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OBJECTIVES: The causes of death among HIV-positive patients may have changed since the introduction of highly active antiretroviral therapy (HAART). We investigated these changes, patients who died without an AIDS diagnosis and factors relating to pre-AIDS deaths. METHODS: Analyses of 1826 deaths among EuroSIDA patients, an observational study of 8556 patients. Incidence rates of pre-AIDS deaths were compared to overall rates. Factors relating to pre-AIDS deaths were identified using Cox regression. RESULTS: Death rates declined from 15.6 to 2.7 per 100 person-years of follow-up (PYFU) between 1994 and 2001. Pre-AIDS incidence declined from 2.4 to 1.1 per 100 PYFU. The ratio of overall to pre-AIDS deaths peaked in 1996 at 8.4 and dropped to < 3 after 1998. The adjusted odds of dying following one AIDS defining event (ADE) increased yearly (odds ratio, 1.53; P < 0.001), conversely the odds of dying following three or more ADE decreased yearly (odds ratio, 0.79; P < 0.001). The proportion of deaths that followed an HIV-related disease decreased by 23% annually; in contrast there was a 32% yearly increase in the proportion of deaths due to known causes other than HIV-related or suicides. Injecting drug users (IDU) were significantly more likely to die before an ADE than homosexuals (relative hazard, 2.97; P < 0.0001) and patients from northern/eastern Europe (relative hazard, 2.01; P < 0.0001) were more likely to die pre-AIDS than southern patients. CONCLUSIONS: The proportion of pre-AIDS deaths increased from 1994 to 2001; however, the incidence of pre-AIDS deaths and deaths overall declined. IDU and subjects from northern/eastern Europe had an increased risk of pre-AIDS death. HIV-positive patients live longer therefore it is essential to continue to monitor all causes of mortality to identify changes.

In most studies, people who have not responded virologically to a protease inhibitor (PI)-containing regimen have tended to experience poor virologic responses to subsequent regimens. We describe the 2-year viral load, CD4 count, and clinical outcome of a multidrug regimen used in 60 people who had not responded virologically to a PI-containing regimen. At baseline, median CD4 count was 126/mm 3 (nadir 30/mm 3 ) and median viral load was 320,000 copies/mL. A median of five antiretroviral drugs had previously been used, of which a median of two were PIs. Of these patients, 16% had previously used another nonnucleoside reverse transcriptase inhibitor besides efavirenz. The multidrug regimen (median 5 drugs) started most commonly included efavirenz (100%), at least one PI (92%, usually indinavir/ritonavir), didanosine (78%), and hydroxyurea (74%). At year 2, 5 patients had died and 5 had no measure available. Nine patients developed a new AIDS event and 10 patients were known to have stopped all antiretroviral therapy. Thirty-one patients (52% of the whole group, 72% of those remaining on therapy with viral load value available) had viral load

This is the author’s version of a work accepted for publication by International Medical Press. Changes resulting from the publishing process, including peer review, editing and formatting, might not be reflected in this document. A definitive version was published in Antiviral Therapy, [7, 1], 2002, © 2002 International Medical Press, There is an increasing proportion of HIV-positive patients exposed to all licensed classes of antiretrovirals, and the response to salvage regimens may be poor. Among over 8500 patients in EuroSIDA, the proportion of treated patients exposed to nucleosides, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitor (NNRTI) increased from 0% in 1996 to 47% in 2001. Four-hundred-and-thirteen patients, who had failed virologically two highly active antiretroviral therapy (HAART) regimens and experienced all three main drug classes, started a salvage regimen of at least three drugs, in which at least one new PI or NNRTI was included. Median viral load was 4.7 log copies/ml [Interquartile range (IQR) 4.2-5.2], CD4 lymphocyte count 150/mm3 (IQR 60-274/mm3) and follow-up 14 months. Of these patients, 283 (69%) subsequently experienced at least a 1 log decline in viral load and 202 (49%) achieved a viral load < 500 copies/ml. Conversely, the CD4 count halved from the baseline value in 88 (21%), and 45 (11%) experienced a new AIDS-defining disease. In multivariable analyses, a 1 log viral load reduction was related to baseline viral load [relative hazard (RH) 1.27 per 1 log higher; P = 0.008], a previous viral load of less than 500 copies/ml (RH 1.69; P = 0.002), more recent initiation of the regimen (RH 1.36 per year more recent; P = 0.02), number of new drugs in the regimen (RH 1.20 per drug; P = 0.02), time since start of antiretroviral therapy (RH 0.94 per extra year; P = 0.035) and time spent on HAART with viral load > 1000 copies/ml (RH 0.96 per extra month; P = 0.0001). Analysis of factors associated with CD4 count decline and new AIDS disease also indicated improved outcomes in more recent times and a tendency for a better response in those starting more new drugs, but no relationship with the total number of drugs. Outcomes in people starting salvage regimens appear to depend on the number of new drugs started but not on the total number of drugs being used.

Background Febrile neutropenia (FN) is a common complication to chemotherapy associated with a high burden of morbidity and mortality. Reliable prediction of individual risk based on pretreatment risk factors allows for stratification of preventive interventions. We aimed to develop such a risk stratification model to predict FN in the 30 days after initiation of chemotherapy. Methods We included consecutive treatment-naïve patients with solid cancers and diffuse large B-cell lymphomas at Copenhagen University Hospital, 2010–2015. Data were obtained from the PERSIMUNE repository of electronic health records. FN was defined as neutrophils ≤0.5 × 10E9/L ​at the time of either a blood culture sample or death. Time from initiation of chemotherapy to FN was analyzed using Fine-Gray models with death as a competing event. Risk factors investigated were: age, sex, body surface area, haemoglobin, albumin, neutrophil-to-lymphocyte ratio, Charlson Comorbidity Index (CCI) and chemotherapy drugs. Parameter estimates were scaled and summed to create the risk score. The scores were grouped into four: low, intermediate, high and very high risk. Results Among 8,585 patients, 467 experienced FN, incidence rate/30 person-days 0.05 (95% CI, 0.05–0.06). Age (1 point if > 65 years), albumin (1 point if < 39 g/L), CCI (1 point if > 2) and chemotherapy (range -5 to 6 points/drug) predicted FN. Median score at inclusion was 2 points (range –5 to 9). The cumulative incidence and the incidence rates and hazard ratios of FN are shown in Figure 1 and Table 1, respectively. Conclusion We developed a risk score to predict FN the first month after initiation of chemotherapy. The score is easy to use and provides good differentiation of risk groups; the score needs independent validation before routine use. Disclosures All authors: No reported disclosures.

Introduction : EuroSIDA has previously reported a poorer clinical prognosis for HIV-positive individuals in Eastern Europe (EE) as compared with patients from other parts of Europe, not solely explained by differences in patient characteristics. We explored regional variability in self-reported HIV management at individual EuroSIDA clinics, with a goal of identifying opportunities to reduce the apparent inequalities in health. Methods : A survey (www.chip.dk/eurosida/csurvey) on HIV management was conducted in early 2014 in all currently active EuroSIDA clinics. Responders in EE were compared with clinics in all other EuroSIDA regions combined (non-EE). Characteristics were compared between regions using Fishers exact test. Results : A total of 80/97 clinics responded (82.5%, 12/15 in EE, 68/82 in non-EE). Participating clinics reported seeing a total of 133,532 patients [a median of 1300 per clinic (IQR 700–2399)]. The majority of clinics requested viral load and CD4 measurements at least every six months for patients on as well as off ART (EE 66.7%, non-EE 75%, p =0,72). Significantly fewer EE clinics performed resistance tests before ART as well as upon treatment failure (Figure 1). Half of the EE clinics indicated following WHO guidelines (EE 50%, non-EE 7.4%, p

The EuroSIDA observational cohort study was initiated in 1993 by Jens Lundgren (Copenhagen HIV Programme) and Andrew Phillips (University College London) as the successor of the AIDS in Europe Study, with the main objective of assessing the impact of antiretroviral drugs on outcomes for the general population of HIV-infected patients living in Europe. As of April 2014 EuroSIDA included 18,786 patients followed at 111 hospitals in 34 European countries plus Argentina and Israel. Since its inception, EuroSIDA has provided data published in 202 papers in peer-reviewed journals, among them 14 papers on hepatitis C virus (HCV) co-infection [1-14] . As the HIV epidemic has evolved and the incidence of AIDS has decreased, the focus of EuroSIDA has shifted to addressing the research questions most pertinent to the clinical care of Europeans living with HIV on a long-term basis. With more than a quarter of all EuroSIDA patients positive for antibodies to HCV, and with growing concern about the burden of liver-related disease and death, hepatitis C research has come to play an increasingly important role in EuroSIDA in recent years. This article will describe key characteristics of the HIV/HCV co-infected population in EuroSIDA, and summarize the most important EuroSIDA co-infection studies.

Objectives Following resolution of hepatitis C virus (HCV) infection, recurrence has been shown to occur in some persons with repeated exposure to HCV. We aimed to investigate the rate and factors associated with HCV RNA recurrence among HIV-1-infected patients with prior spontaneous HCV RNA clearance in the EuroSIDA cohort. Methods All HIV-infected patients with documented prior spontaneous HCV clearance, and at least one subsequently collected plasma sample, were examined. The last sample was tested for HCV RNA and those with HCV RNA ≥ 615 IU/mL were defined as having HCV recurrence and their characteristics were compared with those of patients who were still aviraemic. Logistic regression was used to identify factors associated with HCV recurrence. Results Of 191 eligible patients, 35 [18.3%; 95% confidence interval (CI) 12.8–23.8%] had HCV recurrence. Thirty-three (94.3%) were injecting drug users (IDUs). The median time between the first and last samples was 3.6 years (interquartile range 2.0–5.8 years). After adjustment, those on combination antiretroviral therapy [odds ratio (OR) 0.44; 95% CI 0.20–0.99; P = 0.046] and older persons (OR 0.51 per 10 years older; 95% CI 0.28–0.95; P = 0.033) were less likely to have HCV RNA recurrence, whereas IDUs were over 6 times more likely to have HCV RNA recurrence compared with non-IDUs (OR 6.58; 95% CI 1.48–29.28; P = 0.013). Conclusions Around 1 in 5 HIV-infected patients with prior spontaneous HCV RNA clearance had detectable HCV RNA during follow-up. Our findings underline the importance of maintaining focus on preventive measures to reduce IDU and sharing of contaminated needles. Clinicians should maintain a high degree of vigilance to identify patients with new HCV infection early.

To compare health-related quality of life (HR-QOL) in individuals infected with HIV to general population levels and to assess the relationship between HR-QOL and markers of disease progression in the era of highly active antiretroviral therapy (HAART).This was a cross-sectional questionnaire-based study. This study included 154 individuals at least 18 years old with HIV who either were attending a London hospital or were visited by a community team in Brighton. Study participants were asked to complete two HR-QOL questionnaires. This study used HR-QOL, as measured using the Medical Outcome Study HIV Health Survey (MOS-HIV) and EuroQoL self-report (EQ-5D) questionnaires, as the main outcome measure. Responses on the EQ-5D were compared with a published general population data set. The relationships between scores on the MOS-HIV and EQ-5D questionnaires and a number of independent variables including CD4 count and viral load were also assessed.Each analysis was based on the results of at least 128 questionnaires. The mean MOS-HIV mental and physical component scores were 43.2 (SD = 12.2) and 41.8 (SD = 13.2), respectively. After adjusting for differences in age and gender, it was shown that individuals with HIV reported significantly lower EQ-5D(utility) ( p =.0001) and EQ-5D(VAS) ( p =.0001) compared with the general population. However, further analysis revealed few significant associations between markers of disease progression and HR-QOL.Individuals with HIV generally recorded significantly lower HR-QOL compared with the general population. Thus, prevention of further transmissions of the virus is still likely to prevent significant morbidity losses in addition to mortality losses, despite the availability of HAART. However, disease progression as measured is not clearly related to further reductions in HR-QOL.

Objectives: To assess the incidence and risk factors for hepatotoxicity associated with nevirapine.Design: A prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000.Method: Cutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values.Results: Of a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4-14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan-Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively, in seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity.Conclusions: Hepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk. (C) 2001 Lippincott Williams & Wilkins.

Influence of age on the CD4 cell response to highly active antiretroviral therapy (HAART) was examined in 1956 patients (median age, 37.2 years) in the EuroSIDA study. Median initial CD4 cell count was 192x106 cells/L, follow-up was 31 months, and time to maximum CD4 cell response was 20 months. Age groups were not different for baseline CD4 cell count, baseline human immunodeficiency virus RNA load, or treatment history. CD4 cell increase, stratified by age quartiles, differed during months 3-36 of HAART (P=.023). Maximum CD4 cell increase from start of HAART differed by age group (P=.0003), as did maximum CD4 cell count (P10-4). Multivariate analysis confirmed the inverse relationship between age and maximum CD4 cell response (P=.023). Time to a CD4 increase of200x106 cells/L was shorter for patients in the younger age groups (P=.0026), as confirmed by multivariate analysis (P10-4). Younger age may favor CD4 cell restoration because of preserved thymic function.

Summary Background Risk factors for lipodystrophy in patients infected with HIV-1 treated with highly active antiretroviral therapy (HAART) containing HIV-1 protease inhibitors are poorly understood. We aimed to identify the risk factors for lipodystrophy in antiretroviral-naive HIV-1-infected adults on HAART. Methods Moderate or severe body-fat changes were clinically assessed and categorised as subcutaneous lipoatrophy, central obesity, or both, in all consecutive antiretroviral-naive HIV-1-infected adults who began HAART with two nucleoside reverse transcriptase inhibitors plus at least one protease inhibitor from October, 1996, to September, 1999. A person-years analysis was used to calculate the incidence of types of lipodystrophy, and Cox proportional hazards models were used to describe the univariate and multivariate factors associated with progression to any lipodystrophy. Findings After a median follow-up of 18 months, 85 (17%) of the 494 patients developed some type of lipodystrophy. The incidences of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity were 11·7 (95% CI 9·2–14·2), 9·2 (7·0–11·4), and 7·7 (5·7–9·7) per 100 patient-years. An increased risk for any lipodystrophy was found among women as compared with men (relative hazard 1·87 [1·07–3·28]), heterosexuals (2·86 [1·50–5·48]), and homosexuals (2·17 [1·07–4·42]) as compared with intravenous drug users, with increasing age (1·33 per 10 years older [1·08–1·62]), and with the duration of exposure to antiretroviral therapy (1·57 per 6 months extra [1·30–1·88]) but not with any individual antiretroviral agent. The factors associated with an increased risk for lipodystrophy with subcutaneous lipoatrophy or lipodystrophy with central obesity were very similar to those associated with any lipodystrophy. The duration of indinavir use may represent an additional contribution for the development of lipodystrophy with central obesity (1·26 per 6 months extra [0·99–1·60]); p=0·064). Interpretation Risk factors associated with development of any lipodystrophy, lipodystrophy with subcutaneous lipoatrophy, and lipodystrophy with central obesity in patients infected with HIV-1 who were receiving HAART containing protease inhibitors are multifactorial and overlapping, and cannot be exclusively ascribed to the duration of exposure to an particular antiretroviral agent.

Objective: To establish whether a gender difference in virologic response to highly active antiretroviral treatment (HAART) exists.Methods: A cohort of HIV-positive individuals was examined.Outcomes: Achievement of viral load

1Royal Free Centre for HIV Medicine, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, UK,2NPMS-HHC, St. Stephen's Centre, Chelsea and Westminster Hospital, London, UK,3Global Health Outcomes, Glaxo Wellcome R and D, Greenford, Middlesex, UK,4Royal Free Centre for HIV Medicine, Department of Thoracic Medicine, Royal Free Hospital, London, UK and Joint Departments of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada Objective To assess the cost-effectiveness of highly active antiretroviral therapy (HAART) compared with two nucleoside reverse transcriptase inhibitors (NRTIs) for HIV infected individuals. Design Different data sources on the clinical effects and costs of treatments were combined using a Markov model. Setting English HIV treatment centres. Perspective UK public finance. Interventions HAART – dual NRTI therapy plus a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor – vs. dual NRTI therapy. Participants Hypothetical cohorts of 1000 individuals infected with HIV. Outcome measures Projected life expectancy, cost-effectiveness in UK£ per life-year saved and per quality-adjusted life-years (QALYs) saved. Results Assuming a 2-year additional treatment effect of therapy with HAART produced incremental cost-effectiveness ratios of £14 602 per life-year saved and £17 698 per QALY saved. Conclusions The results were sensitive to a number of assumptions including the cost of HAART and the discount rate, but they suggest that the use of HAART in England is at least moderately cost-effective compared with treatment with two NRTIs alone.

Background Patients with human immunodeficiency virus (HIV) infection and a history of Pneumocystis carinii pneumonia are at high risk for relapse if they are not given secondary prophylaxis. Whether secondary prophylaxis against P. carinii pneumonia can be safely discontinued in patients who have a response to highly active antiretroviral therapy is not known. Methods We analyzed episodes of recurrent P. carinii pneumonia in 325 HIV-infected patients (275 men and 50 women) in eight prospective European cohorts. Between October 1996 and January 2000, these patients discontinued secondary prophylaxis during treatment with at least three anti-HIV drugs after they had at least one peripheral-blood CD4 cell count of more than 200 cells per cubic millimeter. Results Secondary prophylaxis was discontinued at a median CD4 cell count of 350 per cubic millimeter; the median nadir CD4 cell count had been 50 per cubic millimeter. The median duration of the increase in the CD4 cell count to more than 200 per cubic mi...

To describe the reasons for, and factors associated with, modification and discontinuation of highly active antiretroviral therapy (HAART) regimens at a single clinic.A total of 556 patients who started HAART at the Royal Free Hospital were included in analyses. Modification was defined as stopping or switching any antiretrovirals in the regimen, whereas discontinuation was defined as the simultaneous stopping of all antiretrovirals included in the initial regimen. Reasons were classified as immunological/virological failure (IVF) and toxicities and patient choice/poor compliance (TPC).The median CD4 count at starting HAART was 171 x 10(6) cells/l and viral load 5.07 log copies/ml. During a median follow-up of 14.2 months, 247 patients (44.4%) modified their HAART regimen, 72 due to IVF (29.1%) and 159 due to TPC (64.4%) and a total of 148 patients (26.6%) discontinued HAART. Older patients were less likely to modify HAART [relative hazard (RH), 0.73 per 10 years; P = 0.0008], as were previously treatment-naive patients (RH, 0.65; P = 0.0050), those in a clinical trial (RH, 0.64; P = 0.027) and those who started nelfinavir (RH, 0.57; P = 0.035). Patients who started with four or more drugs (RH, 2.21, P0.0001), who included ritonavir in the initial regimen (RH, 1.41; P = 0.035) or who had higher viral loads during follow-up (RH per log increase, 1.51; P0.0001) were more likely to modify HAART.There was a high rate of modification and discontinuation of HAART regimens in the first 12 months, particularly due to toxicities, patient choice or poor compliance.

Objective: To describe the use of second line protease-inhibitor (PI) regimens across Europe and to determine factors associated with virological and immunological response.Design: Analysis of data from 984 patients with a median follow-up of 21 months enrolled in EuroSIDA. Patients started their second PI-containing regimen at least 16 weeks after starting the first PI-containing regimen and with viral load > 1000 copies/ ml.Methods: Virological response was defined as a viral load < 500 copies/ml and immunological response as an increase of 50 x 10(6)/l or more in CD4 lymphocyte count.Results: The median CD4 cell count at starting the second PI was 171 x 10(6) cells/l; viral load was 4.45 log copies/ml. As a second PI regimen, 45% were using a dual PI, while of those on one PI, indinavir (42%) and nelfinavir (34%) were most common. In multivariate Cox models, a higher viral load at starting the second PI relative hazard (RH), 0.67 per 1 log higher; 95% confidence interval (CI), 0.58-0.77; P < 0.0001) and a lower CD4 cell count (RH, 1.15 per 50% higher; 95% CI, 1.06-1.26; P = 0.0014) were associated with a reduced probability of virological response. Those who had achieved viral suppression on the first PI-regimen were more likely to respond to the second (RH, 1.65; 95% CI, 1.30-2.10; P < 0.0001) as were those who added one or two new nucleosides to their second PI.Conclusions: Patients who initiate a second PI regimen at lower viral load, higher CD4 cell count or who added new nucleosides tended to be more likely to achieve a viral load < 500 copies/ml. The roles of cross-resistance and adherence in response to second-line regimens needs further investigation. (C) 2001 Lippincott Williams & Wilkins.

Objective: To describe the short-term changes in CD4 lymphocyte counts after the interruption of antiretroviral HIV therapy in order to increase the understanding of CD4 lymphocyte dynamics, and so that appropriate monitoring strategies can be designed.Methods: We studied 35 HIV-infected patients with late-stage disease who had therapy interruptions leading to high viral load levels, median greater than 750 000 RNA log(10) copies/ml, and in whom two CD4 cell counts (median 28 days apart) were available before beginning a salvage regimen.Results: Overall, there was a substantial decline in CD4 cell counts from a median of 125 to 83 cells/mm(3) in the average 28 day period, with median proportionate and absolute losses of 26% and 24 cells/mm(3) per month, respectively (P < 0.008). This tended to be greater in individuals studied sooner after interrupting therapy (P = 0.03) and in those with CD4 cell counts above the pre-therapy baseline (P = 0.06). There was a strong negative correlation between the proportionate increase in viral load and the absolute change in CD4 cell count (-0.66, P = 0.0002).Conclusion: Patients with relatively advanced HIV infection interrupting antiretroviral therapy after failing a protease inhibitor-containing regimen require frequent monitoring because CD4 cell counts appear to fall quite rapidly, at least in the first few weeks after interruption (C) 2000 Lippincott Williams & Wilkins.

BACKGROUND: Highly active antiretroviral therapy (HAART) is now widely used in clinical practice and gives rise to a range of immunological, virological and clinical responses. OBJECTIVES: To describe the immunological, virological and clinical response to HAART and to examine the frequency of modification of the HAART regimen among patients from a single treatment centre. METHODS: Kaplan-Meier estimation and incidence rates were used to describe responses to HAART (a protease inhibitor or non-nucleoside drug in addition to at least two nucleoside analogues) among 421 patients from the Royal Free Hospital in London. RESULTS: The median CD4 cell count at starting HAART was 186 x 10(6) cells/l [interquartile range (IQR) 76-310] and viral load was 5.13 log10 copies/ml (IQR 4.66-5.56). At 6 months after starting HAART, 51.1% of patients were estimated to have experienced a 100 x 10(6) cells/l increase in CD4 cell count; the median time for viral load to fall below 400 copies/ml was 3.7 months (95% confidence interval 3.2-4.4). At 6 months after the first viral load was 400 copies/ml and 12.4% were estimated to have failed if the more stringent definition of two viral loads above the limit of detection was used. Compared with the pre-HAART era, the incidence of death among patients on HAART was one sixth of that level; new AIDS-defining illnesses was one seventh; and hospital admissions was one fifth. In total, 141 patients (33.5%) stopped at least one of the antiretroviral agents included as part of their HAART regimen; the occurrence of side effects was the most common reason (n = 63; 44.7%). CONCLUSION: A good response occurred to an initial HAART regimen. There was a high rate of virological relapse, which varied considerably according to the definition of failure used. Even so, the rates of clinical progression and hospital admissions observed to date were low. Further follow-up of these patients is required to determine their long-term immunological, virological and clinical outcome.

Objectives: To analyse the survival differences between macro-regions of Europe (northern, central and southern Europe) between 1994 and early 1999, and their possible association with antiretroviral treatment differences.Design: From September 1994 the EuroSIDA study has prospectively followed nonselected HIV-infected people from 50 clinical sites in 18 European countries (n = 7331).Methods: Cox proportional hazards models were used to compare death rates between regions and to investigate the relationship between treatment usage and regional mortality rates. Kaplan-Meier curves were used to compare survival from the first CD4 lymphocyte count of < 200 x 10(6)/l or < 50 x 10(6)/l.Results: At the time of analysis, the median follow-up was 21 months and there was a total of 1544 deaths. In people with a CD4+ cell count that fell below 200 or 50 x 10(6)/l those from central Europe had a better prognosis compared with those from the two other regions (P < 0.05). Patients from central Europe were more frequently exposed to reverse transcriptase inhibitors and protease inhibitors compared with patients from other regions (P < 0.001). There was a significant difference in risk of death between regions after adjustment for baseline differences in demography, presence of AIDS and level of immunodeficiency (risk of death in central Europe was 37% lower than that in southern Europe (P < 0.0001) and 33% lower than in northern Europe (P < 0.0001)). After adjustment for use of individual antiretroviral agents, intensity of treatment regimen, CD4 lymphocyte count, weight, haemoglobin and development of AIDS as time-dependent covariates, the differences became much smaller (risk in central Europe 13% lower than that in southern Europe (P = 0.071) and 15% lower than in northern Europe (P = 0.054).Conclusion: Antiretroviral therapy has been used more aggressively in Europe in recent years, resulting in improved prognosis. In this study we observed that the HIV mortality rate in central Europe was significantly lower than those in northern and southern Europe in the period 1994 to early 1999. This finding appears to be due to the effect on survival of different treatment policies and drug availability in the three regions of Europe during this time period, with central European countries, on average, having introduced more aggressive treatment strategies earlier. (C) 1999 Lippincott Williams & Wilkins.

Objective: To determine the effect of highly active antiretroviral therapy (HAART) on cytomegalovirus (CMV) viraemia and retinitis in patients at high risk of disease.Design: Sixteen patients with CMV viraemia, but no evidence of end organ disease at the time of first receipt of HAART including a protease inhibitor, were studied. No patient had ever received specific anti-CMV therapy.Methods: CMV load in blood was measured using quantitative competitive PCR at baseline and for a median follow-up of 21 months. Regular ophthalmological screening for retinitis was conducted throughout the study period.Results: All 16 patients became CMV negative by PCR following the commencement of HAART. CMV loads prior to treatment ranged From 2.0 x 10(3) to 4.1 x 10(6) copies/ml (median, 7.6 x 10(4) copies/ml). The median time to becoming PCR negative was 13.5 weeks (range, 5-40 weeks). Fourteen patients remained CMV negative throughout follow-up. CMV viraemia recurred in two patients; these individuals were indistinguishable with respect to either baseline parameters or response to antiretroviral therapy. None of the 16 patients developed CMV retinitis.Conclusions: HAART including a protease inhibitor can result in the complete suppression of CMV viraemia, an effect not previously observed in HIV-infected patients in the absence of specific anti-CMV therapy. This response correlated with protection against CMV retinitis in a group of patients at high risk of development of disease. These results help to explain why the natural history of CMV disease has altered since the introduction of such therapeutic regimens. (C) 1999 Lippincott Williams & Wilkins.

OBJECTIVE To describe the changes over time in incidence of hospital admissions among patients with HIV, reasons for hospital admission, duration of stay, relationship with CD4 T-cell count and with antiretroviral treatment. METHODS The incidence of hospital admissions during each calendar year from 1988 to 1997 inclusive was calculated using a person-years analysis. In addition the proportion of patient follow-up spent in hospital and the impact of changing treatment regimens among all patients with HIV aged > or = 14 years and with at least one CD4 T-cell count seen at the Royal Free Hospital, London was also described. RESULTS A total of 1806 patients were investigated with median follow-up of 21.1 months. Among all patients, the proportion of follow-up time spent as an in-patient decreased from 3.9% in 1988 to 1.3% in 1997 (P = 0.0015; test for trend). Hospital admissions for any cause peaked during 1989 at 72.0 per 100 patient years of follow-up (PYFU) and was 28.5 per 100 PYFU during 1997 (P 30% before 1990 to < 5% during 1997 (P = 0.026; test for trend). Hospital admissions varied greatly according to treatment regimen; in 1996 and 1997 just 0.1% of follow-up time of patients on triple antiretroviral treatment regimens was spent as a hospital admission. CONCLUSIONS Admissions to hospital began falling before the introduction of combination therapy and declined strikingly during 1996 and 1997 following the introduction of highly active antiretroviral therapy. These results have important implications for future allocation of resources and for patient management.

Adenoviruses have been described as a cause of diarrhoea in patients infected with the human immunodeficiency virus (HIV). The prevalence of adenoviruses was studied in all HIV-positive patients presenting with diarrhoea at the Royal Free Hospital in London between 1991 and 1995. In addition, all postmortems carried out in HIV-positive individuals registered at the same centre between 1990 and 1997 were reviewed for evidence of adenovirus infection. Adenovirus was detected in 16.1% of patients presenting with diarrhoea. These individuals had a significantly lower CD4 count and were more likely to have had a diagnosis of acquired immunodeficiency syndrome (AIDS) than patients with diarrhoea in whom adenovirus was not detected. The median survival was 1 year compared with 2.4 years for those without adenoviruses; this difference remained significant (P = .008) after controlling for differences in CD4 counts between the groups. Gastrointestinal adenovirus excretion occurs at an advanced stage of HIV disease, and is associated with a poor prognosis. We suggest that adenoviruses may contribute to mortality in this population. J. Med. Virol. 58:280–285, 1999. © 1999 Wiley-Liss, Inc.

Objectives: To describe changes in haemoglobin over time and to determine the joint prognostic value of the current haemoglobin, CD4 lymphocyte count and viral load among patients from across Europe. Patients: The analysis included 6725 patients from EuroSIDA, an observational, prospective cohort of patients with HIV from across Europe. Methods: Normal haemoglobin was defined as haemoglobin greater than 14 g/dl for men and 12 g/dl for women; mild anaemia was 8-14 g/dl for men and 8-12 g/dl for women; severe anaemia was defined as less than 8 g/dl for both males and females. Linear regression techniques were used to estimate the annual change in haemoglobin; standard survival techniques were used to describe disease progression and risk of death. Results: At recruitment to the study, 40.4% had normal levels of haemoglobin, 58.2% had mild anaemia and 1.4% had severe anaemia. At 12 months after recruitment, the proportion of patients estimated to have died was 3.1% [95% confidence interval (CI) 2.3-3.9] for patients without anaemia, 15.9% for patients with mild anaemia (95% Cl 14.5-17.2) and 40.8% for patients with severe anaemia (95% CI 27.9-53.6; P < 0.0001). In a multivariate, time-updated Cox proportional hazards model, adjusted for demographic factors, AIDS status and each antiretroviral treatment as time-dependent covariates, a 1 g/dl decrease in the latest haemoglobin level increased the hazard of death by 57% [relative hazard (RH) 1.57; 95% Cl 1.41-1.75; P < 0.0001], a 50% drop in the most recent CD4 lymphocyte count increased the hazard by 51% (RH 1.51; 95% Cl 1.35-1.70; P < 0.0001) and a log increase in the latest viral load increased the hazard by 37% (RH 1.37; 95% Cl 1.15-1.63; P = 0.0005). Conclusions: Severe anaemia occurred infrequently among these patients but was associated with a much faster rate of disease progression. Among patients with similar CD4 lymphocyte counts and viral load, the latest value of haemoglobin was a strong independent prognostic marker for death.

Summary Background Highly active antiretroviral therapy (HAART) has improved rates of CD4-lymphocyte recovery and decreased the incidence of HIV-1-related morbidity and mortality. We assessed whether prophylaxis against Pneumocystis carinii pneumonia (PCP) can be safely discontinued after HAART is startedt Methods We investigated 7333 HIV-1-infected patients already enrolled in EuroSIDA, a continuing prospective observational cohort study in 52 centres across Europe and Israel. We did a person-years analysis of the rate of discontinuation of PCP prophylaxis and of the incidence of PCP after the introduction of HAART into clinical practice from July, 1996 Findings The rate of discontinuation of primary and secondary PCP prophylaxis increased up to 21–9 discontinuations per 100 person-years of follow-up after March, 1998. 378 patients discontinued primary (319) or secondary (59) prophylaxis a median of 10 months after starting HAART. At discontinuation for primary and secondary prophylaxis, respectively, the median CD4-lymphocyte counts were 274 cells/μL and 270 cells/μL, the median plasma HIV-1 RNA load 500 copies/mL, and the median lowest recorded CD4-lymphocyte counts 123 cells/μL and 60 cells/μL. During 247 person-years of follow-up, no patient developed PCP (incidence density 0 [95% Cl 0-1·5]). Interpretation The risk of PCP after stopping primary prophylaxis, especially in patients on HAART with a rise in CD4-lymphocyte count to more than 200 cells/μL, is sufficiently low to warrant discontinuation of primary PCP prophylaxis. Longer follow-up is needed to confirm a similarly low risk for stopping secondary PCP prophylaxis.

Objectives: To investigate the factors related to viral load becoming undetectable among patients from Southern Alberta who started a protease inhibitor for the first time, and to determine the factors related to subsequent re-emergence of detectable viral load amongst those patients whose viral load initially became undetectable.Subjects and methods: A total of 243 patients from the Southern Alberta Clinic had started a protease inhibitor for the first time and had been followed up for a median time of 32 weeks. Standard survival techniques including Kaplan-Meier techniques and Cox proportional hazards models were used to determine which factors were related to viral load becoming undetectable.Results: At 24 weeks after first exposure to a protease inhibitor, 52.8% of the patients [95% confidence interval (CI), 45.2-56.6] had achieved an undetectable viral load. In a multivariate analysis, those with a higher initial viral load were less likely to become undetectable [relative hazard (RH), 0.50; 95% CI, 0.35-0.70; P < 0.0001], whereas those starting more new drugs (RH per new drug, 1.53; 95% CI, 1.01-2.11; P = 0.048) were significantly more likely to achieve an undetectable viral load. Amongst 111 patients whose viral load became undetectable, Kaplan-Meier analysis indicated that 15.5% of patients experienced re-emergence of detectable viral load at 24 weeks after the first undetectable viral load. A higher CD4 cell count was associated with a lower risk of viral load becoming detectable (RH, 0.73; 95% CI, 0.53-1.00; P = 0.049), as was treatment with indinavir (versus any other protease inhibitor RH, 0.17; 950/;, CI, 0.03-0.86; P = 0.033).Conclusions: A significant proportion of patients in a routine clinic setting achieved an undetectable viral load measurement after first starting a protease inhibitor; viral load in patients with a higher CD4 cell count was more likely to become and stay undetectable. There was no evidence that patients who were drug-naive experienced significantly worse virological effects than drug-experienced patients, as long as the same number of new drugs was started at the date of first exposure to a protease inhibitor. Further follow-up of these patients is warranted to study the longer term effects of treatment with protease inhibitors. (C) 1998 Lippincott Williams & Wilkins

OBJECTIVES: To show how a spurious association between the calendar year of seroconversion and HIV progression arises as a result of censoring the follow-up of individuals at their last visit, when the individuals' visits are intermittent. DESIGN: A notional cohort of 1140 seroconverters and a cohort study of 1270 HIV-infected individuals seroconverted between 1985 and 1994, and followed up to December 1995 (the Italian Seroconversion Study cohort). METHODS: Failure times and rate of the patients attending the clinic over the study period were simulated for the notional cohort. Three separate scenarios with different probabilities of making a visit were considered. Standard survival analysis techniques were used to assess the effect of the year of seroconversion on HIV progression. The progression to a CD4 cell count of 200 x 10(6)/l according to the calendar year of seroconversion in the Italian Seroconversion Study was assessed using different censoring strategies. RESULTS: A spurious effect of the year of seroconversion consistently appeared in 100 repeated simulations. When ignoring the visits occurring after the first year of follow-up in the Italian Seroconversion Study cohort, results supported the hypothesis of no effect of the year from seroconversion. CONCLUSIONS: The choice of the censoring strategy is crucial when assessing the effect of year of seroconversion using survival analysis in cohort studies with intermittent visit structure. Different censoring strategies should be considered before firmly concluding that more virulent strains or the use of treatment are modifying the natural history of HIV disease from cohort studies of this nature.

Objectives: To illustrate a simple approach to adjusting for bias due to drop-outs (i.e., attrition bias) when evaluating the effect of a certain therapy in HIV clinical trials using the mean change in plasma viral load. To evaluate its validity and to compare its performance with that of another simple method for handling dropouts: the last observation carried forward (LOCF) method.Design: Data from a notional treated group of 100 patients followed up to 52 weeks were generated. Attrition bias was introduced by mimicking selective patient dropout (i.e., more likely in patients doing badly).Methods: The difference between the true mean change in HIV RNA levels at 52 weeks and the observed mean change because of drop-outs was calculated (attrition bias). The reduction in bias obtained by using the proposed approach was then calculated and compared with that obtained by using the LOCF method. To assess the performance of the methods over the entire follow-up, the mean areas under the curves were considered.Results: Our method reduced the bias by a clinically relevant amount in a variety of different settings. In most of our simulations, bias was reduced by a larger amount than that obtainable from using the LOCF method.Conclusions: The current situation is that results from trials in HIV infection are invariably presented with no associated attempt to quantify the attrition bias present. Attrition-adjusted plots of mean change in HIV RNA should, we believe, be presented alongside usual plots as a form of sensitivity analysis. (C) 1998 Lippincott-Raven Publishers.

Background. Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers. Methods. Prospective 1-1 case-control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n = 50 matched pairs), non-AIDS-defining (n = 63) events and death (n = 41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers. Results. In sum, 250 patients were included. Median time between first and last sample and last sample and event was 44.6(interquartile range [IQR]: 22.7-72.3) and 3.1(IQR: 1.4-6.4) months. Odds of death decreased by 46.0%(95% confidence interval [CI], 2.0-70.0, P =. 04) for a 2-fold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P >. 05). In patients with current 25(OH)D

Introduction Proteinuria (PTU) is an important marker for the development and progression of renal disease, cardiovascular disease and death, but there is limited information about the prevalence and factors associated with confirmed PTU in predominantly white European HIV+ persons, especially in those with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73 m2. Patients and methods Baseline was defined as the first of two consecutive dipstick urine protein (DPU) measurements during prospective follow-up >1/6/2011 (when systematic data collection began). PTU was defined as two consecutive DUP >1+ (>30 mg/dL) >3 months apart; persons with eGFR 90) and those with prior abacavir use had lower odds of PTU (Figure 1). There was no significant association between past or current use of tenofovir, lopinavir, atazanvir (boosted or unboosted) or any other boosted PI and PTU (p>0.2). During 688.2 person-years of follow up (PYFU), three persons developed chronic kidney disease (CKD; confirmed [>3 months apart] eGFR60 was almost 10 times higher than in those without baseline PTU and eGFR>60 (rate ratio 9.61; 95% CI 0.87–105.9, p=0.065). Conclusions One in 25 persons with eGFR>60 had confirmed proteinuria at baseline. Factors associated with PTU were similar to those associated with CKD. The lack of association with antiretrovirals, particularly tenofovir, may be due to the cross-sectional design of this study, and additional follow-up is required to address progression to PTU in those without PTU at baseline. It may also suggest other markers are needed to capture the deteriorating renal function associated with antiretrovirals may be needed at higher eGFRs. Our findings suggest PTU is an early marker for impaired renal function.

Background : Use of unboosted atazanavir (ATV 400 ) is approved in the US but not in Europe [1]. Due to pharmacokinetic interactions it should not be used with tenofovir but can be used with abacavir/lamivudine (ABC/3TC) [1, 2, 3]. Effectiveness data of ATV 400 +ABC/3TC as a switch strategy in clinical routine however are scant. Methods : We evaluated treatment outcomes of ATV 400 +ABC/3TC in pre-treated subjects in the EuroSIDA cohort with undetectable HIV-1 RNA, and previous ABC experience or assumed previous HLA B57*01 testing. We performed a time to loss of virologic response (TLOVR below 50 c/mL) and a snapshot analysis at 48, 96 and 144 weeks. Virological failure (VF) was defined as a confirmed plasma HIV-1 RNA >50 c/mL. Results : We included 258 subjects: 176 (68%) male, median age 46 (IQR 41, 53) y, 225 (87.2%) white, hepatitis virus co-infection 36%, median baseline CD4 at switch 540 cells (360, 700), time with VL≤ 50 c/mL 45 (24, 69) months. The median calendar year of switching was 2008 (2006, 2010). The 3rd drug in previous regimen was ATV/r in 70 (27.1%), other PI/r in 25 (9.7%), and other 163 (63.2%); 85 (32.9%) had previously failed with a PI. The virological response at 48/96/144 weeks was, respectively, 89.5 [95% CI 85.1, 92.9]/88 [83.4, 91.7]/86.3% [81.6, 90.4] (TLOVR, composite endpoint failure or stop for any reason) and the risk of VF was 8.3/7.6/7.6%. In the snapshot analysis HIV-RNA was below 50 c/mL in 72.5/65.9/51.6%, respectively, and >50 c/mL in 6.6/5.4/4.3%. Only 0.8/1.9/3.5% discontinued due to adverse events. There was a high rate of discontinuations due to other reasons or with VL missing in window. In a multivariate adjusted analysis, we observed an association between VF and nadir CD4 count (RH 0.60 [0.39, 0.93] per 100 cells higher), time with VL≤50 c/mL (RH 0.89 [0.81, 0.98] per 6 months longer) and previous failure with a PI (3.04 [1.36, 6.80]). There was no association with gender, age, hepatitis virus co-infection, CD4 count at time of switching or third drug used in the previous regimen. Conclusions : A switch to ATV 400 +ABC/3TC in selected subjects with HIV-RNA below 50 c/mL is associated with relatively low rates of VF and discontinuation due to adverse events. Use might be considered in those with long-term suppression and without prior PI failure. Larger cohorts are required to further define the appropriate selection criteria. (Published: 2 November 2014) Citation: Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Llibre JM et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19810 http://www.jiasociety.org/index.php/jias/article/view/19810 | http://dx.doi.org/10.7448/IAS.17.4.19810

Objective: To describe survival after a CD4+ T-cell count of less than 5 〈 10 6 /l and to identify possible baseline factors associated with outcome. Design: A prospective cohort study. Setting: A large teaching hospital in North London. Patients and participants: Patients treated at the Royal Free Hospital, London, who had at least one reported CD4+ T-cell count of less than 5 〈 10 6 /l and were being followed up for clinical care prior to the date of this cell count. Main outcome measure: Death. Methods: Proportional hazards models, Kaplan‐Meier analysis. Results: One-hundred and sixty-nine patients were included in the study. The median survival after a very low CD4+ T-cell count was 0.95 years (95% confidence interval, 0.78‐1.19), although 20% survived for over 2 years. Older age and a previous AIDS diagnosis were related to poorer outcome. A higher CD8+ T-cell count at baseline was also associated with a better prognosis. Conclusions: A CD4+ T-cell count of less than 5 〈 10 6 /l did not necessarily mean imminent death, with a median survival after this count of just under 1 year. These results will enable clinicians to provide appropriate counselling for patients at this late stage and to plan terminal care. AIDS 1997, 11:1123‐1127

When investigating variables thought to be of potential importance to AIDS pathogenesis, it is common practice to initially carry out a cross-sectional study comparing those with symptomatic disease/low CD4 counts with those with no symptoms/high CD4 counts. While it is widely appreciated that such studies have weaknesses compared with those involving patient follow-up, the particular biases likely to arise in the context of HIV infection have not been formally evaluated. In an attempt to do this, data on HIV progression for 50,000 notional patients who became infected in the years between 1976 (assumed to be the start of the epidemic) and 2010 were simulated under various scenarios. In Scenario 1, we considered a variable called X, which was specified to be associated with more rapid progression of HIV infection. In Scenario 2, we considered a variable Y, which was specified not to be associated with more rapid progression but which tended to change in value as a result of HIV-induced immunosuppression. Variable Z, in Scenario 3, was specified to be associated with more rapid progression and to change in value when severe immunosuppression developed. Cross-sectional analyses evaluating the association between variables X, Y, and Z and the CD4 count/presence of AIDS were performed for data as of 1980, 1985, 1995, 2000, 2005, and 2010 to assess the extent to which the true role of the three variables could be ascertained. For Scenario 1, cross-sectional analyses performed on these data later in the epidemic falsely suggested that variable X was not related to HIV progression. Variable Y in Scenario 2 falsely appeared to be related to HIV progression, due to the inability of the cross-sectional design to distinguish the fact that changes in variable Y were as a result of immunosuppression and not a possible cause of it. In Scenario 3, variable Z showed a relationship with the presence of AIDS for which the typical interpretation would lead to the suggestion that its effect is in the reverse direction to that which was, in fact, the case. In conclusion, as the HIV epidemic progresses, cross-sectional studies will increasingly tend to give misleading results. Most importantly, it is incorrect to conclude that variables found to have no association with HIV disease stage in such studies are not of potential importance to pathogenesis.

Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009- February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% [95% CI: 1.42-2.34]; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe. © 2013 Sullivan et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: This study aimed to determine incidence rates (IR) and identify risk factors for severe bacterial non-AIDS infections (SBnAI) requiring hospital admission. Methods: Data from the prospective EuroSIDA cohort were utilized to determine IRs of first diagnosis of the following SBnAI requiring hospital admission: bacteremia, endocarditis, meningitis, peritonitis, pneumonia, osteitis, and pyolonephritis. Incidence rate-ratios (IRRs) and risk factors were assessed by Poisson regression. Results: During 35,839 person-years of follow-up (PYFU), 275 patients were diagnosed with SBnAI (IRZ7.67 per 1000 PYFU, 95% confidence interval: 6.79-8.64). The most frequent infections were pneumonia (IRZ5.36, 4.63-6.17), bacteremia (IRZ1.14, 0.82-1.55), and pyelonephritis (IRZ0.67, 0.43-1.00). A strong risk factor for SBnAI was reduced estimated glomerular filtration rate [eGFR] (adjusted IRRZ5.07, 2.12-12.1 and IRRZ2.73, 1.63-4.56 for eGFR 90, respectively). No current combined antiretroviral therapy (cART) compared with current cART use increased the risk of SBnAI ( adjusted IRR = 2.96, 2.03-4.32). Other risk factors for SBnAI included current CD4+ count

Background: CD4 cell count and viral loads are used in clinical trials as surrogate endpoints for assessing efficacy of newly available antiretrovirals. If antiretrovirals act through other pathways or increase the risk of disease this would not be identified prior to licensing. The aim of this study was to investigate the CD4 cell count and viral load-specific rates of fatal and nonfatal AIDS and non-AIDS events according to current antiretrovirals. Methods: Poisson regression was used to compare overall events (fatal or nonfatal AIDS, non-AIDS or death), AIDS events (fatal and nonfatal) or non-AIDS events (fatal or nonfatal) for specific nucleoside pairs and third drugs used with more than 1000 personyears of follow-up (PYFU) after 1 January 2001. Results: Nine thousand, eight hundred and one patients contributed 42372.5 PYFU, during which 1203 (437 AIDS and 766 non-AIDS) events occurred. After adjustment, there was weak evidence of a difference in the overall events rates between nucleoside pairs (global P-value1/40.084), and third drugs (global P-value1/40.031). As compared to zidovudine/lamivudine, patients taking abacavir/lamivudine [adjusted incidence rate ratio (aIRR) 1.22; 95% CI 0.99-1.49] and abacavir and one other nucleoside [aIRR 1.51; 95% CI 1.14-2.02] had an increased incidence of overall events. Comparing the third drugs, those taking unboosted atazanavir had an increased incidence of overall events compared with those taking efavirenz (aIRR 1.46; 95% CI 1.09-1.95). Conclusion: There was little evidence of substantial differences between antiretrovirals in the incidence of clinical disease for a given CD4 cell count or viral load, suggesting there are unlikely to be major unidentified adverse effects of specific antiretrovirals. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIVpositive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: An important dimension of people-centred health systems is the organisation of services around patients’ heterogeneous medical and psychosocial needs rather than around biomedical disease categorisations. This approach may potentially contribute to better treatment outcomes in the field of HIV, since many factors not directly related to HIV, such as the availability of opioid substitution therapy, may determine the extent to which patients benefit from HIV clinical care. Methods: The EuroSIDA study is a prospective observational cohort study that began enrolling patients in 1994. In early 2014, we conducted a 59-item survey of the 98 EuroSIDA clinics. The survey included 10 items relating to various aspects of people-centred health care. Responses from the EuroSIDA East Europe study region (Belarus, Estonia, Lithuania, the Russian Federation and Ukraine [n=12 centres from 5 countries]) were compared to responses from a “non-East Europe” study region comprised of all other EuroSIDA countries (n=70 centres from 26 countries). Differences in responses were assessed using Fisher’s exact test and statistical significance was defined as p Results: Drug/alcohol treatment services and opioid substitution therapy (OST) were not available at many EuroSIDA study clinics, with the East Europe group reporting non-significantly lower levels of these services than the non-East Europe group (33% versus 50% and 25% versus 44% respectively) (Figure 1). The East Europe group lagged further behind the non-East Europe group in regard to levels of mental health treatment and/or referral (42% versus 74%, p=0.039), as well as levels of family planning counselling (33% versus 69%, p=0.026). On-site childcare was available at less than two-thirds of clinics in both East Europe and non-East Europe (50% versus 35%). High proportions of clinics in both regions were found to have on-site pharmacies (92% East Europe versus 93% non-East Europe). Significantly lower levels of East Europe clinics reported having foreign-language interpreters available compared to non-East Europe clinics (25% versus 59%, p=0.038). High levels of both East Europe clinics and non-East Europe clinics reported providing the following services to HIV-positive patients for free: clinic visits (83% versus 77%), antiretroviral therapy (ART) (100% versus 83%), CD4 cell count testing (100% versus 78%) and viral load testing (100% versus 83%) (Figure 2).Drugs for opportunistic infections were provided for free at somewhat smaller proportions of clinics (58% East Europe versus 62% non-East Europe). Discussion: Although neither alcohol and drug treatment services nor OST were available at many EuroSIDA clinics within or outside of the East Europe countries, it is not known whether or not this is problematic, since it is common in some settings to have separate narcological facilities located in close proximity to clinics that provide ART. A question warranting further research, particularly in East Europe EuroSIDA clinics, is whether patients with alcohol and drug addiction have sufficient access to treatment and to OST, either on the premises or elsewhere. The HIV literature has identified health service fees as a major barrier to treatment and care, with one potential consequence being loss to follow-up. In our study, the proportions of clinics providing four types of free services were high for both of the regions being compared. At the same time, East Europe clinics responding to the survey reported having higher loss to follow-up than the comparison region (data not shown). Further research should examine these variables on a clinic-by-clinic basis and in relation to patient socioeconomic status to determine how fees might affect patient outcomes in this regard. The regional difference in the provision of foreign-language interpreters may be due to a lower need in the East Europe group of clinics since most people in those study countries, regardless of nationality, speak Russian. On the other hand, a lack of foreign language interpreters in more than 40% of non-East clinics may be indicative of a service access barrier with greater consequences in some of those countries. Again, a closer examination of key variables on a clinic-by-clinic basis is warranted. Conclusion: This investigation of patient-centred health services at EuroSIDA study clinics has identified some service gaps in the East Europe group of clinics and other service gaps in the full cohort of EuroSIDA study clinics across Europe. Further research is needed to determine the potential impact of these gaps on patient outcomes. Figure 1. Availability of people-centred health services (see figure by following link below) P-values from Fishers exact test for comparing proportions. 1N=81 responses: 11 from East and 70 from non-East. 2N=81 responses: 12 from East and 69 from non-East. 3N=80 responses: 12 from East and 68 from non-East. Figure 2. Availability of free services (see figure by following the link below) P-values from Fishers exact test for comparing proportions. ART = antiretroviral therapy; CD4 = CD4 cell count; VL = viral load; OIs = opportunistic infections. All questions had 81 responses: 12 from East and 69 from non-East.

International audience; 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 (

Purpose of the study: To investigate the impact of ART, HIV viremia and immunosuppression on triglyceride (TG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels. Methods: We considered the cross-sectional associations between TG, TC and HDL-C (mmol/l; first available measurement on/after enrolment in the D:A:D study) and use of ART, HIV viral load (VL; copies/ml), and CD4 count (cells/mm 3 ) measured at the same time. TG was log 10 transformed to ensure normality. Analyses were performed using linear regression and adjusted for other factors known to impact lipid levels (table footnote). ART and VL status were combined (off ARTV IQR 1.52; 1.00-2.45), 45,169 (90.8%) a TC measurement (4.80; 4.00-5.70) and 38,604 (77.6%) a HDL-C measurement (1.12; 0.90-1.40). Most participants were male (74%), of white ethnicity (51%), without AIDS (78%), were not receiving lipid-lowering drugs (4%) and were ART experienced (61%) with 47% previously exposed to PIs, 61% previously exposed to NRTIs and 29% previously exposed to NNRTIs. The median (IQR) age, current CD4 count and CD4 nadir were 38 (36-45) years, 400 (242-590) cells/μl and 240 (100-410) cells/μl respectively. Compared to those on ART with a suppressed VL, all lipids were lower for those off ART (Table); non-suppressive ART was also associated with lower TC and HDL-C levels (no impact on TG). A low current CD4 count was associated with lower lipid levels, whereas a low nadir CD4 count was associated with higher TC and TG levels. Prior AIDS diagnosis was associated with higher TG and TC, but lower HDL-C levels Conclusion: Although specific drug classes were not considered, lipid levels are considerably higher in those on a suppressive ART regimen. The higher TC/TG and lower HDL-C levels seen among those with low nadir CD4 count and with a prior AIDS diagnosis suggests severe immunosuppression may be associated with dyslipidaemia over the long-term. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Kamara D et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18280 http://www.jiasociety.org/index.php/jias/article/view/18280 | http://dx.doi.org/10.7448/IAS.15.6.18280

Background : In the last decade, several outbreaks of sexually acquired acute HCV have been described in men who have sex with men (MSM) infected with HIV in Australia, Europe, and North America. The aims of this study were to determine the incidence of acute HCV within the large EuroSIDA cohort and to explore possible regional differences throughout Europe and in different HIV transmission risk groups. Methods : Baseline was defined as 1st Jan of 2002 or entry into EuroSIDA, whichever comes later. All patients from EuroSIDA who were HCV antibody-negative at baseline and had at least 2 HCV antibody test results available were included into the study. HCV seroconversion was defined as change from negative to positive HCV-antibody test within the observation period from 2002 onwards. Follow-up was counted from baseline to HCV antibody positivity for seroconverters and to the last HCV antibody-negative test result for those that did not seroconvert for HCV. Poisson regression analyses were performed to identify predictive factors for HCV seroconversion. Results : A total of 150 HCV seroconversions (95 [63.3%] in MSM) occurred in 4295 patients during 18,928 person years of follow-up (PYFU), overall incidence of 0.79 acute infections per 100 PYFU (95% CI: 0.67-0.92) (see figure). The incidence of HCV seroconversions increased from 0.47 (CI: 0.19–0.74) in 2002 to 2.34 (CI: 1.24-3.44) in 2010. Similar patterns were observed across all European regions (p=0.89, test for interaction). In multivariate analysis, IDU was associated with a higher incidence rate ratio (IRR) than MSM: 4.59 (2.40-8.80; p

Many studies have focused on chronic kidney disease in HIV-positive individuals, but few have studied the less frequent events, advanced renal disease (ARD) and end-stage renal disease (ESRD). The aim of this study was to investigate incidence, predictors and outcomes for ARD/ESRD and renal death in EuroSIDA. ARD was defined as confirmed eGFR 3 months apart) using Cockcroft-Gault. ESRD was defined as hemo- or peritoneal dialysis >1 month/renal transplant. Renal deaths were defined as renal failure as the underlying cause of death, using CoDe methodology. Patients were followed from baseline (first eGFR after 1/1/2004) until last eGFR, ARD/ESRD/renal death; whichever occurred first. Poisson regression was used to identify predictors. 8817 persons were included, the majority were white (87.3%), males (73.9%) infected though homosexual contact (41.5%) and with a median age of 42 years (IQR 36-49). 45 persons (0.5%) developed the composite endpoint; ARD (24), ESRD (19) and renal death (2) during a median follow up (FU) of 4.5 years (IQR 2.7-5.8), incidence rate (IR) 1.21/1000 PYFU (95% CI 0.86-1.57). Of 312 persons (3.5%) with baseline eGFR

Persistent immunosuppression despite viral suppression (immunovirological discordance, ID) has been associated with higher risk of AIDS and death, although the risk for AIDS seems to decrease with longer time of suppressed viral load (sVL). The impact of ID on a composite endpoint of AIDS/serious non-AIDS/death has not been thoroughly investigated. Patients in EuroSIDA starting ≥1 new antiretroviral drugs after January 2001, when CD4 was 500 copies/mL, and who achieved a sVL ≤50 copies/mL within 1 year were included. Person-years of follow-up (PYFU) accrued from the date of sVL until the first of a new AIDS or severe non-AIDS (SNA) event or death, viral rebound >50 copies/mL (first of 2 consecutive values) or last visit. Rate ratios (RR) were calculated using Poisson regression according to whether or not patient's current CD4 count was still below 200 cells/mm 3 (ID). Models were stratified according to whether or not persons were ART-naive at baseline. Multivariable models included age, HBV/HCV status, mode of HIV transmission, race, cohort, anemia, diabetes, hypertension or current eGFR, current cART, number of previous antiretrovirals, and time to viral suppression. 994 patients satisfied the inclusion criteria and contributed 4520 PYFU. Median age was 41 (IQR 34-47) years and 72.8% were male. 36.5% of patients were ART-naive and started a median of 3 (IQR 2-3) new drugs. 31 AIDS and 58 non-AIDS events occurred, and 31 patients died (7 due to AIDS, 24 due to SNA). The rate of the combined endpoint in patients with ID (50.3 per 1000 PYFU [95% CI 35.2-69.9]) was higher than in patients recovered from ID (22.1 [17.6-27.3], adjusted RR 2.08 [1.32-3.28]; table). This was similar regardless of whether or not people were ART-naive before starting a new drug (interaction test p=0.47). In ID, rate was highest in the first 6 months of sVL (63.1 [33.6-107.9]) and declined thereafter (month 6-12: 60.5 [26.1-119.2],>12 months: 39.8 [22.2-65.6], adjusted RR compared to month 0-6 0.52 [0.24-1.13]). In analyses with endpoints AIDS/death due to AIDS and SNA/death due to SNA separately, the adjusted RR of ID vs. non ID was 4.11 ([1.76-9.60]; p=0.001) and 1.46 ([0.81-2.61]; p=0.207), respectively. ID is a risk factor for clinical disease progression particularly related to AIDS events. In patients with ID, we found a trend for a declining incidence of events with longer periods of sVL, suggesting that sustained viral suppression might be of benefit. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Zoufaly A et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18194 http://www.jiasociety.org/index.php/jias/article/view/18194 | http://dx.doi.org/10.7448/IAS.15.6.18194

Background State-of-the-art care involving the utilisation of multiple health care interventions is the basis for an optimal long-term clinical prognosis for HIV-patients. We evaluated health care for HIV patients based on four key indicators. Methods Four indicators of health care were assessed: Compliance with current guidelines on initiation of: 1) combination antiretroviral therapy (cART); 2) chemoprophylaxis; 3) frequency of laboratory monitoring; and 4) virological response to cART (proportion of patients with HIV-RNA < 500copies/ml for >90% of time on cART). Results 7097 EuroSIDA patients were included from Northern (n = 923), Southern (n = 1059), West Central (n = 1290) East Central (n = 1366), Eastern (n = 1964) Europe, and Argentina (n = 495). Patients in Eastern Europe with a CD4 < 200cells/mm3 were less likely to initiate cART and Pneumocystis jiroveci-chemoprophylaxis compared to patients from all other regions, and less frequently had a laboratory assessment of their disease status. The proportion of patients with virological response was highest in Northern, 89% vs. 84%, 78%, 78%, 61%, 55% in West Central, Southern, East Central Europe, Argentina and Eastern Europe, respectively (p < 0.0001). Compared to Northern, patients from other regions had significantly lower odds of virological response; the difference was most pronounced for Eastern Europe and Argentina (adjusted OR 0.16 [95%CI 0.11-0.23, p < 0.0001]; 0.20[0.14-0.28, p < 0.0001] respectively). Conclusions This assessment of HIV health care utilization revealed pronounced regional differences in adherence to guidelines and can help to identify gaps and direct target interventions. It may serve as a tool for the assessment and benchmarking of the clinical management of HIV patients in any setting worldwide.

Chronic kidney disease (CKD) is an important cause of morbidity and mortality in HIV-positive individuals. Hepatitis C (HCV) co-infection has been associated with increased risk of CKD, but prior studies lack information on potential mechanisms. We evaluated the association between HCV or hepatitis B (HBV) co-infection and progressive CKD among 3,441 antiretroviral-treated clinical trial participants. Progressive CKD was defined as the composite of end-stage renal disease, renal death, or significant glomerular filtration rate (eGFR) decline (25% decline to eGFR 800,000 IU/ml had increased odds (OR 3.07; 95% CI 1.60–5.90). Interleukin-6, hyaluronic acid, and the FIB-4 hepatic fibrosis index were higher among participants who developed progressive CKD, but were no longer associated with progressive CKD after adjustment. Future studies should validate the relationship between HCV viremia and CKD. Trial Registration ClinicalTrials.gov NCT00027352; NCT00004978

Several observational studies have identified tenofovir as an independent risk factor for kidney impairment. Conversely, randomized trials have only demonstrated minor tenofovir-related changes in kidney function, but these studies included patients with normal kidney function and with low underling risk for progression of their renal function, had limited size, and limited follow-up. Several potential mechanisms of tenofovir nephrotoxicity are known. Atazanavir can, equally to indinavir, cause urolithiasis, but both drugs have also been associated with chronic kidney disease (CKD) and fast declining eGFR in persons without clinical symptoms of urolithiasis, especially when the plasma drug concentration is boosted by concomitant ritonavir use. In 2012, only a minority of HIV-positive individuals are affected by drug-induced nephrotoxicity. However, in the future, the clinical impact and hence the requirement for more research in this area will likely increase due to ageing and continued cART exposure of the HIV-positive population.

Background: Despite the known substantial benefits of combination antiretroviral therapy (cART), cumulative adverse effects could still limit the overall long-term treatment benefit. Therefore we investigated changes in the rate of death with increasing exposure to cART. Methods: A total of 12 069 patients were followed from baseline, which was defined as the time of starting cART or enrolment into EuroSIDA whichever occurred later, until death or 6 months after last follow-up visit. Incidence rates of death were calculated per 1000 person-years of follow-up (PYFU) and stratified by time of exposure to cART (>= 3 antiretrovirals): less than 2, 2-3.99, 4-5.99, 6-7.99 and more than 8 years. Duration of cART exposure was the cumulative time actually receiving cART. Poisson regression models were fitted for each cause of death separately. Results: A total of 1297 patients died during 70 613 PYFU [incidence rate 18.3 per 1000 PYFU, 95% confidence interval (CI) 17.4-19.4], 413 due to AIDS (5.85, 95% CI 5.28-6.41) and 884 due to non-AIDS-related cause (12.5, 95% CI 11.7-13.3). After adjustment for confounding variables, including baseline CD4 cell count and HIV RNA, there was a significant decrease in the rate of all-cause and AIDS-related death between 2 and 3.99 years and longer exposure time. In the first 2 years on cART the risk of non-AIDS death was significantly lower, but no significant difference in the rate of non-AIDS-related deaths between 2 and 3.99 years and longer exposure to cART was observed. Conclusion: In conclusion, we found no evidence of an increased risk of both all-cause and non-AIDS-related deaths with long-term cumulative cART exposure. (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Background 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. Methods 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). Results 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%. Conclusions 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.