Clinical characteristics of women with HIV in the RESPOND cohort: A descriptive analysis and comparison to men.

BACKGROUND: Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND. METHODS: RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM. RESULTS: Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/µl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/µL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001). CONCLUSION: RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV.

SARS-CoV-2 testing, positivity, and factors associated with COVID-19 among people with HIV across Europe in the multinational EuroSIDA cohort.

BACKGROUND: Although people with HIV might be at risk of severe outcomes from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus 2019 [COVID-19]), regional and temporal differences in SARS-CoV-2 testing in people with HIV across Europe have not been previously described. METHODS: We described the proportions of testing, positive test results, and hospitalizations due to COVID-19 between 1 January 2020 and 31 December 2021 in the EuroSIDA cohort and the factors associated with being tested for SARS-CoV-2 and with ever testing positive. RESULTS: Of 9012 participants, 2270 (25.2%, 95% confidence interval [CI] 24.3-26.1) had a SARS-CoV-2 polymerase chain reaction test during the study period (range: 38.3% in Northern to 14.6% in Central-Eastern Europe). People from Northern Europe, women, those aged <40 years, those with CD4 cell count <350 cells/mm3, and those with previous cardiovascular disease or malignancy were significantly more likely to have been tested, as were people with HIV in 2021 compared with those in 2020. Overall, 390 people with HIV (4.3%, 95% CI 3.9-4.8) tested positive (range: 2.6% in Northern to 7.1% in Southern Europe), and the odds of testing positive were higher in all regions than in Northern Europe and in 2021 than in 2020. In total, 64 people with HIV (0.7%, 95% CI 0.6-0.9) were hospitalized, of whom 12 died. Compared with 2020, the odds of positive testing decreased in all regions in 2021, and the associations with cardiovascular disease, malignancy, and use of tenofovir disoproxil fumarate disappeared in 2021. Among study participants, 58.9% received a COVID-19 vaccine (range: 72.0% in Southern to 14.8% in Eastern Europe). CONCLUSIONS: We observed large heterogeneity in SARS-CoV-2 testing and positivity and a low proportion of hospital admissions and deaths across the regions of Europe.

Healthcare delivery for HIV-positive people with tuberculosis in Europe.

BACKGROUND: In a 2013 survey, we reported distinct discrepancies in delivery of tuberculosis (TB) and HIV services in eastern Europe (EE) vs. western Europe (WE). OBJECTIVES: To verify the differences in TB and HIV services in EE vs. WE. METHODS: Twenty-three sites completed a survey in 2018 (EE, 14; WE, nine; 88% response rate). Results were compared across as well as within the two regions. When possible, results were compared with the 2013 survey. RESULTS: Delivery of healthcare was significantly less integrated in EE: provision of TB and HIV services at one site (36% in EE vs. 89% in WE; P = 0.034), and continued TB follow-up in one location (42% vs. 100%; P = 0.007). Although access to TB diagnostics, standard TB and HIV drugs was generally good, fewer sites in EE reported unlimited access to rifabutin/multi-drug-resistant TB (MDR-TB) drugs, HIV integrase inhibitors and opioid substitution therapy (OST). Compared with 2013, routine usage of GeneXpert was more common in EE in 2018 (54% vs. 92%; P = 0.073), as was access to moxifloxacin (46% vs. 91%; P = 0.033), linezolid (31% vs. 64%; P = 0.217), and bedaquiline (0% vs. 25%; P = 0.217). Integration of TB and HIV services (46% vs. 39%; P = 1.000) and provision of OST to patients with opioid dependency (54% vs. 46%; P = 0.695) remained unchanged. CONCLUSION: Delivery of TB and HIV healthcare, including integration of TB and HIV care and access to MDR-TB drugs, still differs between WE and EE, as well as between individual EE sites.

A new health care index predicts short term mortality for TB and HIV co-infected people.

BACKGROUND: Using 2004-2007 TB:HIV Study data from Europe and Latin America, we previously generated a health care index (HCI) for TB and HIV co-infected people. With improvements in diagnostic and management practices, we have now updated the HCI with new data.METHODS: We evaluated nine aspects of health care in Cox proportional hazards models on time from TB diagnosis to death. Kaplan-Meier methods were used to estimate the probability of death by HCI quartile.RESULTS: Of 1396 eligible individuals (72% male, 59% from Eastern Europe), 269 died within 12 months. Use of rifamycin/isoniazid/pyrazinamide-based treatment (HR 0.67, 95% CI 0.50-0.89), TB drug susceptibility testing (DST) and number of active TB drugs (DST + <3 drugs (HR 1.09, 95% CI 0.80-1.48), DST + ≥3 drugs (HR 0.49, 95% CI 0.35-0.70) vs. no DST), recent HIV-RNA measurement (HR 0.64, 95% CI 0.50-0.82) and combination antiretroviral therapy use (HR 0.72, 95% CI 0.53-0.97) were associated with mortality. These factors contributed respectively 5, -1, 8, 5 and 4 to the HCI. Lower HCI was associated with an increased probability of death; 30% (95% CI 26-35) vs. 9% (95% CI 6-13) in the lowest vs. the highest quartile.CONCLUSION: We found five potentially modifiable health care components that were associated with mortality among TB-HIV positive individuals. Validation of our HCI in other TB cohorts could enhance our findings.

Treatment outcomes of integrase inhibitors, boosted protease inhibitors and nonnucleoside reverse transcriptase inhibitors in antiretroviral-naïve persons starting treatment.

OBJECTIVES: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. METHODS: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12 ± 3 months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL < 200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4 count > 750 cells/µL or a 33% increase where the baseline CD4 count was ≥ 500 cells/µL. Poisson regression compared clinical failures (AIDS/death ≥ 14 days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. RESULTS: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged > 50 years, 2539 (49.4%) had CD4 counts < 350 cells/µL and 1891 (36.8%) had VL > 100 000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40-50 and > 50 years), CD4 count categories (≤ 350 vs. > 350 cells/µL) and VL categories at ART initiation (≤ 100 000 vs. > 100 000 copies/mL), with all investigated interactions being nonsignificant (P > 0.05). CONCLUSIONS: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

The EuroSIDA study: 25 years of scientific achievements.

The EuroSIDA study was initiated in 1994 and follows adult people living with HIV (PLHIV) in 100 collaborating clinics across 35 countries covering all European regions, Israel and Argentina. The study aims to study the long-term virological, immunological and clinical outcomes of PLHIV and to monitor temporal changes and regional differences in outcomes across Europe. Annually collected data include basic demographic characteristics, information on AIDS- and non-AIDS-related clinical events, and details about antiretroviral therapy (ART), hepatitis C treatment and other medications, in addition to a range of laboratory values. The summer 2016 data set held data from a total of 23 071 individuals contributing 174 481 person-years of follow-up, while EuroSIDA's unique plasma repository held over 160 000 samples. Over the past 25 years, close to 300 articles have been published in peer-reviewed journals (h-index 52), covering a range of scientific focus areas, including monitoring of clinical and virological outcomes, ART uptake, efficacy and adverse events, the influence of hepatitis virus coinfection, variation in the quality of HIV care and management across settings and regions, and biomarker research. Recognizing that there remain unresolved issues in the clinical care and management of PLHIV in Europe, EuroSIDA was one of the cohorts to found The International Cohort Consortium of Infectious Disease (RESPOND) cohort consortium on infectious diseases in 2017. In celebration of the EuroSIDA study's 25th anniversary, this article aims to summarize key scientific findings and outline current and future scientific focus areas.

Prevalence of impaired renal function in virologically suppressed people living with HIV compared with controls: the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

OBJECTIVES: While renal impairment is reported more frequently in people living with HIV (PLWH) than in the general population, the PLWH samples in previous studies have generally been dominated by those at high renal risk. METHODS: Caucasian PLWH who were virologically suppressed on antiretroviral treatment and did not have injecting drug use or hepatitis C were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Sex- and age-matched controls were recruited 1:4 from the Copenhagen General Population Study up to November 2016. We defined renal impairment as one measurement of estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 , and assessed associated factors using adjusted logistic regression models. The impact of HIV-related factors was explored in a subanalysis. RESULTS: Among 598 PLWH and 2598 controls, the prevalence of renal impairment was 3.7% [95% confidence interval (CI) 2.3-5.5%] and 1.7% (95% CI 1.2-2.2%; P = 0.0014), respectively. After adjustment, HIV status was independently associated with renal impairment [odds ratio (OR) 3.4; 95% CI 1.8-6.3]. In addition, older age [OR 5.4 (95% CI 3.9-7.5) per 10 years], female sex [OR 5.0 (95% CI 2.6-9.8)] and diabetes [OR 2.9 (95% CI 1.3-6.7)] were strongly associated with renal impairment. The association between HIV status and renal impairment became stronger with older age (P = 0.02 for interaction). Current and nadir CD4 counts, duration of HIV infection and previous AIDS-defining diagnosis were not associated with renal impairment among virologically suppressed PLWH. CONCLUSIONS: The prevalence of renal impairment is low among low-risk virologically suppressed Caucasian PLWH, but remains significantly higher than in controls. Renal impairment therefore remains a concern in all PLWH and requires ongoing attention.

Establishing a hepatitis C continuum of care among HIV/hepatitis C virus-coinfected individuals in EuroSIDA.

OBJECTIVES: The aim of the study was to establish a methodology for evaluating the hepatitis C continuum of care in HIV/hepatitis C virus (HCV)-coinfected individuals and to characterize the continuum in Europe on 1 January 2015, prior to widespread access to direct-acting antiviral (DAA) therapy. METHODS: Stages included in the continuum were as follows: anti-HCV antibody positive, HCV RNA tested, currently HCV RNA positive, ever HCV RNA positive, ever received HCV treatment, completed HCV treatment, follow-up HCV RNA test, and cure. Sustained virological response (SVR) could only be assessed for those with a follow-up HCV RNA test and was defined as a negative HCV RNA result measured > 12 or 24 weeks after stopping treatment. RESULTS: Numbers and percentages for the stages of the HCV continuum of care were as follows: anti-HCV positive (n = 5173), HCV RNA tested (4207 of 5173; 81.3%), currently HCV RNA positive (3179 of 5173; 61.5%), ever HCV RNA positive (n = 3876), initiated HCV treatment (1693 of 3876; 43.7%), completed HCV treatment (1598 of 3876; 41.2%), follow-up HCV RNA test to allow SVR assessment (1195 of 3876; 30.8%), and cure (629 of 3876; 16.2%). The proportion that achieved SVR was 52.6% (629 of 1195). There were significant differences between regions at each stage of the continuum (P < 0.0001). CONCLUSIONS: In the proposed HCV continuum of care for HIV/HCV-coinfected individuals, we found major gaps at all stages, with almost 20% of anti-HCV-positive individuals having no documented HCV RNA test and a low proportion achieving SVR, in the pre-DAA era.

Diagnostic performance of clinical characteristics to detect airflow limitation in people living with HIV and in uninfected controls.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. METHODS: Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. RESULTS: A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self-reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack-years smoked [0.65; 95% confidence interval (CI) 0.58-0.72] and wheezing (0.64; 95% CI 0.57-0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63-0.79) versus 0.65 (95% CI 0.63-0.68), respectively; P = 0.06]. CONCLUSIONS: Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH.

Cytomegalovirus (CMV) Disease Despite Weekly Preemptive CMV Strategy for Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation.

BACKGROUND: Transplant recipients presenting with cytomegalovirus (CMV) disease at the time of diagnosis of CMV DNAemia pose a challenge to a preemptive CMV management strategy. However, the rate and risk factors of such failure remain uncertain. METHODS: Solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT) recipients with a first episode of CMV polymerase chain reaction (PCR) DNAemia within the first year posttransplantation were evaluated (n = 335). Patient records were reviewed for presence of CMV disease at the time of CMV DNAemia diagnosis. The distribution and prevalence of CMV disease were estimated, and the odds ratio (OR) of CMV disease was modeled using logistic regression. RESULTS: The prevalence of CMV disease increased for both SOT and HSCT with increasing diagnostic CMV PCR load and with screening intervals >14 days. The only independent risk factor in multivariate analysis was increasing CMV DNAemia load of the diagnostic CMV PCR (OR = 6.16; 95% confidence interval, 2.09-18.11). Among recipients receiving weekly screening (n = 147), 16 (10.8%) had CMV disease at the time of diagnosis of CMV DNAemia (median DNAemia load 628 IU/mL; interquartile range, 432-1274); 93.8% of these cases were HSCT and lung transplant recipients. CONCLUSIONS: Despite application of weekly screening intervals, HSCT and lung transplant recipients in particular presented with CMV disease at the time of diagnosis of CMV DNAemia. Additional research to improve the management of patients at risk of presenting with CMV disease at low levels of CMV DNAemia and despite weekly screening is warranted.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort.

OBJECTIVES: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. METHODS: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. RESULTS: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. CONCLUSIONS: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir-based and non-raltegravir-based combination antiretroviral therapy regimens.

OBJECTIVES: There are currently few data on the long-term risk of cancer and death in individuals taking raltegravir (RAL). The aim of this analysis was to evaluate whether there is evidence for an association. METHODS: The EuroSIDA cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after 21 December 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between 1 January 2005 and 20 December 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. Baseline characteristics were compared using logistic regression. The incidences of newly diagnosed malignancies and death were compared using Poisson regression. RESULTS: The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended to be higher in the RAL cohort vs. the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95-1.80] and vs. the CONC cohort (aOR 1.89; 95% CI 1.37-2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84-1.46) per 100 PYFU in the RAL cohort vs. 1.20 (95% CI 0.90-1.61) and 0.83 (95% CI 0.70-0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47-1.14 for RALvs. HIST; RR 0.95; 95% CI 0.65-1.39 for RALvs. CONC] or mortality (adjusted RR 0.87; 95% CI 0.53-1.43 for RALvs. HIST; RR 1.14; 95% CI 0.76-1.72 for RALvs. CONC). CONCLUSIONS: We found no evidence for an oncogenic risk or poorer survival associated with using RAL compared with control groups.

Management of MDR-TB in HIV co-infected patients in Eastern Europe: Results from the TB:HIV study.

OBJECTIVES: Mortality among HIV patients with tuberculosis (TB) remains high in Eastern Europe (EE), but details of TB and HIV management remain scarce. METHODS: In this prospective study, we describe the TB treatment regimens of patients with multi-drug resistant (MDR) TB and use of antiretroviral therapy (ART). RESULTS: A total of 105 HIV-positive patients had MDR-TB (including 33 with extensive drug resistance) and 130 pan-susceptible TB. Adequate initial TB treatment was provided for 8% of patients with MDR-TB compared with 80% of those with pan-susceptible TB. By twelve months, an estimated 57.3% (95%CI 41.5-74.1) of MDR-TB patients had started adequate treatment. While 67% received ART, HIV-RNA suppression was demonstrated in only 23%. CONCLUSIONS: Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care.

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

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Reference curves aid the evaluation of the immune response early after antiretroviral therapy initiation that leads to viral control.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Hepatitis C virus (HCV) RNA profiles among chronic HIV/HCV-coinfected individuals in ESPRIT; spontaneous HCV RNA clearance observed in nine individuals.

OBJECTIVES: Studies have shown that hepatitis C virus (HCV) RNA levels remain stable over time in HIV/HCV-coinfected individuals taking combination antiretroviral therapy (cART), while spontaneous clearance of HCV RNA during the persistent infection phase has been documented only rarely among those with the CC interleukin (IL)-28B genotype. This study describes HCV RNA profiles and factors associated with changes over time in HCV RNA levels in the ESPRIT study. METHODS: HIV/HCV-coinfected individuals positive for HCV RNA were included in the study. Follow-up was counted from the first HCV RNA positive test and censored at the initiation of interferon-based treatment. HCV RNA and IL-28B measurements were performed in the same reference laboratory. Random effects mixed models were used to analyse changes over time in HCV RNA. RESULTS: A total of 312 ESPRIT patients were included in the study (151 in the arm receiving subcutaneous recombinant IL-2 and 161 in the control arm). Most of the patients were white (89%) and male (76%), and they had a median of 5 HCV RNA measurements per person [interquartile range (IQR) 3-6; range 1-9]. Median follow-up was 5 years (IQR: 2-6 years). At baseline, 96% of patients were taking cART and 93% had undetectable HIV RNA. Mean HCV RNA levels decreased by 13% per year over the study period [95% confidence interval (CI) 8-18%; P < 0.0001]. Baseline HCV RNA levels and the change over time in HCV RNA did not differ by randomization arm (P = 0.16 and P = 0.56, respectively). Nine individuals spontaneously cleared HCV RNA during follow-up [IL-28B genotypes: CC, five patients (56%); CT, four patients (44%)]. CONCLUSIONS: HCV RNA levels decreased over time in this population with well-controlled HIV infection. Spontaneous clearance of HCV RNA was documented in five individuals with IL-28B genotype CC and four with the CT genotype.

Infection-related and -unrelated malignancies, HIV and the aging population.

OBJECTIVES: HIV-positive people have increased risk of infection-related malignancies (IRMs) and infection-unrelated malignancies (IURMs). The aim of the study was to determine the impact of aging on future IRM and IURM incidence. METHODS: People enrolled in EuroSIDA and followed from the latest of the first visit or 1 January 2001 until the last visit or death were included in the study. Poisson regression was used to investigate the impact of aging on the incidence of IRMs and IURMs, adjusting for demographic, clinical and laboratory confounders. Linear exponential smoothing models forecasted future incidence. RESULTS: A total of 15 648 people contributed 95 033 person-years of follow-up, of whom 610 developed 643 malignancies [IRMs: 388 (60%); IURMs: 255 (40%)]. After adjustment, a higher IRM incidence was associated with a lower CD4 count [adjusted incidence rate ratio (aIRR) CD4 count < 200 cells/µL: 3.77; 95% confidence interval (CI) 2.59, 5.51; compared with ≥ 500 cells/µL], independent of age, while a CD4 count < 200 cells/µL was associated with IURMs in people aged < 50 years only (aIRR: 2.51; 95% CI 1.40-4.54). Smoking was associated with IURMs (aIRR: 1.75; 95% CI 1.23, 2.49) compared with never smokers in people aged ≥ 50 years only, and not with IRMs. The incidences of both IURMs and IRMs increased with older age. It was projected that the incidence of IRMs would decrease by 29% over a 5-year period from 3.1 (95% CI 1.5-5.9) per 1000 person-years in 2011, whereas the IURM incidence would increase by 44% from 4.1 (95% CI 2.2-7.2) per 1000 person-years over the same period. CONCLUSIONS: Demographic and HIV-related risk factors for IURMs (aging and smoking) and IRMs (immunodeficiency and ongoing viral replication) differ markedly and the contribution from IURMs relative to IRMs will continue to increase as a result of aging of the HIV-infected population, high smoking and lung cancer prevalence and a low prevalence of untreated HIV infection. These findings suggest the need for targeted preventive measures and evaluation of the cost-benefit of screening for IURMs in HIV-infected populations.

European AIDS Clinical Society Standard of Care meeting on HIV and related coinfections: The Rome Statements.

OBJECTIVES: The objective of the 1st European AIDS Clinical Society meeting on Standard of Care in Europe was to raise awareness of the European scenario and come to an agreement on actions that could be taken in the future. METHODS: Data-driven presentations were given on specific topics followed by interactive panel discussions. RESULTS: In Eastern European countries, the epidemic is largely driven by injecting drug use, in contrast with Western Europe where the infection mainly occurs through heterosexual contact. A high proportion of people living with HIV remain unaware of their infection. Substantial differences exist in Eastern Europe and Central Asia with respect to treatment coverage, regimen availability and continuity of drug supply. In 2012, tuberculosis case notification rates were 5-10 times higher in Eastern Europe compared with Western Europe, with an alarming proportion of newly diagnosed multi-drug-resistant cases. Hepatitis C is widespread in selected geographical areas and risk groups. CONCLUSIONS: The key conclusion from the meeting was that a high-priority group of actions could be identified, including: increasing HIV awareness and testing, improving training for health care providers, ensuring equitable patient access to treatments and diagnostics for HIV and comorbidities, and implementing best practices in infection control and treatment of HIV-infected patients coinfected with tuberculosis and hepatitis C virus, for whom direct acting antiviral treatment. should be considered.

Short-term weight gain after antiretroviral therapy initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study.

OBJECTIVES: The aim of the study was to assess the impact of the gain in body mass index (BMI) observed immediately after antiretroviral therapy (ART) initiation on the subsequent risk of cardiovascular disease (CVD) and diabetes. METHODS: We analysed data from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) cohort study. Outcomes were development of (i) CVD (composite of myocardial infarction/stroke/coronary procedure) and (ii) diabetes. The main exposure variable was change in BMI from ART initiation (pre-ART) to 1 year after initiation (continuous variable) in treatment-naïve individuals initiating ART with no history of CVD or diabetes (for respective outcomes). BMI [weight (kg)/(height (m))(2)] was categorized as underweight (< 18.5), normal (18.5-25), overweight (25-30) and obese (> 30). Poisson regression models were fitted stratified for each pre-ART BMI category to allow for category-specific estimates of incidence rate ratio (IRR). Models were adjusted for pre-ART BMI and CD4 count, key known risk factors (time-updated where possible) and calendar year. RESULTS: A total of 97 CVD events occurred in 43,982 person-years (n = 9321) and 125 diabetes events in 43,278 person-years (n = 9193). In fully adjusted analyses for CVD, the IRR/unit gain in BMI (95% confidence interval) in the first year of ART, by pre-ART BMI category, was: underweight, 0.90 (0.60-1.37); normal, 1.18 (1.05-1.33); overweight, 0.87 (0.70-1.10), and obese, 0.95 (0.71-1.28) (P for interaction = 0.04). For diabetes, the IRR/unit gain in BMI was 1.11 (95% confidence interval 1.03 to 1.21), regardless of pre-ART BMI (P for interaction > 0.05). CONCLUSIONS: Short-term gain in BMI following ART initiation appeared to increase the longer term risk of CVD, but only in those with pre-ART BMI in the normal range. It was also associated with increased risk of diabetes regardless of pre-ART BMI.