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The EuroSIDA study was initiated in 1994 and follows adult people living with HIV (PLHIV) in 100 collaborating clinics across 35 countries covering all European regions, Israel and Argentina. The study aims to study the long-term virological, immunological and clinical outcomes of PLHIV and to monitor temporal changes and regional differences in outcomes across Europe. Annually collected data include basic demographic characteristics, information on AIDS- and non-AIDS-related clinical events, and details about antiretroviral therapy (ART), hepatitis C treatment and other medications, in addition to a range of laboratory values. The summer 2016 data set held data from a total of 23 071 individuals contributing 174 481 person-years of follow-up, while EuroSIDA's unique plasma repository held over 160 000 samples. Over the past 25 years, close to 300 articles have been published in peer-reviewed journals (h-index 52), covering a range of scientific focus areas, including monitoring of clinical and virological outcomes, ART uptake, efficacy and adverse events, the influence of hepatitis virus coinfection, variation in the quality of HIV care and management across settings and regions, and biomarker research. Recognizing that there remain unresolved issues in the clinical care and management of PLHIV in Europe, EuroSIDA was one of the cohorts to found The International Cohort Consortium of Infectious Disease (RESPOND) cohort consortium on infectious diseases in 2017. In celebration of the EuroSIDA study's 25th anniversary, this article aims to summarize key scientific findings and outline current and future scientific focus areas., (© 2019 British HIV Association.)

Background and Purpose: Some clinical studies have reported increased myocardial infarction in people living with human immunodeficiency virus (HIV) taking the antiretroviral abacavir sulphate (ABC). Given that clinical studies contain confounding variables (e.g., HIV-associated factors), we investigated the pharmacological effects of antiretrovirals on platelet function in HIV-negative volunteers in order to identify mechanisms of increased cardiovascular risk., Experimental Approach: Platelets were isolated from healthy volunteers and HIV-negative subjects enrolled on a Phase I clinical trial and platelet function evaluated using aggregometry and flow cytometry. In vivo platelet thromboembolism was monitored in anaesthetized mice., Key Results: Human platelet aggregation was unaffected by all antiretrovirals tested, but ABC treatment led uniquely to increased platelet granule release. ABC also interrupted NO-mediated inhibition of platelet aggregation and increased in vivo aggregation in mice. Another antiretroviral, tenofovir, did not affect platelet function. Furthermore, aggregation and activation of platelets isolated from 20 subjects taking clinically relevant doses of tenofovir were comparable to baseline samples., Conclusions and Implications: ABC can enhance platelet activation, independently of variables that confound clinical studies, suggesting a potential pharmacological effect that is absent with tenofovir. Mechanistically, we propose that ABC enhances platelet degranulation and interrupts NO-mediated platelet inhibition. The interaction of ABC with NO signalling is demonstrated by ABC-mediated enhancement of aggregation in vivo and in vitro that persisted in the presence of NO. Although an association between ABC and platelet activation has not been confirmed in patients, these findings provide evidence of a mechanistic link between platelet activation and antiretroviral therapy., (© 2019 The British Pharmacological Society.)

Objectives: A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined., Methods: We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomization. The key covariables considered for this analysis were race, and hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA ≤ 50 and ≤ 400 HIV-1 RNA copies/mL using logistic regression. Because of the strong association between region of randomization and baseline low HIV RNA, analyses were stratified by region., Results: We found that, of 4676 eligible participants randomized in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA ≤ 50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher high-density lipoprotein (HDL) cholesterol levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA., Conclusions: In a modern cohort of individuals with early untreated HIV infection, we found that HIV exposure routes other than male homosexual contact and higher HDL cholesterol were associated with increased odds of low HIV RNA., (© 2015 British HIV Association.)

Objectives: We compared the use of computational models developed with and without HIV genotype vs. genotyping itself to predict effective regimens for patients experiencing first-line virological failure., Methods: Two sets of models predicted virological response for 99 three-drug regimens for patients on a failing regimen of two nucleoside/nucleotide reverse transcriptase inhibitors and one nonnucleoside reverse transcriptase inhibitor in the Second-Line study. One set used viral load, CD4 count, genotype, plus treatment history and time to follow-up to make its predictions; the second set did not include genotype. Genotypic sensitivity scores were derived and the ranking of the alternative regimens compared with those of the models. The accuracy of the models and that of genotyping as predictors of the virological responses to second-line regimens were compared., Results: The rankings of alternative regimens by the two sets of models were significantly correlated in 60-69% of cases, and the rankings by the models that use a genotype and genotyping itself were significantly correlated in 60% of cases. The two sets of models identified alternative regimens that were predicted to be effective in 97% and 100% of cases, respectively. The area under the receiver-operating curve was 0.72 and 0.74 for the two sets of models, respectively, and significantly lower at 0.55 for genotyping., Conclusions: The two sets of models performed comparably well and significantly outperformed genotyping as predictors of response. The models identified alternative regimens predicted to be effective in almost all cases. It is encouraging that models that do not require a genotype were able to predict responses to common second-line therapies in settings where genotyping is unavailable., (© 2014 British HIV Association.)

Objectives: Current British HIV Association (BHIVA) guidelines recommend that all patients with a CD4 count <350 cells/μL are offered highly active antiretroviral therapy (HAART). We identified risk factors for delayed initiation of HAART following a CD4 count <350 cells/μL., Methods: All adults under follow-up in 2008 who had a first confirmed CD4 count <350 cells/μL from 2004 to 2008, who had not initiated treatment and who had >6 months of follow-up were included in the study. Characteristics at the time of the low CD4 cell count and over follow-up were compared to identify factors associated with delayed HAART uptake. Analyses used proportional hazards regression with fixed (sex/risk group, age, ethnicity, AIDS, baseline CD4 cell count and calendar year) and time-updated (frequency of CD4 cell count measurement, proportion of CD4 counts <350 cells/μL, latest CD4 cell count, CD4 percentage and viral load) covariates., Results: Of 4871 patients with a confirmed low CD4 cell count, 436 (8.9%) remained untreated. In multivariable analyses, those starting HAART were older [adjusted relative hazard (aRH)/10  years 1.15], were more likely to be female heterosexual (aRH 1.13), were more likely to have had AIDS (aRH 1.14), had a greater number of CD4 measurements < 350 cells/μL (aRH/additional count 1.18), had a lower CD4 count over follow-up (aRH/50 cells/μL higher 0.57), had a lower CD4 percentage (aRH/5% higher 0.90) and had a higher viral load (aRH/log(10) HIV-1 RNA copies/ml higher 1.06). Injecting drug users (aRH 0.53), women infected with HIV via nonsexual or injecting drug use routes (aRH 0.75) and those of unknown ethnicity (aRH 0.69) were less likely to commence HAART., Conclusion: A substantial minority of patients with a CD4 count < 350 cells/μL remain untreated despite its indication., (© 2011 British HIV Association.)

Objective: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends., Methods: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated., Findings: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load., Conclusions: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART., (2011 British HIV Association.)

Objective: We investigated whether adverse responses to highly active antiretroviral therapy (HAART) associated with late HIV presentation are secondary to low CD4 cell count per se or other confounding factors., Methods: A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study of individuals starting HAART in 1998-2007 was carried out, comparing late presenters (presenting/starting HAART at a CD4 count <200 cells/μL) with late starters (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count<200 cells/μL), using 'ideal starters' (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count of 200-350 cells/μL) as a comparator. Virological, immunological and clinical (new AIDS event/death) outcomes at 48 and 96 weeks were analysed, with the analysis being limited to those remaining on HAART for>3 months., Results: A total of 4978 of 9095 individuals starting first-line HAART with HIV RNA>500 HIV-1 RNA copies/mL were included in the analysis: 2741 late presenters, 947 late starters and 1290 ideal starters. Late presenters were more commonly female, heterosexual and Black African. Most started nonnucleoside reverse transcriptase inhibitors (NNRTIs); 48-week virological suppression was similar in late presenters and starters (and marginally lower than in ideal starters); by week 96 differences were reduced and nonsignificant. The median CD4 cell count increase in late presenters was significantly lower than that in late starters (weeks 48 and 96). During year 1, new clinical events were more frequent for late presenters [odds ratio (OR) 2.04; 95% confidence interval (CI) 1.19-3.51; P=0.01]; by year 2, event rates were similar in all groups., Conclusion: Amongst patients who initiate, and remain on, HAART, late presentation is associated with lower rates of virological suppression, blunted CD4 cell count increases and more clinical events compared with late starters in year 1, but similar clinical and immunological outcomes by year 2 to those of both late and ideal starters. Differences between late presenters and late starters suggest that factors other than CD4 cell count alone may be driving adverse treatment outcomes in late-presenting individuals.

Background and Purpose: Data describing the incidence and survival of HIV-related central nervous system diseases (CNS-D) in recent years are sparse., Methods: Between 1996 and 2007, adult subjects without previous CNS-D within a large UK cohort were included (n=30,954). CNS-D were HIV encephalopathy (HIVe), progressive multifocal leucoencephalopathy (PML), cerebral toxoplasmosis (TOXO) and cryptococcal meningitis (CRYP). Associations between demographic, clinical and laboratory parameters with incidence and survival of CNS-D were evaluated using Poisson regression analysis and Kaplan-Meier techniques., Results: Six hundred and thirteen new CNS-D occurred in 574 subjects (HIVe:187, PML:113, TOXO:184, CRYP:129). Incidence of all CNS-D declined from 13.1 per 1000 PY in 1996/1997 to 1.0 per 1000 PY in 2006/2007 (P=0.0001). Current CD4+ cell count below 200 cells/ul and plasma HIV RNA above 100,000 copies/ml were independently associated with the development of CNS-D. Calendar year 1996/1997, older age, prior AIDS diagnosis and PML diagnosis were significantly associated with shorter survival., Conclusions: An ongoing decline in the incidence of CNS-D has been observed in very recent years. Mortality following such a diagnosis remains high., (© 2010 The Author(s). European Journal of Neurology © 2010 EFNS.)

Objectives: Patients starting highly active antiretroviral therapy (HAART) may have a suboptimal CD4 increase despite rapid virological suppression. The frequency and the significance for patient care of this discordant response are uncertain. This study was designed to determine the incidence of a discordant response at two time-points, soon after 6 months and at 12 months, and to determine the relationship with clinical outcomes., Methods: Data obtained in the UK Collaborative HIV Cohort Study were analysed. A total of 2584 treatment-naïve patients starting HAART with HIV viral load (VL) > 1000 HIV-1 RNA copies/mL at baseline and < 50 copies/mL within 6 months were included in the analysis. Patients were classified at either 6-10 (midpoint 8) months or 10-14 (midpoint 12) months as having a discordant (CD4 count increase < 100 cells/microL from baseline) or concordant response (CD4 count increase >or= 100 cells/microL)., Results: Discordant responses occurred in 32.1% of patients at 8 months and in 24.2% at 12 months; 35% of those discordant at 8 months were concordant at 12 months. A discordant response was associated with older age, lower baseline VL, and (at 12 months) higher baseline CD4 cell count. In a multivariate analysis it was associated with an increased risk of death, more strongly at 12 months [incidence rate ratio (IRR) 3.35, 95% confidence interval (CI) 1.73-6.47, P < 0.001] than at 8 months (IRR 2.08, 95% CI 1.19-3.64, P = 0.010), but not with new AIDS events., Conclusions: Discordant responders have a worse outcome, but assessment at 12 months may be preferred, given the number of 'slow' responders. Management strategies to improve outcomes for discordant responders need to be investigated.

We investigated the relationship between ritonavir concentrations and changes in lipids, vascular inflammation markers, CD36, and adipophilin expression in volunteers randomly assigned to groups receiving 100 mg of ritonavir once daily or twice daily. In both groups decreases in high-density lipoprotein (HDL) (6%, P = 0.010; and 10%, P < 0.001, respectively) and CD36 (14%, P = 0.012; and 16%, P = 0.006, respectively) and increases in the vascular inflammation marker sCD40L (12%, P = 0.008; 19%, P = 0.003, respectively) were seen. Increases in adipophilin (30%, P = 0.044) and triglycerides (32%, P = 0.044) were seen only in the group receiving ritonavir twice daily. The ritonavir concentration in the plasma correlated with changes in triglycerides, HDL, and adipophilin (r = 0.34, P = 0.030; r = 0.33, P = 0.040; and r = 0.4, P = 0.01, respectively).

Objective: The aim of this study was to describe the relationship between age and the time to treatment discontinuation in the absence of virological failure as well as the development of specific laboratory abnormalities, in patients starting highly active antiretroviral therapy (HAART) for the first time., Methods: Analyses included 8708 antiretroviral-naïve patients from the UK Collaborative HIV Cohort (CHIC) study who started HAART from 1998 onwards. We considered time to the first discontinuation of any drug in the initial HAART regimen for reasons other than virological failure; the association between this and age at the start of HAART was determined using proportional hazards regression after adjustment for potential confounders. The incidence of specific laboratory abnormalities in the first year after starting HAART was compared in those of different ages using multiple logistic regression., Results: A total of 2650 patients discontinued at least one drug in their HAART regimen in the first year for reasons other than virological failure; after controlling for confounders, those aged < 30 years at the time of starting HAART were more likely to discontinue than those aged 30-39 years [relative hazard (RH) 1.12; 95% confidence interval (CI) 1.01, 1.24] as were those aged > or = 50 years (RH 1.14; 95% CI 1.00, 1.31). There were strong associations between greater age and raised total cholesterol, decreased haemoglobin and raised triglycerides over the first year, although the latter disappeared after adjustment for pre-HAART levels, suggesting that this finding reflected higher pre-HAART triglyceride levels in older individuals., Conclusions: Continued attempts to improve the tolerability of HAART regimens may help to sustain the good outcomes in all age groups over the longer term.

HIV should preferably be diagnosed in its earlier stages. To optimize the chances of doing so, HIV testing in patients presenting with one of several indicator diseases and conditions is recommended. Patients presenting with tuberculosis and other AIDS-defining conditions should be tested. Patients with sexually transmitted diseases should be offered an HIV test, as should patients with certain types of cancers and laboratory abnormalities. Governments should consider adopting opt-out testing for pregnant women. These recommendations should be considered for implementation by all types of health professionals across Europe, and audits to study the extent of their being followed, conducted and reported to the European AIDS Clinical Society webpage (http://www.eacs.eu).

We investigated the pharmacokinetics and safety of saquinavir/ritonavir when administered with omeprazole simultaneously and 2 h apart to human immunodeficiency virus (HIV) subjects. Saquinavir/ritonavir 12-h pharmacokinetics was assessed with and without omeprazole 40 mg. Subjects were randomized to group A (saquinavir/ritonavir and omeprazole simultaneously/2 h apart) or group B (saquinavir/ritonavir and omeprazole 2 h apart/simultaneously). Saquinavir/ritonavir pharmacokinetics was assessed on days 1, 8, and 22. Within-subject changes were evaluated by geometric mean ratios and 90% confidence interval (CI). Twelve subjects completed the study. GM (90% CI) for saquinavir area under the curve (AUC)(0-12) (ng h/ml), trough concentration (C(trough)) (ng/ml), and maximum concentration (C(max)) (ng/ml) were 14,698 (13,242-20,636), 433 (368-758), 2,513 (2,243-3,329) without omeprazole; 22,646 (18,536-131,861), 750 (619-1,280), 3,890 (3,223-5,133) with omeprazole simultaneously; and 24,549 (20,884-38,894), 851 (720-1,782), 4,141 (3,554-5,992) with omeprazole 2 h earlier. Simultaneous administration of omeprazole significantly increased saquinavir AUC(0-12), C(trough), and C(max) by 54, 73, and 55%, whereas staggered administration by 67, 97, and 65%. No grade 3/4 toxicity or lab abnormalities were observed. In the presence of omeprazole, saquinavir plasma exposure is significantly increased in HIV-infected subjects whether administered simultaneously or 2 h apart.

Background: We describe the patterns of antiretroviral drug use at treatment initiation from 1996 to 2005 in a large UK multicentre cohort., Methods: We examined trends over time and across 10 clinical sites in stage of disease and type of antiretroviral therapy (ART). Multivariable regression was used to identify factors associated with the CD4 cell count at ART initiation, and with the choice of a protease inhibitor (PI) over a nonnucleoside reverse transcriptase inhibitor (NNRTI), and use of nevirapine over efavirenz., Results: A total of 14 252 patients initiated ART, of whom 54% had a CD4 count <200 cells/microL. The most important predictors of starting ART at a lower CD4 cell count were being male, nonwhite, and heterosexual or an injecting drug user (P<0.0001). Among those starting ART, the use of highly active ART increased from 23% in 1996 to >96% from 2000 onwards. There were differences over time and across the clinics in the use of PIs vs. NNRTIs, in the choice of specific PIs, NNRTIs and nucleoside reverse transcriptase inhibitor (NRTI) backbone, and in the rate at which prescribing practices changed., Conclusions: Clinic site and calendar year were important determinants of choice of drug at ART initiation, whereas clinical and demographic characteristics were more important in influencing the CD4 cell count at initiation of ART.

Introduction: Epstein-Barr virus (EBV) is detected in the cerebrospinal fluid (CSF) in people with HIV infection who develop primary cerebral lymphoma (PCL). However, EBV may also be detected in the CSF of patients without PCL, and here the significance is uncertain., Methods: Ninety-eight HIV-positive patients had lumbar punctures performed and polymerase chain reaction (PCR) for EBV was undertaken on the CSF. Thirty-eight patients had non-Hodgkin's lymphoma (NHL), including four with PCL. Sixty patients had a CSF examination for other indications. The clinicopathological details, symptoms, diagnosis, CSF and neuroimaging findings and therapy at time of CSF were recorded and correlated with CSF EBV PCR results., Results: EBV was detected in the CSF in three of four patients (75%) with PCL, one of three (33%) with systemic lymphoma and meningeal involvement, and four of 31 (13%) with systemic lymphoma and no meningeal disease. Seven of 60 patients (12%) without lymphoma were CSF EBV-positive. There were no differences in immunological, clinical, biochemical or radiological parameters between patients with and without EBV in the CSF. After a median follow-up time of 30 weeks (maximum 102 weeks), none of the seven CSF EBV-positive patients has developed PCL., Conclusion: EBV was detected in up to 12% of patients with neurological symptoms but without lymphoma. A positive result did not correlate with more advanced immunosuppression or a particular neurological diagnosis. Patients with EBV in their CSF did not appear to be at increased risk of developing PCL in the short term.

Objectives: We examined whether the timing of initiation of antiretroviral therapy (ART) in routine clinical practice reflected treatment guidelines, which have evolved towards recommending starting therapy at lower CD4 cell counts., Methods: We analysed longitudinal data on 10,820 patients enrolled in the UK Collaborative HIV Cohort (UK CHIC) Study, which includes seven large clinical centres in south-east England. CD4 cell and viral load measurements performed in the period between 1 January 1997 and 31 December 2003 were classified according to whether ART was subsequently initiated or deferred, to estimate the probability of ART initiation by CD4 count and viral load over time. The effect of nonclinical factors (age, sex, ethnicity, and exposure category) was analysed by logistic regression. Kaplan-Meier analysis was used to estimate the proportion of patients who had initiated ART by a particular CD4 count among 'early' presenters (initial CD4 cell count >500 cells/microL)., Results: There was a tendency to initiate ART at lower CD4 cell counts over time in the years 1997-2000, especially in the range 200-500 cells/microL, with little change thereafter. An estimated 34% of HIV-infected individuals having presented early initiated ART at a CD4 count <200 cells/microL. We also found an independent influence of viral load, which was particularly pronounced for CD4 <350 cells/microL. Use of injection drugs was the only nonclinical factor associated with initiation of ART at lower CD4 cell counts., Conclusions: The initiation of ART in the clinics included in this analysis reflected evolving treatment guidelines. However, an unexpectedly high proportion of patients started ART at lower CD4 counts than recommended, which is only partly explained by late presentation.

Background: ESPRIT is a randomized trial comparing the clinical impact of interleukin (IL)-2 plus antiretrovirals vs antiretrovirals alone. Identification of factors that influence the relationship between IL-2 and CD4 count recovery will enable better personalization of treatment with IL-2 in HIV-1-positive individuals. The IL-2 induction phase consists of three dosing cycles over 6-8 months (7.5 MIU twice a day, for 5 days every 8 weeks)., Methods: We included patients initiating IL-2 at the 7.5 MIU dose with an 8-month CD4 count, measured at least 30 days after their last cycle. We identified baseline predictors of CD4 count changes over 8 months using linear regression., Results: Of 2090 patients assigned IL-2, 1673 (80%) were included in the analysis. The median (interquartile range) baseline CD4 count was 461 (370, 587) cells/microL with a median increase of 233 (90, 411) cells/microL at month 8. After adjustments, significant predictors of CD4 count change included CD4 nadir (29.8 cells/microL greater increase per 100 cells/microL higher; P<0.0001), last CD4 count before baseline (mean 36.0 cells/microL greater increase per 100 cells/microL higher; P<0.0001), time from antiretroviral start to baseline (8.3 cells/microL smaller increase per year longer; P=0.001), age (11.7 cells/microL smaller increase per 5 years older; P=0.005) and race (79.7 cells/microL greater increase for black patients vs white patients; P=0.003). A linear relationship existed between total IL-2 dose in the first cycle and CD4 count change (73.1 cells/microL greater increase per 15 MIU higher; P<0.0001)., Conclusions: Prior nadir and current CD4 counts, age and IL-2 dose are major determinants of CD4 increases induced by with intermittent administration of IL-2 in HIV-1-positive individuals on antiretrovirals. The clinical function of these induced CD4 cells is under study.

Background: Initiation of efavirenz is commonly associated with sleep disturbances. Assessment of sleep using the electroencephalogram and electromyogram enables sleep staging to be performed and changes following the introduction of therapy to be evaluated., Methodology: Using standardized sleep-staging methodology, we investigated sleep staging and sleep quality by patient self-report in an open-label cohort pilot study. Assessments were performed prior to the initiation of efavirenz, 2 weeks after the initiation of efavirenz and 3 months after the initiation of efavirenz. The study included HIV-positive individuals without central neurological disease who were naive to antiretroviral treatment. All patients initiated treatment with two nucleoside reverse transcriptase inhibitors in combination with efavirenz., Results: Ten patients completed all three study visits. Patients reported an increase in recollection of dreams and morning sluggishness after the initiation of efavirenz which persisted for 3 months. Sleep-staging data indicated a modest reduction in stage 2 sleep with a corresponding increase in deep sleep stage 4 and a modest increase in rapid eye movement (REM) sleep. Overall sleep maintenance efficiency did not significantly change from baseline. Changes in sleep staging were most marked 2 weeks after the initiation of efavirenz but remained different from baseline patterns at 3 months., Conclusion: The data indicate that efavirenz has a modest but persistent impact on the time spent in several key sleep stages. Patients reported persistence of dream recollection but remained satisfied with sleep quality and overall quality of life.

Objectives Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m(2), or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weight, immune markers and perception of treatment were the main outcome measures. Results Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusions Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

Tenofovir (TDF) co-administered with didanosine (ddI) 400 mg increases ddI plasma concentrations by up to 60%, raising concerns over toxicity. To limit this interaction, the dosage of ddI may be reduced to 250 mg once daily when co-prescribed with TDF. In this clinical cohort, highly active antiretroviral therapy regimens containing TDF and ddI 250 mg were significantly better tolerated than combinations with TDF and ddI at a dose of 400 mg. Low-dose ddI 250 mg once daily plus TDF as part of antiretroviral therapy was effective.

Objectives: We aimed to provide evidence of thymic reconstitution after highly active antiretroviral therapy (HAART) in HIV-1 infected patients and to correlate this with the restoration of peripheral naïve T cells., Methods: Positron emission tomography (PET) enables definitive evidence of thymic activity, indicating functional potential. In this case study, a single patient who initiated HAART demonstrated reconstitution of the naïve T-cell pool and underwent thymic PET scans at baseline and 2 and 6 months following initiation of therapy. Two patients who failed to demonstrate such reconstitution acted as controls. These patients (mean age 27 years) had chronic HIV infection with low CD4 T-cell counts (mean 82, range 9-160 cells/microL blood). Increased function of the thymus visualized by PET was correlated with phenotypic changes in CD4 and CD8 T cells in the periphery measured by flow cytometry, and with numbers of recent thymic emigrants measured by quantification of the numbers of T-cell receptor excision circles (TRECs) in peripheral cells., Results: In one patient, clear correlations could be drawn between visible activity within the thymus, as measured by increased [F18]fluorodeoxyglucose (FDG) uptake, and regeneration of naïve CD4 (CD45RA/CD62L) T cells, increased numbers of CD4 T cells, controlled viraemia and increased numbers of recent thymic emigrants. A second patient displayed no increase in peripheral CD4 count and no increase in thymic activity. The third patient elected to stop therapy following the 2-month time point., Conclusions: The use of PET suggests that thymic activity may increase after HAART, indicating that the thymus has the potential to be functional even in HIV-1 infected persons with low CD4 T-cell counts.

Background: Lactic acidosis is a life-threatening event during antiretroviral therapy (ART). Hyperlactataemia may be a prelude to acidosis. Our database study suggested that female gender, intercurrent illness and didanosine (ddI)-based regimens may increase risk of lactic acidosis. The aim of this matched case-control study was to identify risk factors for hyperlactataemia requiring screening., Methods: Cases were defined as patients with two consecutive lactate samples > or =3.5 mmol/L taken more than 1 week apart. Cases were matched to two controls on gender, use of ddI and total duration of therapy using a 6-month window on either side. Controls never had raised lactate >2.5 mmol/L. A conditional logistic regression analysis using the PHREG procedure in SAS (SAS Institute Inc, Cary, NC) was performed with a discreet logistic model stratified by matching variables., Results: Twenty-one cases were matched to 42 controls. In the univariate model, current use of stavudine (d4T), total cholesterol >5.3 mmol/L and glucose levels > or =5.2 mmol/L gave increased likelihood of persistent hyperlactataemia. The multivariate model showed current use of d4T to be a significant independent predictor of persistent hyperlactataemia., Conclusions: The results of this case-control study indicate that, when controlling for ddI use, d4T use is an additional risk factor for hyperlactataemia.

Objective: To assess the antiviral efficacy, safety, and adherence in subjects who switched to Trizivir following long-term HIV-1 RNA suppression., Study Design: A randomized, open-label, multicentre, 48-week comparative study in subjects who have received two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or an nonnucleoside reverse transcriptase inhibitor or three nucleoside reverse transcriptase inhibitors for at least 6 months, with a history of undetectable plasma HIV-1 RNA since initiation of therapy and plasma viral load of < 50 HIV-1 RNA copies/mL at screening., Methods: Subjects were randomized 1:1 to continue their current treatment or to switch to a simplified treatment with Trizivir administered twice daily. Assessments included plasma HIV-1 RNA, lymphocyte counts, clinical laboratory evaluations, adverse events, and adherence to treatment (obtained via subject self-report). Treatment failure was defined as a plasma viral load of >/= 400 HIV-1 RNA copies/mL on two consecutive occasions or premature discontinuation of randomized treatment., Results: At week 48, the proportion of treatment failures in Trizivir arm (23/106, 22%) was noninferior to that observed in continued arm (23/103, 22%) with a treatment difference stratified by prior ART of 1.2%[-10.1; 12.5]. Incidence of adverse events was similar in both treatment groups. The incidence of possible hypersensitivity reaction in the Trizivir trade mark arm was 10%. Significant reductions in cholesterol and triglyceride plasma levels were observed in the Trizivir arm (P < 0.001 and P = 0.006, respectively)., Conclusion: Switching to Trizivir offers a potent and simplified regimen with equivalent efficacy and significant improvement in lipid abnormalities compared to continued triple therapy.

Background: Few UK studies have systematically investigated which antiretroviral therapy (ART) combinations HIV-infected people are commenced on, when they start and reasons for stopping or changing their regimens., Objective: To describe when HIV-infected ART-naive patients started first-, second- or third-line triple ART, classes of drugs prescribed and whether stopping ART was associated with virological, immunological or clinical indicators of treatment failure., Design: A multicentre prospective open cohort study, employing the National Prospective Monitoring System on the use, cost and outcome of HIV service provision in UK hospitals-HIV Health-economics Collaboration (NPMS-HHC)., Setting: Five hundred and eighty-five ART-naive patients seen in one London and two non-London HIV clinics between 1 January 1998 and 31 December 1999., Results: Of 4,044 HIV-infected individuals seen, 585 (15%) were ART naive. Median time interval (interquartile range, IQR) between HIV diagnosis and starting triple ART was 800 (63-2,094) days. Median CD4 count when first diagnosed with HIV infection was 278 (IQR 127-481) cells/ micro L which dropped to 190 (IQR 86-297) cells/ micro L when starting triple ART. Of these 585 patients, 162 started second-line and 46 third-line ART during the study period. Of those patients who stopped ART, 51% did not have evidence of virological, immunological or clinical indicators of therapy failure., Conclusions: Reasons for the delay between diagnosis of HIV infection and starting ART are varied. The large proportion of individuals who stopped ART for reasons other than virological, immunological or clinical indicators of therapy failure, are most likely due to drug-associated toxicity. Both of these findings need to be elucidated in greater detail through prospective studies.

Objective: Our objective was to monitor the effect of steroid therapy on the thymic output and function of late-stage HIV-1-infected patients undergoing highly active antiretroviral therapy (HAART)., Design: The indirect measurement of T cells that have recently emigrated from the thymus as a means of quantifying thymic output, and therefore thymic function, was achieved through use of the polymerase chain reaction-based signal joint T cell receptor rearrangement excision circles (sjTREC) assay. Proliferative capacity and interleukin (IL)-2 and IL-4 production by T cells after antigenic, mitogenic and IL-2 stimulation were also analysed., Method: Measurements were made of sjTREC levels in peripheral blood mononuclear cell DNA samples from five HIV-1 infected patients (one on steroid therapy prior to and at the time of sample extraction) receiving HAART. IL-2 and IL-4 production and proliferative capacity were also measured in three patients, including the patient receiving steroids., Result: The sjTREC assay gave an extremely weak result for the patient on steroids but, under the same assay conditions, provided clear, positive readings for the four patients not on steroids. Comparison of the patients' cytokine profiles revealed that IL-2 production was generally low or absent in all three patients tested but that IL-4 production was significantly higher in the patient given steroids. Functional potential as revealed by proliferation assays showed very low or absent cellular proliferation., Conclusion: The thymic contribution to the restoration of T lymphocyte numbers, particularly during the treatment of HIV-1 infection, may become compromised if thymic inhibitory factors such as steroids are used. Furthermore, the use of steroids may also favour the development of a T helper 2 response, which could prove particularly undesirable during HIV-1 infection.

Objectives: To determine whether systemic or deep fungal infections can be prevented, a double-blind, placebo-controlled, phase III trial of itraconazole prophylaxis was undertaken in HIV-infected patients., Methods: HIV-1 infected patients with CD4 counts < 300 cells/microL were treated with itraconazole (200 mg per day) or matching placebo and followed for 2 years. Development of deep fungal infections, episodes of mucocutaneous candidiasis, change in CD4 count, survival and safety data were collected at each study visit., Results: Three hundred and seventy-four patients received study medication, 187 were given itraconazole and 187 matching placebo. Time to development of deep fungal infection did not differ between groups, in an intention to treat analysis. Low CD4 cell count and prior use of Pneumocystis carinii pneumonia (PCP) prophylaxis were significantly associated with a more rapid development of deep fungal infection (P = 0.044 and 0.017, respectively). Itraconazole treatment significantly reduced the incidence of oral candidosis (25% vs. 48% P < 0.001) and time to development of oral candidosis (508 vs. 413 days, P < 0.001) but not the number of deep fungal infections (11 vs. 13). Survival did not differ significantly between groups (nine vs. 14 deaths). CD4 counts decreased significantly over time in both study arms. Adverse events did not differ between groups; 20% vs. 23% stopped study medication due to an adverse experience., Conclusions: Although itraconazole prophylaxis significantly reduced the number and time to development of oral candidosis, too few episodes of deep fungal infection were noted to determine whether itraconazole prophylaxis was effective for this condition. Chronic itraconazole treatment is well tolerated in HIV-infected patients with marked immunodeficiency.

Objectives: To evaluate whether successful, long-term immune reconstitution in vivo can be achieved in end-stage AIDS patients following antiretroviral therapy (ART)., Methods: A 1-year prospective study of changes of CD4+ and CD8+ T-cell surface phenotypes, T-cell receptor (TCR) repertoires and capacity to control in vivo replication of cytomegalovirus (CMV) was performed in five treatment-naive end-stage AIDS patients (median CD4+ T-cell counts of 19 cells/microL) following therapy. Proportions of CD45RA+, CD45RO+ and CD28+ cells within the CD4+ and CD8+ subsets, were determined by flow cytometry. Changes in TCR Vbeta repertoires within the CD4+ and CD8+ T-cell compartments were evaluated using CDR3 spectratyping. CMV replication was determined by a sensitive polymerase chain reaction (PCR) assay using whole blood., Results: Following ART, proportionate increases in 'naive' (CD45RA+) and 'memory' (CD45RO+) T cells were observed within both CD4+ and CD8+ T-cell subsets, while increased numbers of CD28+ T cells were mainly observed within the CD4+ subset. Diversification of CD4+ and CD8+ TCR repertoires was established concomitantly with renewed in vivo control of CMV replication., Conclusions: An important degree of molecular and functional immune recovery is possible in end-stage AIDS patients introduced to therapy. Diversification of TCR repertoires and the in vivo restoration of immunocompetence to control opportunistic infections clearly show that an important degree of molecular immune reconstitution is established following the initiation of ART even in late-stage AIDS.

Objective: As the pro-inflammatory cytokine tumour necrosis factor-alpha is greater in microsporidiosis than cryptosporidiosis, there may be a distinct metabolic response between the two organisms., Design: Male HIV seropositive subjects with an untreated AIDS-defining diagnosis of microsporidiosis or cryptosporidiosis had measurement of oxygen consumption and carbon dioxide production by indirect calorimetry and body composition analysis to express resting energy expenditure (REE) and substrate oxidation per kilogram of metabolically active tissue., Methods: Resting energy expenditure (REE), non-protein respiratory quotient (NPRQ), fat and carbohydrate oxidation were calculated from respiratory gas analysis. Fat, fat-free and appendicular muscle masses were measured by dual-energy X-ray absorptiometry. Subjects with protozoal diarrhoea were compared to other newly diagnosed, active opportunistic infections. Controls were asymptomatic HIV-seropositive men matched by peripheral CD4 count., Results: Seven subjects with microsporidiosis and six with cryptosporidiosis were compared with 24 subjects with other AIDS-defining diagnosis (Pneumocystis carinii pneumonia, cytomegalovirus enteritis and Mycobacterium avium-intracellulare) and 10 controls free from secondary infection. Subjects with cryptosporidiosis had a decreased REE, a significantly increased NPRQ (P< 0.05), decreased fat oxidation (P < 0.05) and increased carbohydrate oxidation compared to microsporidiosis. Subjects with other AIDS diagnoses had an increased REE (P < 0.01) and fat oxidation and decreased carbohydrate oxidation compared to cryptosporidiosis, and a similar metabolic response to microsporidiosis., Conclusions: The metabolic response to cryptosporidiosis differs from microsporidiosis and associated weight loss may be mediated by different mechanisms. Metabolism in other AIDS diagnoses, including microsporidiosis, is compatible with a cachectic response.

An interactive voting session at the end of the European symposium on evolving therapies provided an opportunity for panel discussion on various therapeutic options based on a series of case studies. The interactive voting and subsequent discussion focused on the preferred options for first-line, second-line and salvage therapy. In addition, issues of compliance and drug resistance were addressed. All case studies were entirely hypothetical and were projected into the future when it is anticipated that today's investigational drugs are likely to be available for general use.

Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI) is now regarded as the standard of care in the treatment of HIV infection. However, over the next few years it is anticipated that clinician will become increasingly concerned with the quality of clinical data, the cost of treatment and virological failure. Several causes of virological failure have already been identified including compliance, toxicity, pharmacokinetic interactions, resistance and lack of potency. Many studies have been performed to investigate new combination regimens and new drugs to find solutions to these problems. In addition, new targets for antiviral drugs are also being investigated.