Collaboration Of Observational HIV Epidemiological Research Europe Research Articles

No need for secondary Pneumocystis jirovecii pneumonia prophylaxis in adult people living with HIV from Europe on ART with suppressed viraemia and a CD4 cell count greater than 100cells/µL.

IntroductionSince the beginning of the HIV epidemic in resource‐rich countries, Pneumocystis jirovecii pneumonia (PjP) is one of the most frequent opportunistic AIDS‐defining infections. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) has shown that primary Pneumocystis jirovecii Pneumonia (PjP) prophylaxis can be safely withdrawn in patients with CD4 counts of 100 to 200 cells/µL if plasma HIV‐RNA is suppressed on combination antiretroviral therapy. Whether this holds true for secondary prophylaxis is not known, and this has proved difficult to determine due to the much lower population at risk.MethodsWe estimated the incidence of secondary PjP by including patient data collected from 1998 to 2015 from the COHERE cohort collaboration according to time‐updated CD4 counts, HIV‐RNA and use of PjP prophylaxis in persons >16 years of age. We fitted a Poisson generalized additive model in which the smoothed effect of CD4 was modelled by a restricted cubic spline, and HIV‐RNA was stratified as low (<400), medium (400 to 10,000) or high (>10,000copies/mL).ResultsThere were 373 recurrences of PjP during 74,295 person‐years (py) in 10,476 patients. The PjP incidence in the different plasma HIV‐RNA strata differed significantly and was lowest in the low stratum. For patients off prophylaxis with CD4 counts between 100 and 200 cells/µL and HIV‐RNA below 400 copies/mL, the incidence of recurrent PjP was 3.9 (95% CI: 2.0 to 5.8) per 1000 py, not significantly different from patients on prophylaxis in the same stratum (1.9, 95% CI: 0.1 to 3.7).ConclusionsHIV viraemia importantly affects the risk of recurrent PjP. In virologically suppressed patients on ART with CD4 counts of 100 to 200/µL, the incidence of PjP off prophylaxis is below 10/1000 py. Secondary PjP prophylaxis may be safely withheld in such patients. While European guidelines recommend discontinuing secondary PjP prophylaxis only if CD4 counts rise above 200 cells/mL, the latest US Guidelines consider secondary prophylaxis discontinuation even in patients with a CD4 count above 100 cells/µL and suppressed viral load. Our results strengthen and support this US recommendation.

Estimating the burden of HIV late presentation and its attributable morbidity and mortality across Europe 2010\u20132016

BackgroundLate presentation (LP), defined as a CD4 count < 350/mm3 or an AIDS-event at HIV-diagnosis, remains a significant problem across Europe. Linking cohort and surveillance data, we assessed the country-specific burden of LP during 2010–2016 and the occurrence of new AIDS events or deaths within 12 months of HIV-diagnosis believed to be attributable to LP.MethodsCountry-specific percentages of LP and AIDS-events/death rates (assessed with Poisson regression) observed in The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) and EuroSIDA cohorts, were applied to new HIV-diagnoses reported to the European Centre for Disease Prevention and Control. The estimated number of LP in the whole population was then calculated, as was the number of excess AIDS-events/deaths in the first 12 months following HIV-diagnosis assumed to be attributable to LP (difference in estimated events between LP and non-LP).ResultsThirty-nine thousand two hundred four persons were included from the COHERE and EuroSIDA cohorts, of whom 18,967 (48.4%; 95% Confidence Interval [CI] 47.9–48.9) were classified as LP, ranging from 36.9% in Estonia (95%CI 25.2–48.7) and Ukraine (95%CI 30.0–43.8) to 64.2% in Poland (95%CI 57.2–71.3). We estimated a total of > 320,000 LP and 12,050 new AIDS-events/deaths attributable to LP during 2010–2016, with the highest estimated numbers of LP and excess AIDS-events/deaths in Eastern Europe. Country-level estimates of excess events ranged from 17 AIDS-events/deaths (95%CI 0–533) in Denmark to 10,357 (95%CI 7768-147,448) in Russia.ConclusionsAcross countries in Europe, the burden of LP was high, with the highest estimated number of LP and excess AIDS-events/deaths being in Eastern Europe. Effective strategies are needed to reduce LP and the attributable morbidity and mortality that could be potentially avoided.

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

Many questions about the long-term effects of combination antiretroviral therapy (cART) on clinical outcomes in people living with HIV (PLWH) and their impact on health systems remain unanswered. The Collaboration of Observational HIV Epidemiological Research Europe (COHERE) was formed in 2005 to pool and harmonize existing longitudinal data on people living with HIV in Europe, to answer key research questions that could not be addressed adequately by individual cohorts. Key research questions include long-term prognosis, rare outcomes, and variations across patient groups, settings and health systems. COHERE uses the HIV Cohorts Data Exchange Protocol, a standardized and validated method of data structure and transfer, to compile data from over 40 cohorts of PLWH residing in Europe, representing 331 481 individuals, including 2808 children (<13), representing 2 135 896 person-years of follow-up. COHERE compiles data on clinical characteristics, antiretroviral therapy and other medications, HIV seroconversion, opportunistic infections, laboratory results and socio demographic data. External collaborators interested in conducting a project in COHERE should submit a project proposal to the Regional Coordinating Centres in Bordeaux and Copenhagen for review by COHERE’s governing bodies (see www.cohere.org for further information).

Chronic Hepatitis B and C Virus Infection and Risk for Non-Hodgkin Lymphoma in HIV-Infected Patients: A Cohort Study.

Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIV-infected patients. Cohort study. 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. A total of 52479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. In HIV-infected patients receiving ART, chronic co-infection with HBV and HCV is associated with an increased risk for NHL. European Union Seventh Framework Programme.

Reference curves for CD4 T-cell count response to combination antiretroviral therapy in HIV-1-infected treatment-naïve patients.

The aim of this work was to provide a reference for the CD4 T-cell count response in the early months after the initiation of combination antiretroviral therapy (cART) in HIV-1-infected patients. All patients in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) cohort who were aged ≥ 18 years and started cART for the first time between 1 January 2005 and 1 January 2010 and who had at least one available measurement of CD4 count and a viral load ≤ 50 HIV-1 RNA copies/mL at 6 months (± 3 months) after cART initiation were included in the study. Unadjusted and adjusted references curves and predictions were obtained using quantile regressions. A total of 28 992 patients were included in the study. The median CD4 T-cell count at treatment initiation was 249 [interquartile range (IQR) 150, 336] cells/μL. The median observed CD4 counts at 6, 9 and 12 months were 382 (IQR 256, 515), 402 (IQR 274, 543) and 420 (IQR 293, 565) cells/μL. The two main factors explaining the variation of CD4 count at 6 months were AIDS stage and CD4 count at cART initiation. A CD4 count increase of ≥ 100 cells/mL is generally required in order that patients stay 'on track' (i.e. with a CD4 count at the same percentile as when they started), with slightly higher gains required for those starting with CD4 counts in the higher percentiles. Individual predictions adjusted for factors influencing CD4 count were more precise. Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

Economic and health implications from earlier detection of HIV infection in the United Kingdom.

PurposeTo model the budget and survival impact of implementing interventions to increase the proportion of HIV infections detected early in a given UK population.Patients and methodsA Microsoft Excel decision model was designed to generate a set of outcomes for a defined population. Survival was modeled on the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study extrapolated to a 5-year horizon as a constant hazard. Hazard rates were specific to age, sex, and whether detection was early or late. The primary outcomes for each year up to 5 years were: annual costs, numbers of infected cases, hospital admissions, and surviving cases. Three locations in the UK were chosen to model outcomes across a range of HIV prevalence areas: Lambeth, Southwark, and Lewisham (LSL), Greater Manchester Cluster (GMC), and Kent and Medway (K&M).ResultsIn LSL, the projected cumulative cost savings over 5 years were £3,210,206 or £5,290,206 when including the value of the 104 life-years saved. Savings were insensitive to transmission rates, but sensitive in direct proportion to the percentage shift from late to early detection. In GMC, savings were in a similar proportion to LSL, but the magnitude was smaller, as a consequence of the lower base-case HIV prevalence. In K&M, with a smaller population and lower HIV prevalence than GMC, savings were commensurately smaller (£733,202 cumulatively over 5 years).ConclusionThe results strengthen the rationale for implementing increased testing in high prevalence areas. However, in areas of low prevalence, it is unlikely that costs will be returned over a 5-year period.

Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013.

Late presentation (LP) for HIV care across Europe remains a significant issue. We provide a cross-European update from 34 countries on the prevalence and risk factors of LP for 2010-2013. People aged ≥ 16 presenting for HIV care (earliest of HIV-diagnosis, first clinic visit or cohort enrollment) after 1 January 2010 with available CD4 count within six months of presentation were included. LP was defined as presentation with a CD4 count < 350/mm(3) or an AIDS defining event (at any CD4), in the six months following HIV diagnosis. Logistic regression investigated changes in LP over time. A total of 30,454 people were included. The median CD4 count at presentation was 368/mm(3) (interquartile range (IQR) 193-555/mm(3)), with no change over time (p = 0.70). In 2010, 4,775/10,766 (47.5%) were LP whereas in 2013, 1,642/3,375 (48.7%) were LP (p = 0.63). LP was most common in central Europe (4,791/9,625, 49.8%), followed by northern (5,704/11,692; 48.8%), southern (3,550/7,760; 45.8%) and eastern Europe (541/1,377; 38.3%; p < 0.0001). There was a significant increase in LP in male and female people who inject drugs (PWID) (adjusted odds ratio (aOR)/year later 1.16; 95% confidence interval (CI): 1.02-1.32), and a significant decline in LP in northern Europe (aOR/year later 0.89; 95% CI: 0.85-0.94). Further improvements in effective HIV testing strategies, with a focus on vulnerable groups, are required across the European continent.

Risk Factors and Outcomes for Late Presentation for HIV-Positive Persons in Europe: Results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE)

Few studies have monitored late presentation (LP) of HIV infection over the European continent, including Eastern Europe. Study objectives were to explore the impact of LP on AIDS and mortality. LP was defined in Collaboration of Observational HIV Epidemiological Research Europe (COHERE) as HIV diagnosis with a CD4 count <350/mm(3) or an AIDS diagnosis within 6 months of HIV diagnosis among persons presenting for care between 1 January 2000 and 30 June 2011. Logistic regression was used to identify factors associated with LP and Poisson regression to explore the impact on AIDS/death. 84,524 individuals from 23 cohorts in 35 countries contributed data; 45,488 were LP (53.8%). LP was highest in heterosexual males (66.1%), Southern European countries (57.0%), and persons originating from Africa (65.1%). LP decreased from 57.3% in 2000 to 51.7% in 2010/2011 (adjusted odds ratio [aOR] 0.96; 95% CI 0.95-0.97). LP decreased over time in both Central and Northern Europe among homosexual men, and male and female heterosexuals, but increased over time for female heterosexuals and male intravenous drug users (IDUs) from Southern Europe and in male and female IDUs from Eastern Europe. 8,187 AIDS/deaths occurred during 327,003 person-years of follow-up. In the first year after HIV diagnosis, LP was associated with over a 13-fold increased incidence of AIDS/death in Southern Europe (adjusted incidence rate ratio [aIRR] 13.02; 95% CI 8.19-20.70) and over a 6-fold increased rate in Eastern Europe (aIRR 6.64; 95% CI 3.55-12.43). LP has decreased over time across Europe, but remains a significant issue in the region in all HIV exposure groups. LP increased in male IDUs and female heterosexuals from Southern Europe and IDUs in Eastern Europe. LP was associated with an increased rate of AIDS/deaths, particularly in the first year after HIV diagnosis, with significant variation across Europe. Earlier and more widespread testing, timely referrals after testing positive, and improved retention in care strategies are required to further reduce the incidence of LP.

The Incidence of AIDS-Defining Illnesses at a Current CD4 Count ≥200 Cells/µL in the Post–Combination Antiretroviral Therapy Era

Few studies consider the incidence of individual AIDS-defining illnesses (ADIs) at higher CD4 counts, relevant on a population level for monitoring and resource allocation. Individuals from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) aged ≥14 years with ≥1 CD4 count of ≥200 µL between 1998 and 2010 were included. Incidence rates (per 1000 person-years of follow-up [PYFU]) were calculated for each ADI within different CD4 strata; Poisson regression, using generalized estimating equations and robust standard errors, was used to model rates of ADIs with current CD4 ≥500/µL. A total of 12 135 ADIs occurred at a CD4 count of ≥200 cells/µL among 207 539 persons with 1 154 803 PYFU. Incidence rates declined from 20.5 per 1000 PYFU (95% confidence interval [CI], 20.0-21.1 per 1000 PYFU) with current CD4 200-349 cells/µL to 4.1 per 1000 PYFU (95% CI, 3.6-4.6 per 1000 PYFU) with current CD4 ≥ 1000 cells/µL. Persons with a current CD4 of 500-749 cells/µL had a significantly higher rate of ADIs (adjusted incidence rate ratio [aIRR], 1.20; 95% CI, 1.10-1.32), whereas those with a current CD4 of ≥1000 cells/µL had a similar rate (aIRR, 0.92; 95% CI, .79-1.07), compared to a current CD4 of 750-999 cells/µL. Results were consistent in persons with high or low viral load. Findings were stronger for malignant ADIs (aIRR, 1.52; 95% CI, 1.25-1.86) than for nonmalignant ADIs (aIRR, 1.12; 95% CI, 1.01-1.25), comparing persons with a current CD4 of 500-749 cells/µL to 750-999 cells/µL. The incidence of ADIs was higher in individuals with a current CD4 count of 500-749 cells/µL compared to those with a CD4 count of 750-999 cells/µL, but did not decrease further at higher CD4 counts. Results were similar in patients virologically suppressed on combination antiretroviral therapy, suggesting that immune reconstitution is not complete until the CD4 increases to >750 cells/µL.

Calendar Time Trends in the Incidence and Prevalence of Triple-Class Virologic Failure in Antiretroviral Drug-Experienced People With HIV in Europe

Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0-7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.

Prognosis of HIV-associated non-Hodgkin lymphoma in patients starting combination antiretroviral therapy

We examined survival and prognostic factors of patients who developed HIV-associated non-Hodgkin lymphoma (NHL) in the era of combination antiretroviral therapy (cART). Multicohort collaboration of 33 European cohorts. We included all cART-naive patients enrolled in cohorts participating in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) who were aged 16 years or older, started cART at some point after 1 January 1998 and developed NHL after 1 January 1998. Patients had to have a CD4 cell count after 1 January 1998 and one at diagnosis of the NHL. Survival and prognostic factors were estimated using Weibull models, with random effects accounting for heterogeneity between cohorts. Of 67 659 patients who were followed up during 304 940 person-years, 1176 patients were diagnosed with NHL. Eight hundred and forty-seven patients (72%) from 22 cohorts met inclusion criteria. Survival at 1 year was 66% [95% confidence interval (CI) 63-70%] for systemic NHL (n = 763) and 54% (95% CI: 43-65%) for primary brain lymphoma (n = 84). Risk factors for death included low nadir CD4 cell counts and a history of injection drug use. Patients developing NHL on cART had an increased risk of death compared with patients who were cART naive at diagnosis. In the era of cART two-thirds of patients diagnosed with HIV-related systemic NHL survive for longer than 1 year after diagnosis. Survival is poorer in patients diagnosed with primary brain lymphoma. More advanced immunodeficiency is the dominant prognostic factor for mortality in patients with HIV-related NHL.

Impact of Combined Anti-Retroviral Therapy on HIV-Associated Non-Hodgkin-Lymphoma - a Prospective European Multi-Cohort Study on Behalf of the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) Study Group

Background: Following its introduction in 1996, combination antiretroviral therapy (cART) has led to a substantial reduction in HIV-associated morbidity and mortality. The decline has, however, been less pronounced for non-Hodgkin lymphoma (NHL) than for other HIV-related complications, and NHL has become the most common cancer associated with HIV. Within the framework of a large prospective European multi-cohort project, the Collaboration of Observational HIV Epidemiological Research Europe (COHERE), we studied the incidence and risk factors for the development and survival of NHL in HIV-infected patients in the cART era.Methods: We analyzed the data of HIV- infected adult patients (aged >16 years) who were cART naïve at inclusion and started cART after 01.01.1998, at a time when cART had become well established and widely used in Europe. cART was defined as a regimen of at least 3 antiretroviral drugs. Patients had to have CD4 count measurements available before the start of cART and the diagnosis of NHL. Patients developing NHL before receiving cART (“not on cART”) and patients developing NHL while receiving cART (“on cART”) were analyzed separately. Both patients with Primary Brain Lymphoma (PBL) and systemic NHL were included in the analysis. Incidence rates were calculated based on the Poisson distribution; risk factors were estimated using crude and adjusted Weibull models, with random effects to account for heterogeneity between cohorts. Models with time varying covariates were used to explore the effects of CD4 cell counts and plasma HIV-RNA loads over time. Survival was estimated using Kaplan-Meier life table probabilities, with 95% confidence intervals (95% CI).Results: For the incidence analysis 56,305 patients from 22 cohort studies across Europe with 212,042 person-years at risk were evaluated. The incidence for NHL (both systemic NHL and PBL) in patients not on cART was 519 (95% CI 448 to 602) per 100,000 personyears compared to 229 (95% CI 208 to 252) per 100,000 person-years in those on cART. The corresponding rates for PBL were 57 (95% CI 36 to 89) per 100,000 person-years and 24 (95% CI 18 to 33) per 100,000 person years. In cART naïve patients risk factors for NHL were older age and low CD4 cell count nadirs. When included as time up-dated variables, high plasma HIV-1 RNA loads and low CD4 cell counts emerged as important risk factors. In patients receiving cART risk factors included low CD4 cell count nadirs, older age, and groups associated with HHV-8 infection, i.e. men having sex with men and patients with a previous diagnosis of Kaposi Sarcoma. Time up-dated HIV-1 RNA plasma concentration and CD4 cell count were also associated with developing NHL while on cART. For the survival analysis 847 NHL patients were eligible. Of those, 364 (43%) were cART naïve at diagnosis of NHL. After one year 66% (95% CI 63%–70%) of patients with systemic NHL and 54% (95% CI 43%–65%) of patients with PBL were alive. Risk factors for death were diagnosis of PBL, low CD4 cell count nadir and history of injection drug use.Conclusions: Combined anti-retroviral therapy reduces the risk of developing NHL. In the era of cART more advanced immunodeficiency is the dominant risk factors for developing NHL both in patients receiving and not receiving cART. Two thirds of patients diagnosed with HIV-related NHL other than PBL survive for longer than one year after diagnosis. Survival is poorer in patients diagnosed with PBL.