Cohort Profile: Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord

Widespread access to effective combination antiretroviral therapy (cART), beginning in 1996, dramatically reduced the number of AIDS-related events and deaths in people living with HIV (PLWH) in high-income settings.1 The study of prognosis and specific clinical outcomes therefore requires larger populations. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) was founded in 2005 to continue to advance epidemiological research on the prognosis of PLWH in Europe. COHERE has expanded and strengthened collaborative efforts in Europe and facilitated those with other regions by ensuring that longitudinal data, the product of early investments in clinic-based databases and observational studies, were compiled and harmonized. In 2011, COHERE joined three other European HIV collaborations, PENTA, EuroSIDA and CASCADE, to form ‘EuroCoord’, a network of excellence funded by the European Commission Seventh Framework Programme.2 COHERE also collaborates with the ART Cohort Collaboration (ART-CC) and the International Epidemiologic Databases to Evaluate AIDS (IeDEA) global network.3,4 COHERE operates according to the principles set out in Box 1: COHERE’s Principles COHERE should neither threaten nor compete with the scientific agendas of participating cohorts/cohort collaborations. The individual contributing cohorts must express their interest in participating in COHERE. The scientific questions addressed by COHERE are determined by consensus according to both their scientific relevance and originality (not being addressed elsewhere). Individual cohorts may veto the use of their data in any new project. Two regional coordinating centres (RCCs), based at the University of Bordeaux’s Institut de Santé Publique, d’Épidémiologie et de Développement (ISPED) in Bordeaux, France, and the Center for Health and Infectious Diseases Research (CHIP), Department of Infectious Diseases and Rheumatology, Rigshospitalet, in Copenhagen, Denmark, maintain COHERE’s infrastructure. The COHERE steering committee (SC)--composed of representatives from the participating cohorts--oversees the COHERE Collaboration, ensuring compliance with its principles; it also elects the chair and the regional representatives to the COHERE executive committee (EC). The EC--composed of three representatives from each of the two regions, and the two RCC Heads)--acts as the functional link between the RCCs and the SC. COHERE projects are organized by ‘themes’ (Prognosis and the effect of antiretroviral therapy (ART), Hepatitis, Opportunistic Infections, Malignancies, Late Presentation, and Socioeconomic Inequalities) to encourage collaboration and streamline the project proposal process. Theme leads stimulate scientific enquiry within their theme and develop projects. A detailed account of how COHERE operates is described in the Manual of Operations [www.cohere.org]. COHERE has grown from 33 cohorts in 2005 to 40 in 2015. COHERE initially approached cohorts because of their proven ability to address scientific questions and collect good quality data at clinical sites. As COHERE is a project-based collaboration, the data pooled in annual mergers depend on the projects included. Western European countries with longstanding national cohorts contribute a large proportion of person-years of follow-up, but there is an increasing number of individuals in care in Eastern Europe, primarily via the EuroSIDA network.5Figure 1 presents the number of people living with HIV (excluding deaths) included in COHERE as of 31 December 2011 as a percentage of UNAIDS 2011 estimates of people living with HIV by country. Persons Living with HIV (PLHIV) in COHERE as of 31/12/2011 as a proportion of 2011 UNAIDS estimates of PLHIV per country. COHERE includes: clinic- hospital-based cohorts of HIV-infected individuals, where data are extracted primarily from medical records in the context of routine care; and interval cohorts of specific populations of HIV-infected people, where data are collected at regular intervals that are unrelated to participants’ ongoing health care. Since people with HIV are seen regularly over a long period of time at a clinic/hospital, and are not just attending at times when they are symptomatic, the group of people seen at a given hospital naturally forms a cohort. Table 1a and b highlights the demographic characteristics and prognostic markers of HIV in those aged 13 and older, enrolled in adult cohorts. Approximately a quarter of the COHERE sample is female (27%). The median age at inclusion is 35 years [interquartile range (IQR): 30, 43]. The primary mode of HIV transmission is sexual contact [homosexual/bisexual contact (38.7%), heterosexual contact (37%)], followed by injection drug use (IDU) (13.5%)]. Overall, 71.6% of the sample has never had a clinical AIDS diagnosis before, nor during enrolment. The median CD4 cell count at enrolment, defined as the period 6 months preceding and 1 month following the enrolment date, was 340 cells/mm3 (IQR: 170, 530) in adults (Table 2a). Of those with available CD4 cell counts at enrolment, 29% had < 200 cells/mm3, 22% had between 200 and 350 cells/mm3 and 49% had > 350 cells/mm3. Of those younger than age 13 (N = 2808, representing 23 458 persons), 93.7% were infected via vertical transmission and 73.4% had never had an AIDS diagnosis (Table 2b). Description of the cohort type, eligibility criteria, period of ‘enrolment’, and location of data collection of the adult or mixed (adult/paediatric) cohorts participating in COHERE (circa 2015) * Austria, France, Germany, Greece, Italy, Netherlands, Norway, Spain (Badalona, Barcelona, Madrid Valencia), Sweden, Switzerland, United Kingdom ^ Belgium, Denmark, Germany, Netherlands, Poland, Italy, Spain, Sweden, Ukraine, United Kingdom ^^ Argentina, Austria, Belarus, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Georgia, Greece, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg,Netherlands, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Ukraine, United Kingdom) Description of the cohort type, eligibility criteria, period of ‘enrolment’, and location of data collection of the adult or mixed (adult/paediatric) cohorts participating in COHERE (circa 2015) * Austria, France, Germany, Greece, Italy, Netherlands, Norway, Spain (Badalona, Barcelona, Madrid Valencia), Sweden, Switzerland, United Kingdom ^ Belgium, Denmark, Germany, Netherlands, Poland, Italy, Spain, Sweden, Ukraine, United Kingdom ^^ Argentina, Austria, Belarus, Belgium, Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Georgia, Greece, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg,Netherlands, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Ukraine, United Kingdom) Description of the cohort type, eligibility criteria, period of ‘enrolment’, and location of data collection of ‘paediatric’ or adolescent cohorts participating in COHERE (circa 2015) Description of the cohort type, eligibility criteria, period of ‘enrolment’, and location of data collection of ‘paediatric’ or adolescent cohorts participating in COHERE (circa 2015) The 2014 merger included data from 331 481 individuals, including 2808 children (aged less than 13 years), representing 2 135 896 person-years of follow-up. Table 2a Number of individuals, person-years of follow-up, patient demographics, prior AIDS status, mode of infection, median CD4 cell count and logarithm viral load in individuals older than 13 years old, (COHERE, 2014 merger) * Enrolment : measurements taken in the period six months prior to and one month after the variable “enrolment date” ** Includes a small proportion of MSM + IDU *** Cohorts who have merged administratively but which represent ‘one cohort’ insofar as COHERE governance Number of individuals, person-years of follow-up, patient demographics, prior AIDS status, mode of infection, median CD4 cell count and logarithm viral load in individuals older than 13 years old, (COHERE, 2014 merger) * Enrolment : measurements taken in the period six months prior to and one month after the variable “enrolment date” ** Includes a small proportion of MSM + IDU *** Cohorts who have merged administratively but which represent ‘one cohort’ insofar as COHERE governance Number of individuals, person-years of follow-up, patient demographics, prior AIDS status, mode of infection, median CD4 cell count and logarithm viral load in individuals enrolled in ‘paediatric’ cohorts or enrolled in mixed cohorts and younger than 13 years old, (COHERE, 2014 merger) * Enrolment : measurements taken in the period six months prior to and one month after the variable “enrolment date” ** Mixed (adult/paediatric) cohorts Number of individuals, person-years of follow-up, patient demographics, prior AIDS status, mode of infection, median CD4 cell count and logarithm viral load in individuals enrolled in ‘paediatric’ cohorts or enrolled in mixed cohorts and younger than 13 years old, (COHERE, 2014 merger) * Enrolment : measurements taken in the period six months prior to and one month after the variable “enrolment date” ** Mixed (adult/paediatric) cohorts As a consortium of cohorts comprising clinic and interval cohorts, patient follow-up varies. For clinic or hospital-based cohorts, average patient follow-up reflects current standards of care in those countries. A derived measure of lost to follow-up (LTFU) was constructed by estimating the median last clinical encounter (defined as either the latest visit and/or the date of latest laboratory test) per active cohort. Those individuals who had not had a clinical encounter in the 18 months preceding this date were considered to be LTFU. Those who died during the same period were excluded. On average, 25% of the COHERE 2014 sample met this definition of LTFU, with variation between cohorts. LTFU in paediatric cohorts was estimated among those under age 17, as many cohorts discontinue follow-up at age 18. LTFU among paediatric patients youger than 17 (N = 1960) was 20% overall and ranged from 1.8% to 22% across cohorts. COHERE has benefited from dynamic data management processes, which have evolved to accommodate new projects and scientific questions. COHERE’s data managers (DMs) work with project leads and statisticians to conduct preliminary surveys, feasibility studies and, occasionally, to collect additional data. COHERE collects data on basic clinical information including: date of first HIV-positive test, estimated date of seroconversion, cART and other medications, opportunistic infections and laboratory results (CD4, CD8, plasma viral load values, hepatitis B and C serological tests and HIV drug resistance tests), as well as socio-demographic data (see www.hicdep.org for more information about the definition of different variables). COHERE, via EuroCoord, conducts an inventory of data items and biological samples collected by participating cohorts. The submission of data to COHERE is facilitated by the use of the HIV Cohorts Data Exchange Protocol (HICDEP), a flexible data structure developed in 2004, to guide the mapping of individual cohort data into a standard format to facilitate data merging.6 For approved projects, COHERE DMs organize data collection by developing a standardized operating procedure (SOP) for individual cohort DMs. Data are submitted in two stages via the HIV-Distributed Data Management (HIV-DDM) Tool.7 This implies that data submissions must therefore pass all format and edit checks, defined in HICDEP, before the submission can be completed. Additional inconsistencies are identified centrally. Cohorts are given an 8-week window to address said data inconsistencies before completing the second and final submission. Once data are merged, likely duplicate patient records between and within cohorts are identified using probability linkage. Data items used are gender, year of birth, treatment history, viral load measurements and CD4 cell counts. Duplicate records are reconciled based on previous agreements between participating cohorts. DMs identified and resolved 20 953 duplicate records in 2014. Cohorts resolve issues identified over time, ultimately improving data quality with each merger. To ensure transparency, the content of each merger together with cohort’s QA check feedback is summarized in a report. DMs extract data for projects based on specified and agreed eligibility criteria. After signing a data protection agreement, project leads are sent data extractions in a secure format. Projects within the COHERE collaboration have led to the publication of 28 articles in peer-reviewed journals as of April 2016, contributing high-quality evidence that has informed clinical and public health decision-making. The ‘Prognosis and the effect of ART’ group focuses on clinical outcomes in patients treated with cART. The effect of age on the response to cART was studied in around 50 000 antiretroviral-naive individuals. Older individuals were characterized by low pre-ART CD4 cell counts, and experienced poorer immunological responses but better virological responses, indicating those who are diagnosed or treated late are at increased risk of clinical events.8 Non-IDU HIV-infected individuals who achieved high CD4 cell counts after starting cART were found to have mortality patterns similar to those in the general population. Mortality was found to be persistently higher in individuals with a previous AIDS diagnosis,9 whereas the incidence of AIDS events continued to decline until CD4 cell counts were greater than 750 cells/mm.3,10 In patients with viral suppression, the risk of new AIDS events or death followed a CD4 cell count gradient, even benefiting those with a CD4 cell count ≥ 500 cells/mm3.11 Individuals who were virally suppressed on cART for more than 3 years, but had incomplete CD4 cell recovery, experienced substantially higher rates of mortality from both AIDS and non-AIDS causes, suggesting that these individuals should be monitored for diseases not conventionally considered HIV-related, especially non-AIDS defining cancers and liver diseases.12 Future research will focus on new markers of the risk of morbidity and cause-specific mortality, outcomes in individuals treated for many years and outcomes in people ageing with HIV, particularly in the context of multi-morbidity and polypharmacy. The COHERE’s Pursuing Later Treatment Options (PLATO) II project looked at the rate of development of virological failure in adults, adolescents and children. When virological failure has occurred with at least two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), a non-nucleoside reverse transcriptase inhibitor (NNRTI) and a ritonavir-boosted protease inhibitor (PI), patients are said to have experienced triple-class virological failure (TCVF). Fewer than 9% of adult patients had experienced TCVF at year 9 after starting cART.13 The risk of TCVF was somewhat higher in children and particularly higher in adolescents.14 Virological suppression after TCVF was found to have increased from 20% in 2000 to 58% in 2009. Rates of AIDS and death also declined over time in people with TCVF.15 The incidence of TCVF in people on cART declined after 2008, and prevalence stabilized at around 2.5%.16 An approximately linear inverse relationship between log10 viral load and CD4 cell count in people with TCVF points to likely immunological benefits of reducing viral load, even by modest amounts, without necessarily resulting in an undetectable viral load.17 Late presentation is defined as an HIV diagnosis with a CD4 cell count < 350/mm3 or an AIDS diagnosis, regardless of CD4 cell count, within 6 months of HIV diagnosis. This definition was applied to 84 524 PLWH presenting for care between 1 January 2000 and 30 June 2011 in Europe. Late presentation was present in over half (53.8%) of the sample. It decreased over time in both Central and Northern Europe among homosexual men and heterosexuals but, in contrast, increased over time in Southern Europe among female heterosexuals and male IDUs and in Eastern Europe among IDUs. Late presentation was associated with increased mortality, especially in the first year after diagnosis, with significant variation across Europe.18 Further analyses study in late presentation within different regions and demographic have evidence of patterns in late presentation in Europe and have informed around and more for HIV and to HIV Of HIV-infected people, either present late with an opportunistic or are at significant risk of an The COHERE group has described both the and the incidence of in patients on cART with high CD4 cell including viral suppression as a it was found that be in an additional of patients when with based on CD4 cell which informed both the and the European treatment The group is similar analyses for and other and to the on the for specific The early of cART in the of has to be in clinical in but in Western with clinical this may not be the COHERE projects are the effect on mortality of the time of cART after a diagnosis of or results from a COHERE, and collaboration have that early cART not mortality in AIDS patients with in high-income and overall mortality was than that by the clinical in analyses how specific morbidity and mortality in the cART The COHERE group has on defining the risk and prognosis of cancers in the cART with a focus on and primary and, more The incidence of primary and were substantially reduced in patients on and of therapy at high CD4 cell counts is for these In contrast, the incidence of was not reduced by cART. CD4 cell counts declined suppression of on cART were at increased risk of analyses are in collaboration with the regions of The immunological over the of treatment and their effect on mortality were estimated in adults (aged ≥ of had treatment = and = CD4 cell counts decreased over the first but stabilized from with on The group is to the effect of the of in The Socioeconomic group studies in outcomes by and as a for in European countries with health care it has that individuals with not from cART and have a poorer response to Mortality in has found to be with which has to the COHERE’s larger sample has this group to study mortality in men and from among and how are at an increased risk of work which was in the first of UNAIDS The group to in cause-specific mortality by of COHERE in is a research which has both within and Europe. work on data HIV health and and its have this collaboration and COHERE’s in data has benefited other regional collaborations. to streamline data submission with the and cohort and reduced the of DMs. COHERE has for and COHERE’s is its of of across age and and the study of The of COHERE’s Europe, benefiting the global COHERE data are of those in care in countries with large regional and national cohorts. cohorts COHERE to across countries. of as populations has a as a of informed in countries as well as to COHERE HICDEP, the in data quality an ongoing In collaboration with COHERE has an for the collection and of of deaths in infected individuals. a proportion of deaths by non-AIDS of death is to and risk The of the of in Protocol a for and a data on of death and contributing in infected developed by the collaboration, has a COHERE’s ability to and to to new research it is the of cohort and clinic-based databases to clinical outcomes that were not initially of As the cohort of PLWH in Europe as and diseases have to the study of prognosis in the of cART. COHERE and its contributing cohorts were more be on HIV databases with other health databases hospital or other COHERE has with the patient via its patient on the COHERE SC. Data from COHERE to the of high-quality treatment and people living with HIV the of the as well as the ongoing of older with from COHERE have informed and the patient with and about treatment and standards of care. COHERE is a collaboration, which is in its and It to new evidence on clinical particularly late presentation and which clinical and public health As PLWH with a infection, between and cohorts of individuals are to the of HIV from its treatment and especially those to COHERE from of European cohorts in the COHERE cohorts must be to their data to and to the data submission out in the COHERE Data Management COHERE DMs the data submission to facilitate data Those in using COHERE data to conduct a project can a COHERE and a Data from from will the same as those from within the study are in the COHERE Manual of Operations [www.cohere.org]. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) is a cohort consortium that was set to address scientific questions that not be addressed by cohorts because of sample COHERE has grown from 33 cohorts in 2005 to 40 in 2015. The 2014 representing projects, compiled data from 331 481 individuals from European including 2808 children than 13 years), representing 2 135 896 person-years of follow-up. As a consortium of cohorts comprising and interval cohorts, the of patient follow-up varies. For clinic- or hospital-based cohorts, average patient follow-up reflects current standards of care in those countries. COHERE data on clinical antiretroviral therapy and other medications, estimated date of HIV seroconversion, opportunistic laboratory results and socio-demographic data according to the of projects. in a project in COHERE should a project proposal to the regional coordinating centres in and for by COHERE’s for The COHERE study group has de et HIV The and the The research to these results has from the European Seventh Framework under A of the of the participating cohorts can be found at contributing HIV AIDS Treatment de University cohort coordinating leads and of was a of the HIV until for and from also studies for and is a at has from the has from and The other have of interest to