinfection among adults with a positive or unknown HIV-serostatus were identified from 2003 to 2016 in two national registries: the ATHENA cohort and the National Registry for Notifiable Diseases. For 2013–2016, cases were linked, and two-way capture–recapture analysis was carried out. Results During 2013–2016, there were an estimated 282 (95% confidence interval (CI): 264–301) acute HCV infections among adults with HIV. The addition of cases with an unknown HIV-serostatus increased the matches (from n = 107 to n = 129), and subsequently increased the estimated total: 330 (95%CI: 309–351). Under-reporting was estimated at 14–20%. Conclusion Under-reporting of acute HCV infection among people with HIV could partially be explained by an unknown HIV-serostatus, or by differences in HCV stage (acute or chronic) at first diagnosis. Surveillance data should ideally include both acute and chronic HCV infections, and enable to distinguish these as well as initial- and re-infections. National surveillance of acute HCV can be improved by increased notification of infections.

Background: In December 2019, a newly identified coronavirus (SARS-CoV-2) emerged in Wuhan, China, causing respiratory disease (COVID-19) presenting with fever

In ART programs in sub-Saharan Africa, a growing proportion of HIV-infected persons initiating first-line antiretroviral therapy (ART) have a history of prior antiretroviral drug use (PAU). We assessed the effect of PAU on the risk of pre-treatment drug resistance (PDR) and virological failure (VF) in a multicountry cohort of HIV-infected adults initiated on a standard non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART. Multivariate logistic regression was used to assess the associations between PAU, PDR and VF (defined as viral load ≥400 cps/mL). Causal mediation analysis was used to assess the proportion of the effect of PAU on VF that could be eliminated by intervening on PDR. Of 2737 participants, 122 (4.5%) had a history of PAU. Participants with PAU had a 7.2-fold (95% CI 4.4–11.7) risk of carrying PDR and a 3.1-fold (95% CI 1.6–6.1) increased risk of VF, compared to antiretroviral-naïve participants. Controlling for PDR would eliminate nearly half the effect of PAU on the risk of VF. Patients with a history of PAU are at increased risk of ART failure, which is to a large extent attributable to PDR. These findings support the recent WHO recommendations for use of differentiated, non-NNRTI-based empiric first-line therapy in patients with PAU.

OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).DESIGN: Multicountry prospective cohort.METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4 cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4 strata.RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4 cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4 cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4 cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4 cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4 cell count less than 200 cells/μl, and comparable across the higher CD4 strata. Older age, male sex, and lower pre-ART CD4 cell count were strongly associated with suboptimal immune recovery.CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4 cell count.

We estimated and compared the risk of clinically identified acquired drug resistance under immediate initiation [the currently recommended antiretroviral therapy (ART) initiation strategy], initiation with CD4 cell count less than 500 cells/μl and initiation with CD4 cell count less than 350 cells/μl.Cohort study based on routinely collected data from the HIV-CAUSAL collaboration.For each individual, baseline was the earliest time when all eligibility criteria (ART-naive, AIDS free, and others) were met after 1999. Acquired drug resistance was defined using the Stanford classification as resistance to any antiretroviral drug that was clinically identified at least 6 months after ART initiation. We used the parametric g-formula to adjust for time-varying (CD4 cell count, HIV RNA, AIDS, ART regimen, and drug resistance testing) and baseline (calendar period, mode of acquisition, sex, age, geographical origin, ethnicity and cohort) characteristics.In 50 981 eligible individuals, 10% had CD4 cell count more than 500 cells/μl at baseline, and 63% initiated ART during follow-up. Of 2672 tests for acquired drug resistance, 794 found resistance. The estimated 7-year risk (95% confidence interval) of acquired drug resistance was 3.2% (2.8,3.5) for immediate initiation, 3.1% (2.7,3.3) for initiation with CD4 cell count less than 500 cells/μl, and 2.8% (2.5,3.0) for initiation with CD4 cell count less than 350 cells/μl. In analyses restricted to individuals with baseline in 2005-2015, the corresponding estimates were 1.9% (1.8, 2.5), 1.9% (1.7, 2.4), and 1.8% (1.7, 2.2).Our findings suggest that the risk of acquired drug resistance is very low, especially in recent calendar periods, and that immediate ART initiation only slightly increases the risk. It is unlikely that drug resistance will jeopardize the proven benefits of immediate ART initiation.

BACKGROUND: Implementation of ultrasensitive HIV drug resistance tests for routine clinical use is hampered by uncertainty about the clinical relevance of drug-resistant minority variants. We assessed different detection thresholds for pretreatment drug resistance to predict an increased risk of virological failure.METHODS: We did a case-control study nested within a prospective multicountry cohort. Our study included patients from 12 clinical sites in Kenya, Nigeria, South Africa, Uganda, and Zambia. We defined cases as patients with virological failure (ie, those who had either viral load ≥400 copies per mL at 12 months or had switched to second-line antiretroviral therapy [ART] as a result of virological failure before 12 months) and controls as those with viral suppression (viral load FINDINGS: Paired viral load results before ART and at month 12 of follow-up were available from 1896 participants. We identified 178 patients with virological failure and selected 338 matched controls. We excluded 117 patients from pretreatment drug resistance analysis; therefore, 152 cases of virological failure and 247 controls were included in the final analysis. With the IAS-USA mutation list, at a detection threshold of 20% or more in patients with pretreatment drug resistance, the adjusted odds ratio (OR) for virological failure was 9·2 (95% CI 4·2-20·1) compared with those without pretreatment drug resistance. Lowering the threshold resulted in adjusted ORs of virological failure of 6·8 (95% CI 3·3-13·9) at the 10% threshold, 7·6 (3·4-17·1) at the 5% threshold, and 4·5 (2·0-10·2) at the 1% threshold. Lowering the detection threshold from 20% improved the sensitivity (ie, ability to identify cases) from 12% (n=18) to 13% (n=19) at detection threshold 10%, to 15% (n=23) at detection threshold 5%, and to 17% (n=26) at detection threshold 1%, but caused a slight reduction in specificity (ie, ability to identify controls) from 98% (n=241) to 96% (n=238) at the 10% threshold, 96% (n=236) at the 5% threshold, and a larger reduction to 92% (n=227) at the 1% threshold. Diagnostic ORs were 5·4 (95% CI 2·1-13·9) at the 20% threshold, 3·8 (1·7-8·6) at the 10% threshold, 3·8 (1·8-8·1) at the 5% threshold, and 2·3 (1·2-4·2) at the 1% threshold. Use of the Stanford HIVDB genotypic sensitivity scores yielded similar ORs for virological failure, sensitivities, specificities, and diagnostic ORs.INTERPRETATION: Ultrasensitive resistance testing for pretreatment drug resistance improved identification of people at risk of virological failure; however, this came with a reduction in our ability to identify people with viral suppression, especially at very low thresholds. Further modelling is needed to estimate the optimal trade-off for the 5% and 20% thresholds, balancing improved case finding against unnecessary regimen switching.FUNDING: The Netherlands Ministry of Foreign Affairs, IrsiCaixa, and European Union.

Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged ≤12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL > 1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs > 1000 copies/mL or death after 6months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis. Results: Among 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P=0.01). Conclusions: Almost one-third of children experienced VF within 24months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children ≤3 years should be initiated on a PI-based regimen as per WHO guidelines.

Objectives Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. Methods HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. Results At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P Conclusions Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

BACKGROUND: The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking.METHODS: We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis.RESULTS: Seventy-two studies, reporting on 51 347 children (aged CONCLUSIONS: Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached.

Background. As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. Methods. HIV-1–infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. Results. Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)–based (hazard ratio, 7.10; 95% confidence interval, 3.40–14.83; P < .001) or PI-based (7.59; 3.02–19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49–17.98; P < .001), and suboptimal adherence (3.05; 1.71–5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. Conclusions. Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Although the advantages of early infant HIV diagnosis and treatment initiation are well established, children often present late to HIV programs in resource-limited settings. We aimed to assess factors related to the timing of treatment initiation among HIV-infected children attending three clinical sites in Uganda. Clinical and demographic determinants associated with early disease (WHO clinical stages 1-2) or late disease (stages 3-4) stage at presentation were assessed using multilevel logistic regression. Additionally, semistructured interviews with caregivers and health workers were conducted to qualitatively explore determinants of late disease stage at presentation. Of 306 children initiating first-line regimens, 72% presented late. Risk factors for late presentation were age below 2 years old (OR 2.83,P=0.014), living without parents (OR 3.93,P=0.002), unemployment of the caregiver (OR 4.26,P=0.001), lack of perinatal HIV prophylaxis (OR 5.66,P=0.028), and high transportation costs to the clinic (OR 2.51,P=0.072). Forty-nine interviews were conducted, confirming the identified risk factors and additionally pointing to inconsistent referral from perinatal care, caregivers’ unawareness of HIV symptoms, fear, and stigma as important barriers. The problem of late disease at presentation requires a multifactorial approach, addressing both health system and individual-level factors.

Background. After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. Methods. In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) >1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to >1 prescribed drug. We assessed the effect of pretreatment drug resistance on all-cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. Results. Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49-9.68; P =. 005) but was not associated with mortality (aHR 0.75, 95% CI,. 24-2.35; P =. 617) or new AIDS events (aHR 1.06, 95% CI,. 68-1.64; P =. 807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL > 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL > 1000 cps/mL and >1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. Conclusions. Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices.

Background.More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. Methods.We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. Results.Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. Conclusions.Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.

On Tuesday 14 October 2014, 850 family members, friends, colleagues, prominent scientists and dignitaries from all over the world gathered in Amsterdam to pay tribute to the lives and legacies of Joep Lange and Jacqueline van Tongeren. The remembrance was held at the Amsterdam Medical Centre (AMC) where Joep and Jacqueline met and worked together for many years. The day was organized by the AMC, the Amsterdam Institute for Global Health and Development (AIGHD) and PharmAccess Foundation. The latter two were both founded by Joep. A morning symposium titled ‘Research in action: from AIDS to global health to impact’ highlighted Joep's scientific legacy (Figure 1). During the remembrance in the afternoon, a range of speakers shared memories of Joep and Jacqueline. As was the case during their lives, the personal and the professional were closely intertwined throughout the day. As Prof Peter Piot said, Joep and Jacqueline shared a common perspective on life: ‘La folie suprême est de voir la vie comme elle est et non comme elle devrait être.’ If there was one thing that defined them both, it was indeed that they saw life – and lived it – not as it was, but as it should be. ‘Joep's place in history is really as the visionary architect of combination therapy,’ Prof Piot stated, adding that ‘it cannot be stressed enough that he was ahead of his time, a true innovator.’ Joep's contribution didn't stop at science. Dr Khama Rogo of the World Bank explained that ‘it's not enough to be a doctor or a researcher if you're not also an activist.’ Joep fully understood the importance of translating research into action and generating impact for people. Prof Marcel Levi, chairman of the AMC, summarized the enormity of the impact Joep had on the world with the words ‘it's rare to know someone who has saved millions of lives.’ The scientific symposium traced Joep's career, starting in the early eighties with the treatment of the first AIDS patients and the design of antiretroviral therapy, moving towards the emerging field of global health and ending with his most recent focus: using knowledge derived from scientific research to improve access to quality health care in real-world settings. From Prof Françoise Barré-Sinoussi, who won the Nobel Prize for the discovery of HIV, to Prof Michael Merson, who founded Duke University's Global Health Institute, the list of presenters reads like a who's who of people involved at key moments in the history of HIV and global health (Figure 2). ‘And Joep,’ as Barré-Sinoussi said, ‘contributed to all eras of HIV.’ More memories of Joep and Jacqueline shared throughout the day are available at http://www.joepandjacqueline.org/remembrance/ .

Introduction: As access to prevention of mother-to-child transmission (PMTCT) efforts has increased, the total number of children being born with HIV has significantly decreased. However, those children who do become infected after PMTCT failure are at particular risk of HIV drug resistance, selected by exposure to maternal or paediatric antiretroviral drugs used before, during or after birth. As a consequence, the response to antiretroviral therapy (ART) in these children may be compromised, particularly when non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used as part of the first-line regimen. We review evidence guiding choices of first- and second-line ART. Discussion: Children generally respond relatively well to ART. Clinical trials show the superiority of protease inhibitor (PI)- over NNRTI-based treatment in young children, but observational reports of NNRTI-containing regimens are usually favourable as well. This is reassuring as national guidelines often still recommend the use of NNRTI-based treatment for PMTCT-unexposed young children, due to the higher costs of PIs. After failure of NNRTI-based, first-line treatment, the rate of acquired drug resistance is high, but HIV may well be suppressed by PIs in second-line ART. By contrast, there are currently no adequate alternatives in resource-limited settings (RLS) for children failing either first- or second-line, PI-containing regimens. Conclusions: Affordable salvage treatment options for children in RLS are urgently needed.

BACKGROUND: Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens.METHODS: Children ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml.RESULTS: 60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure.CONCLUSIONS: No PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART.

Introduction : Pre-treatment HIV drug resistance (PDR) is an increasing problem in sub-Saharan Africa. Children are an especially vulnerable population to develop PDR given that paediatric second-line treatment options are limited. Although monitoring of PDR is important, data on the paediatric prevalence in sub-Saharan Africa and its consequences for treatment outcomes are scarce. We designed a prospective paediatric cohort study to document the prevalence of PDR and its effect on subsequent treatment failure in Nigeria, the country with the second highest number of HIV-infected children in the world. Methods : HIV-1-infected children ≤12 years, who had not been exposed to drugs for the prevention of mother-to-child transmission (PMTCT), were enrolled between 2012 and 2013, and followed up for 24 months in Lagos, Nigeria. Pre-antiretroviral treatment (ART) population-based pol genotypic testing and six-monthly viral load (VL) testing were performed. Logistic regression analysis was used to assess the effect of PDR (World Health Organization (WHO) list for transmitted drug resistance) on subsequent treatment failure (two consecutive VL measurements >1000 cps/ml or death). Results : Of the total 82 PMTCT-naive children, 13 (15.9%) had PDR. All 13 children harboured non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations, of whom seven also had nucleoside reverse transcriptase inhibitor resistance. After 24 months, 33% had experienced treatment failure. Treatment failure was associated with PDR and a higher log VL before treatment initiation (adjusted odds ratio (aOR) 7.53 (95%CI 1.61–35.15) and 2.85 (95%CI 1.04–7.78), respectively). Discussion : PDR was present in one out of six Nigerian children. These high numbers corroborate with recent findings in other African countries. The presence of PDR was relevant as it was the strongest predictor of first-line treatment failure. Conclusions : Our findings stress the importance of implementing fully active regimens in children living with HIV. This includes the implementation of protease inhibitor (PI)-based first-line ART, as is recommended by the WHO for all HIV-infected children