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Background According to guidelines all HIV–HBV-coinfected patients should receive tenofovir-based combination antiretroviral therapy (cART). We aimed to investigate uptake and outcomes of tenofovir-based cART among HIV–HBV patients in the EuroSIDA study.Methods All hepatitis B surface antigen (HBsAg)+ patients followed up after 1 March 2002 were included. Changes in the proportion taking tenofovir-based cART over time were described. Poisson regression was used to investigate the relationship between tenofovir use and clinical events.Results 953 HIV–HBV patients were included. Median age was 41 years and patients were predominantly male (85%), White (82%) and ART-experienced (88%). 697 and 256 were from Western and Eastern Europe, respectively. 55 started cART during follow-up, the proportion starting with CD4+T-cell count <350 cells/mm3decreased from 85% to 52% in the periods 2002–2006 to 2007–2015. Tenofovir use, among those taking cART, increased from 4% in 2002 to 73% in 2015. Compared to West, tenofovir use was lower in East in 2005 (7% versus 42%), and remained lower in 2015 (63% versus 76%). Among 602 patients taking tenofovir-based cART during follow-up, 155 (26%) discontinued tenofovir. 27 of all discontinuations were due to adverse effects. Only 14 started entecavir and/or adefovir after tenofovir discontinuation, whereas 10 started pegylated interferon. Tenofovir use was not significantly associated with lower risk of liver-related clinical events (n=51), adjusted incidence rate ratio (IRR) 0.64 (95% CI 0.35, 1.18) for comparing patients on tenofovir with those off tenofovir.Conclusions Although use of tenofovir-based cART among HIV–HBV patients has increased across Europe, a substantial proportion are still starting cART late and are receiving suboptimal HBV therapy.

Background It is common practice to use prostate specific antigen (PSA) =4.0 ng/ml as a clinical indicator for men at risk of prostate cancer (PCa), however, this is unverified in HIV+ men. We aimed to describe kinetics and predictive value of PSA for PCa in HIV+ men.Methods A nested case control study of 21 men with PCa and 40 matched-controls within EuroSIDA was conducted. Prospectively stored plasma samples before PCa (or matched date in controls) were measured for the following markers: total PSA (tPSA), free PSA (fPSA), testosterone and sex hormone binding globulin (SHBG). Conditional logistic regression models investigated associations between markers and PCa. Mixed models were used to describe kinetics. Sensitivity and specificity of using tPSA >4 ng/ml to predict PCa was calculated. Receiver operating characteristic curves were used to identify optimal cutoffs in HIV+ men for total PSA.Results 61 HIV+ men were included with a median 6 (IQR 2–9) years follow-up. Levels of tPSA increased by 13.7% per year (95% CI 10.3, 17.3) in cases, but was stable in controls (-0.4%; 95% CI -2.5, 1.7). Elevated PSA was associated with higher odds of PCa at first (OR for twofold higher 4.7; 95% CI 1.7, 12.9; P=0.01) and last sample (8.1; 95% CI 1.1, 58.9; P=0.04). A similar relationship was seen between fPSA and PCa. Testosterone and SHBG level were not associated with PCa. tPSA level >4 ng/ml had 99% specificity and 38% sensitivity. The optimal PSA cutoff was 1.5 ng/ml overall (specificity =84%, sensitivity =81%).Conclusions PSA was highly predictive of PCa in HIV+ men; however, the commonly used PSA>4 ng/ml to indicate high PCa risk was not sensitive in our population and use of the lower cutoff of PSA>1.5 ng/ml warrants consideration.

Background Antiretroviral (ART) drugs have been associated with higher triglycerides (TG), higher total cholesterol (TC) and lower high-density lipoprotein cholesterol (HDL-C) levels. Associations between lipid levels with HIV viraemia and immunosuppression in the presence of ART remain unclear.Methods Participants from the D:A:D study with at least one TG/TC/HDL-C measurement were included. Linear mixed effect models were used to determine the association of ART, viral load (VL), nadir and current CD4+T-cell count and previous AIDS diagnosis with lipids.Results Of 49,717 participants, 90%, 92% and 80% contributed at least one TG/TC/HDL-C measurement (median follow-up 6.8, 6.8 and 5.0 years, respectively). Predicted mean (95% CI) baseline levels for TG, TC and HDL-C (mmol/l), were 2.10 (2.05, 2.14), 4.94 (4.91, 4.98) and 1.08 (1.07, 1.10), respectively. Lopinavir was associated with the worst TG profile, (27.2% higher levels compared to atazanavir; 95% CI 25.2%, 29.2%), and darunavir had a similar profile as atazanavir. The nucleoside pair lamivudine/tenofovir was associated with the most favourable TG profile (-2.8%; -3.5%, -2.0%) compared with emtricitabine/tenofovir, whereas lamivudine/abacavir (+10.2%; +9.3%, +11.2%) and lamivudine/ stavudine (+8.0%; +6.9%, +9.0%), were associated with the worst. Raltegravir was associated with lower TG (-5.2%; -6.4%, -3.9%), and nevirapine had a more favourable HDL-C profile (+11.3%; +10.8%, +11.7%) than efavirenz (+5.3%; 5.0%, 5.7%), compared to atazanavir. Higher VLs were associated with lower TG/TC/HDL-C, whereas higher CD4+T-cell counts were associated with higher TG/TC/HDL-C.Conclusions TG, TC and HDL-C levels, which generally improved over time, are dependent on ART, viraemia and, to a lesser extent, immunosuppression.

Background The aim of this study was to determine whether there is a protective effect of combination anti-retroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression.Methods A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4+T-cell count ≤200 cells/mm3were stratified into five groups: group 1, viral load (VL)<50 copies/ml on cART; group 2, VL 50-99,999 copies/ml on cART; group 3, VL 50-99,999 copies/ml off cART; group 4, VL≥100,000 copies/ml on cART; and group 5, VL≥100,000 copies/ml off cART. Poisson regression was used to identify the risk of (non-fatal or fatal) AIDS- and non-AIDS-related events considered together (AIDS/non-AIDS) or separately as AIDS or non-AIDS events within each group.Results There were 428 AIDS/non-AIDS events during 3,780 person-years of follow-up. Compared with group 1, those in group 2 had a similar incidence of AIDS/ non-AIDS events (incidence rate ratio [IRR] 1.04; 95% CI 0.79–1.36). Groups 3, 4 and 5 had significantly higher incidence rates of AIDS/non-AIDS events compared with group 1; incidence rates increased from group 3 (IRR 1.78; 95% CI 1.25–2.55) to group 5 (IRR 2.36; 95% CI 1.66–3.40), demonstrating the increased incidence of AIDS/non-AIDS events associated with increasing viraemia. After adjustment, the use of cART was associated with a 40% reduction in the incidence of AIDS/non-AIDS events in patients with VL 50–99,999 copies/ml (IRR 0.59; 95% CI 0.41–0.85) and in those with a VL>100,000 copies/ml (IRR 0.66; 95% CI 0.44–1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately.Conclusions In patients with ongoing severe immuno-suppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure.

Background Data from randomized trials on the development of anaemia after interruption of therapy are not well-described.Methods A total of 2,248 patients from the SMART study were included. We used Cox proportional hazards models to investigate development of new (=12 mg/dl for females and=14 mg/dl for males) or worsening (=8 mg/dl if anaemic at randomization) anaemia and Poisson regression analyses to explore the relationship between anaemia and the development of AIDS, death or non-AIDS events.Results Overall, 759 patients developed new or worsening anaemia: 420/1,106 (38.0%) in the drug conservation (DC) arm and 339/1127 (30.1%) in the viral suppression (VS) arm (P<0.0001). At 4 months after randomization, patients in the DC arm had a significantly increased risk of developing new or worsening anaemia (adjusted relative hazard 1.56, 95% CI 1.28–1.89). Currently anaemic patients had an increased incidence of AIDS (adjusted incidence rate ratio [IRR] 2.31, 95% CI 1.34–3.98), death (adjusted IRR 2.19, 95% CI 1.23–3.87) and non-AIDS events (adjusted IRR 2.98, 95% CI 2.01–4.40) compared to non-anaemic patients.Conclusions Patients who interrupted combination anti-retroviral therapy had a higher risk of new or worsening anaemia. Anaemic patients had a higher incidence of AIDS, non-AIDS defining events or deaths, possibly due to deteriorating health and subclinical disease.

Background Patients receiving combination antiretroviral therapy (cART) might continue treatment with a virologically failing regimen. We sought to identify annual change in CD4+T-cell count according to levels of viraemia in patients on cART.Methods A total of 111,371 CD4+T-cell counts and viral load measurements in 8,227 patients were analysed. Annual change in CD4+T-cell numbers was estimated using mixed models.Results After adjustment, the estimated average annual change in CD4+T-cell count significantly increased when viral load was <500 copies/ml (30.4 cells/mm3, 95% confidence interval [CI] 26.6–34.3), was stable when viral load was 500–9,999 copies/ml (3.1 cells/mm3, 95% CI -5.3–11.5) and decreased when viral load was =10,000 copies/ml (-14.8 cells/mm3, 95% CI -4.5– - 25.1). Patients taking a boosted protease inhibitor (PI) regimen had more positive annual CD4+T-cell count changes than patients taking other regimens for any given viral load strata: 30.9 cells/mm3(95% CI 27.7–34.1) when viral load was <500 copies/ml, 14.2 cells/mm3(95% CI -2.1–30.4) when viral load was 500–9,999 copies/ml and -19.9 cells/mm3(95% CI -36.6– -3.3) when viral load was =10,000 copies/ml. By contrast, among patients taking a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, the CD4+T-cell count significantly decreased when the viral load was 500–9,999 copies/ml (-18.6 cells/mm3, 95% CI -33.8– - 3.5) and decreased at a faster rate when the viral load was =10,000 copies/ml (-44.4 cells/mm3, 95% CI -62.0– -26.9; P=0.0012, test for interaction).Conclusions On average, CD4+T-cell counts did not significantly decrease until the viral load exceeded 10,000 copies/ml in patients treated with a boosted PI-containing cART regimen, but decreased in patients taking an NNRTI-based cART regimen when viral load was 500–9,999 copies/ml.

Background Incidence and risk factors of HIV-associated non-Hodgkin's lymphoma (NHL) are not well defined in the era of combination antiretroviral therapy (cART).Methods A total of 56,305 adult HIV type-1 (HIV-1)-infected patients who started cART in 1 of 22 prospective studies in Europe were included. Weibull random effects models were used to estimate hazard ratios (HRs) for developing systemic NHL and included CD4+T-cell counts and viral load as time-updated variables.Results During the 212,042 person-years of follow-up, 521 patients were diagnosed with systemic NHL and 62 with primary brain lymphoma (PBL). The incidence rate of systemic NHL was 463 per 100,000 person-years not on cART and 205 per 100,000 person-years in treated patients for a rate ratio of 0.44 (95% confidence interval [CI] 0.37–0.53). The corresponding incidence rates of PBL were 57 and 24 per 100,000 person-years (rate ratio 0.43, 95% CI 0.25-0.73). Suppression of HIV-1 replication on cART (HR 0.60, 95% CI 0.44-0.81, comparing =500 with 10,000-99,999 copies/ml) and increases in CD4+T-cell counts (HR 0.30, 0.22-0.42, comparing =350 with 100-199 cells/pl) were protective; a history of Kaposi's sarcoma (HR 1.70, 1.08-2.68, compared to no history of AIDS), transmission through sex between men (HR 1.57, 1.19-2.08, compared with heterosexual transmission) and older age (HR 3.71, 2.37-5.80, comparing =50 with 16-29 years) were risk factors for systemic NHL.Conclusions The incidence rates of both systemic NHL and PBL were substantially reduced in patients on cART. Timely initiation of therapy is key to the prevention of NHL in the era of cART.

Background Conflicting data exist regarding the effect of efavirenz (EFV) plasma concentrations on central nervous system (CNS) toxicity. We aimed to determine whether patients with high EFV plasma concentrations have an increased likelihood of toxicity-driven EFV discontinuations.Methods EFV plasma concentrations were measured from patients in the EuroSIDA study starting EFV after 1 January 1999. Patients with a plasma concentration available were divided into those that discontinued EFV because of any toxicity or by the choice of the patient or physician within 2 years (TOXPC group) and those that continued EFV for =2 years (no toxicity group). Multivariable logistic regression modelling was used to investigate the effects of the EFV plasma concentration and those of other potentially relevant factors on the risk of toxicity-induced EFV discontinuations.Results A total of 843 patients were included. Of these patients, 138 patients (16.4%) discontinued EFV because of TOXPC and 705 (83.6%) patients continued EFV for =2 years. A total of 20 (14.5%) patients in the TOXPC group had high EFV plasma concentrations (>4.0 mg/l) compared with 99 (14.0%) patients in the no toxicity group (P=0.890). A positive hepatitis C status (P=0.026), but not the EFV plasma concentration, was an independent predictor of toxicity-driven EFV discontinuations.Conclusions No association was found between EFV plasma concentrations and the risk of EFV discontinuations because of (CNS) toxicity. This result questions the designation of EFV plasma concentrations >4.0 mg/l as being ‘toxic’, at least when defined by treatment discontinuation.

Background In HIV type-1-infected patients starting highly active antiretroviral therapy (HAART), the prognostic value of haemoglobin when starting HAART, and of changes in haemoglobin levels, are not well defined.Methods We combined data from 10 prospective studies of 12,100 previously untreated individuals (25% women). A total of 4,222 patients (35%) were anaemic: 131 patients (1.1%) had severe (<8.0 g/dl), 1,120 (9%) had moderate (male 8.0–<11.0 g/dl and female 8.0–<10.0 g/ dl) and 2,971 (25%) had mild (male 11.0–<13.0 g/dl and female 10.0–<12.0 g/dl) anaemia. We separately analysed progression to AIDS or death from baseline and from 6 months using Weibull models, adjusting for CD4+T-cell count, age, sex and other variables.Results During 48,420 person-years of follow-up 1,448 patients developed at least one AIDS event and 857 patients died. Anaemia at baseline was independently associated with higher mortality: the adjusted hazard ratio (95% confidence interval) for mild anaemia was 1.42 (1.17–1.73), for moderate anaemia 2.56 (2.07–3.18) and for severe anaemia 5.26 (3.55–7.81). Corresponding figures for progression to AIDS were 1.60 (1.37–1.86), 2.00 (1.66–2.40) and 2.24 (1.46–3.42). At 6 months the prevalence of anaemia declined to 26%. Baseline anaemia continued to predict mortality (and to a lesser extent progression to AIDS) in patients with normal haemoglobin or mild anaemia at 6 months.Conclusions Anaemia at the start of HAART is an important factor for short- and long-term prognosis, including in patients whose haemoglobin levels improved or normalized during the first 6 months of HAART.

Background The aim of the study was to investigate the incidence of abacavir-related hypersensitivity reaction (HSR) and associated deaths in EuroSIDA HIV-1-infected patients.Methods Poisson regression models were developed to compare incidence of abacavir discontinuation according to the line of therapy within which abacavir was received, geographical regions, calendar time and drug formulation (abacavir/lamivudine combination tablet versus abacavir as a single drug or abacavir/zidovudine/ lamivudine combination).Results Of 3,278 patients that started abacavir, 2,101 (64.1%) discontinued. Of these, 167 (5.1%) discontinued abacavir within 3 months due to HSR with an incidence of 22.1 (95% confidence interval [CI] 18.7–25.4) per 100 person-years of follow-up. After adjustment for gender, prior AIDS, hepatitis C serostatus, baseline CD4+T-cell count, region and calendar time, HSR incidence was significantly higher in those starting abacavir in a first-line regimen compared with second-line (incidence rate ratio [IRR] 2.04 [95% CI 1.24–3.38]; P=0.005). There was no significant difference between regions. HSR incidence from 2005 onwards was significantly lower compared with 1999–2000 (IRR 0.54 [95% CI 0.32–0.92]; P=0.024). There was a lower observed incidence in patients starting abacavir/lamivudine compared with other formulations (IRR 0.33 [95% CI 0.13 –0.88]; P=0.027), however, available data were limited.Conclusions Incidence of abacavir-related HSR is higher in patients starting abacavir in first-line therapy, which could indicate increased over-diagnosis. HSR incidence has decreased in recent years, which might reflect the wider availability of genetic screening and improved awareness of symptoms. There were no reported deaths due to abacavir HSR.

Introduction It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+T-cell counts is also observed when NVPc is initiated in cART-experienced patients.Patients and methods 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+T-cell counts at initiation of NVPc (high [H], >400/mm3or >250/mm3for male or female, respectively, or low [L], =400/mm3or =250/mm3for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC).Results After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group (n=588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n=62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34–0.94; P=0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23–0.87; P=0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to <3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0–6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60–1.38; P=0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77–1.66; P=0.52).Conclusions Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretro-viral-experienced than in antiretroviral-naive patients with high CD4+T-cell counts.

Background Combination antiretroviral therapy (cART) may vary in ability to suppress viral load and increase CD4+T-cell count in people infected with different HIV-1 subtypes, possibly due to differences in resistance development. Antiretroviral drugs have predominantly been developed in Western Europe/North America on the basis of the most prevalent subtype, B. However, non-B subtypes are increasingly spreading worldwide.Objective To compare virological and immunological response to cART between patients infected with B and non-B subtypes across Europe.Design EuroSIDA prospective, observational cohort with 11,928 HIV-1-infected patients.Methods Response to cART was analysed in patients with subtypes determined pre-cART, via multivariable logistic regression on the first measurements 6–12 months after starting cART. A virological response was defined as a viral load <500 copies/ml and immunological response as a CD4+T-cell count increase of =100 cells/mm3.Results Forty-five percent of patients were antiretroviral naive at initiation of cART. Virological suppression was achieved by 58% of 689 subtype-B-infected patients and 66% of 102 non-B-infected patients (P=0.159). After adjustment for potential confounders, there was no significant difference in odds of achieving virological suppression (non-B compared with B; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 0.58–1.93, P=0.866). An immunological response was achieved by 43% of 753 B-infected patients and 48% of 114 non-B-infected patients (P=0.334). After adjustment, there was no significant difference in odds of an immunological response (OR: 1.17, 95% CI: 0.73–1.87, P=0.524).Conclusions There was no evidence of significant differences in virological or immunological response to cART between patients infected with HIV-1 B and non-B subtypes.

Background Liver damage associated with hepatitis C (HCV) may influence the likelihood of experiencing discontinuation due to toxicities or patient/physician choice (TOXPC) in patients taking combination antiretroviral therapy (cART). Little information to address this concern is available from clinical trials as patients with HCV are often excluded.Aims To compare incidence rates of discontinuation due to TOXPC associated with specific antiretrovial drugs in patients with or without HCV.Patients/methods A total of 4929 patients from EuroSIDA under follow-up from January 1999 on a specific nucleoside pair (zidovudine/lamivudine, didanosine/stavudine, stavudine/lamivudine, or other) with a third drug (abacavir, nelfinavir, indinavir, nevirapine, efavirenz, lopinavir/ ritonavir or other boosted-protease inhibitor (PI)-containing regimen) and with known HCV serostatus were studied for the incidence of discontinuation of any nucleoside pair or third drug due to TOXPC. Incidence rate ratios were derived from Poisson regression models.Results In total 1358 patients had HCV (27.5%). During 12 799 person-years of follow-up there were 2141 discontinuations due to TOXPC for nucleoside pairs and 2501 for third drugs. The incidence of discontinuation due to TOXPC was consistently higher in patients with HCV after stratification by nucleoside pair or third drug. After adjustment for CD4+count, gender, exposure group, time on HAART, region and treatment regimen, there were few differences in the rate of discontinuation due to TOXPC in those with HCV compared with those without for any nucleoside pairs or third drugs. Similar results were seen when concentrating on discontinuation due to toxicities alone.Conclusions Although patients with HCV generally had higher rates of discontinuation due to TOXPC compared with patients without HCV, there was little evidence to suggest that this was associated with any specific nucleoside pair or third drug used as part of cART. Our results do not suggest that any specific component of cART is more poorly tolerated in patients with HCV or that the presence of HCV should influence the choice between antiretrovirals used as part of a cART regimen.