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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 350 cells/μL; starting HAART 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.

OBJECTIVES The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine, efavirenz and lopinavir regimens based on these measures. METHODS Patients starting a nevirapine, efavirenz or lopinavir-based cART regimen for the first time after 1 January 2000 were included in the analysis. Follow-up started ≥ 3 months after initiation of treatment if viral load was

BACKGROUND AND OBJECTIVES Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300cells/μL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. METHODS Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. RESULTS IL-2 cycling was most intense in years 1-2. Over ≈7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P=0.68]. Median CD4 counts prior to pneumonia were 570cells/μL (IL-2 arm) and 463cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log(10) higher VL 1.28; 95% CI 1.11, 1.47; P

Background. Robust long-term estimates of the risk of development of drug resistance are needed for human immunodeficiency virus (HIV)-infected patients starting combination antiretroviral therapy (cART) regimens currently used in routine clinical practice.Methods. We followed a large cohort of patients seen in 1 of 11 HIV clinics in the United Kingdom after starting cART with nucleoside reverse-transcriptase inhibitors and either a nonnucleoside reverse-transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI/r). Survival analysis was employed to estimate the incidence of virological failure and of detected drug resistance.Results. Seven thousand eight hundred ninety-one patients were included; 6448 (82%) started cART with an NNRTI and 1423 (17%) with a PI/r. The cumulative risk of virological failure by 8 years was 28%. The cumulative probabilities of detecting any mutation, >= 1 major nucleoside reverse-transcriptase inhibitor International AIDS Society-United States of America (IAS-USA) mutation, >= 1 major NNRTI IAS-USA mutation (in those starting an NNRTI), and >= 1 major PI IAS-USA mutation (in those starting a PI) were 17%, 14%, 15%, and 7%, respectively, by 8 years. The probability of detecting PI mutations in people who started PI/r-based regimens was lower than that of detecting NNRTI mutations in those starting NNRTI-based regimens (adjusted relative hazard, 0.36; 95% confidence interval, 0.26-0.50; P < .001). The risk of detecting nucleoside resistance did not vary according to whether an NNRTI or a PI/r was used in the regimen (adjusted relative hazard, 1.00; 95% confidence interval, 0.80-1.26; P = .98).Conclusions. In patients who started modern cART in clinical practice in the United Kingdom, virological failure by 8 years was relatively common and was paralleled by an appreciable risk of resistance detection, although the detection rate of class-specific resistance was lower for those who started a PI/r-based regimen.

Contains fulltext : 88346.pdf (Publisher’s version ) (Closed access) INTRODUCTION: This study describes the characteristics of the metabolic syndrome in HIV-positive patients in the Data Collection on Adverse Events of Anti-HIV Drugs study and discusses the impact of different methodological approaches on estimates of the prevalence of metabolic syndrome over time. METHODS: We described the prevalence of the metabolic syndrome in patients under follow-up at the end of six calendar periods from 2000 to 2007. The definition that was used for the metabolic syndrome was modified to take account of the use of lipid-lowering and antihypertensive medication, measurement variability and missing values, and assessed the impact of these modifications on the estimated prevalence. RESULTS: For all definitions considered, there was an increasing prevalence of the metabolic syndrome over time, although the prevalence estimates themselves varied widely. Using our primary definition, we found an increase in prevalence from 19.4% in 2000/2001 to 41.6% in 2006/2007. Modification of the definition to incorporate antihypertensive and lipid-lowering medication had relatively little impact on the prevalence estimates, as did modification to allow for missing data. In contrast, modification to allow the metabolic syndrome to be reversible and to allow for measurement variability lowered prevalence estimates substantially. DISCUSSION: The prevalence of the metabolic syndrome in cohort studies is largely based on the use of nonstandardized measurements as they are captured in daily clinical care. As a result, bias is easily introduced, particularly when measurements are both highly variable and may be missing. We suggest that the prevalence of the metabolic syndrome in cohort studies should be based on two consecutive measurements of the laboratory components in the syndrome definition.

OBJECTIVE: To investigate the incidence of, and risk factors for, tuberculosis among HIV clinic attendees in the United Kingdom. DESIGN AND METHODS: Observational cohort study of 27 868 individuals in the United Kingdom Collaborative HIV Cohort collaboration, 1996-2005. RESULTS: Among individuals not taking combination antiretroviral therapy (cART), tuberculosis incidence was considerably higher among individuals of black African vs. white or other ethnicities {incidence rates 9.9 [95% confidence intervals (CIs) 7.2, 12.6], 2.5 [95% CI 1.8, 3.0] and 4.4 [95% CI 2.7, 6.0] episodes per 1000 person-years, respectively}. Tuberculosis incidence decreased with time after starting cART; among black Africans, incidence was consistently higher and remained substantial (5.3 per 1000 person-years) at 24 months and longer after starting cART. The strongest independent risk factors for tuberculosis after cART start were most recent CD4 cell count: adjusted rate ratios (aRR) 10.65 (95% CI 6.11, 18.57), 3.40 (95% CI 2.05, 5.65), 1.77 (95% CI 1.06, 2.96) and 1.84 (95% CI 1.09, 3.12) for individuals with CD4 cell counts less than 50, 50-199, 200-349 and 350-499 cells/microl, respectively, compared with at least 500 cells/microl; and black African vs. white ethnicity [aRR 2.93 (95% CI 1.89, 4.54)]. HIV risk group, shorter time on cART, later calendar period and unsuppressed viral load were also independently associated with incident tuberculosis. CONCLUSIONS: Tuberculosis incidence among people attending UK HIV clinics is substantial, particularly among those with non-white ethnicity and low CD4 cell counts, even after starting cART. Earlier HIV diagnosis is needed in order to implement interventions to prevent tuberculosis; tuberculosis preventive therapy should be considered in addition to cART.

Objective: To describe the clinical epidemiology of HIV-associated end-stage renal failure (HIV/ESRF) from 1998 to 2007 in the United Kingdom.Design: Observational cohort study.Setting: Seven leading HIV centres and affiliated renal clinics in the United Kingdom.Participants: A total of 21 951 patients in whom renal function was measured.Main outcome measure: Development of end-stage renal failure (ESRF) as defined by initiation of permanent renal replacement therapy (pRRT).Results: Sixty-eight (0.31%) patients had HIV/ESRF, 44 (64.7%) of whom were black. The prevalence of ESRF in black patients increased over time from 0.26% in 1998-1999 to 0.92%. in 2006-2007 (P for trend = 0.001). Overall 5-year survival from starting pRRT was 70.3%, and significantly better for black patients compared to those of other ethnicities (85.2 vs. 43.4%, P = 0.001). In multivariable analysis, black ethnicity was associated with a higher risk of ESRF [HR 6.93, 95% confidence interval (CI) 3.56, 13.48], whereas a higher current CD4 cell count was associated with reduced risk (HR: 0.83, 95% CI 0.76, 0.95) per 50 cells higher). No association was seen between current viral load or current highly active antiretroviral therapy (HAART) status and ESRF. On the basis of these observations, we estimate that 231 HIV-infected patients required pRRT in the United Kingdom in 2007, and an HIV prevalence of 0.51% among the United Kingdom pRRT recipients in that year.Conclusion: The prevalence of HIV/ESRF increased during the HAART era to reach nearly 10% in black patients, in whom favourable survival rates were observed. Earlier HIV diagnosis will be an important strategy to stern the rising trend of HIV/ESRF. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

We examined the prevalence of hepatitis C virus (HCV) infection among HIV-positive individuals in the UK, trends in HCV testing and the impact of HCV on HIV treatment outcomes. Trends over time in HCV prevalence were calculated using each patient's most recent HCV status at the end of each calendar year. Logistic regression was used to identify factors associated with having a HCV antibody test, and Cox regression was used to determine whether HCV status was associated with the time to experiencing an immunological response to highly active antiretroviral treatment (HAART), time to virological response and viral rebound. Of the 31,765 HIV-positive individuals seen for care between January 1996 and September 2007, 20,365 (64.1%) individuals were tested for HCV, and 1807 (8.9%) had detectable HCV antibody. The proportion of patients in follow-up ever tested for HCV increased over time, from 782/8505 (9.2%) in 1996 to 14,280/17,872 (79.9%) in 2007. Nine thousand six hundred and sixty-nine individuals started HAART for the first time in or after January 2000, of whom, 396 (4.1%) were HCV positive. Presence of HCV infection did not affect initial virological response, virological rebound or immunological response. The cumulative prevalence of HCV in the UK CHIC Study is 8.9%. Despite UK guidelines, over 20% of HIV-positive individuals have not had their HCV status determined by 2007. HCV infection had no impact on HIV virological outcomes or immunological response to HIV treatment. The long-term impact on morbidity and mortality remain to be determined.

BACKGROUND: PARV4 is a human parvovirus that was first detected in and cloned from an individual with a human immunodeficiency virus (HIV) seroconversion-like illness and that subsequently persisted in the lymphoid tissue and bone marrow. In contrast to human parvovirus B19 infections, PARV4 infections are most frequently detected in injection drug users (IDUs), particularly those who are coinfected with HIV type 1 (HIV-1). To investigate the routes of transmission of PARV4 and to ascertain whether infections are acquired through plasma-derived blood products, we developed a novel anti-PARV4 enzyme-linked immunosorbent assay (ELISA) to determine its seroprevalence in subjects with parenteral exposure. METHODS: PARV4 viral protein 2 (VP2) was expressed and used as antigen in an indirect ELISA, to detect anti-PARV4 immunoglobulin G. RESULTS: All 50 adult control subjects who were nonparenterally exposed to PARV4 were anti-PARV4 negative, in contrast to HIV-infected and HIV-uninfected IDUs, who had antibody frequencies of 67% and 33%, respectively. Predominantly parenteral transmission was confirmed by the finding of similar frequencies of infection among HIV-coinfected and HIV-uninfected hemophiliacs (11 of 20 individuals and 4 of 15 individuals, respectively) who were treated with nonvirally inactivated factor VIII/factor IX, whereas all but 1 of the 35 nonhemophiliac siblings of these siblings were found to be seronegative (despite having close household contact). CONCLUSIONS: The present study provides convincing evidence that PARV4 is primarily transmitted parenterally. Evidence for widespread infection of hemophiliacs treated with nonvirally inactivated clotting factor creates fresh safety concerns for plasma-derived blood products, particularly because parvoviruses are relatively resistant to virus inactivation.

Udgivelsesdato: 2009-Jan-2 BACKGROUND: Cystatin C has been proposed as an alternative marker of renal function. We sought to determine whether participants randomized to episodic use of antiretroviral therapy guided by CD4 cell count (drug conservation) had altered cystatin C levels compared with those randomized to continuous antiretroviral therapy (viral suppression) in the Strategies for Management of Antiretroviral Therapy trial, and to identify factors associated with increased cystatin C. METHODS: Cystatin C was measured in plasma collected at randomization, 1, 2, 4, 8 and 12 months after randomization in a random sample of 249 and 250 participants in the drug conservation and viral suppression groups, respectively. Logistic regression was used to model the odds of at least 0.15 mg/dl increase in cystatin C (1 SD) in the first month after randomization, adjusting for demographic and clinical characteristics. RESULTS: At randomization, mean (SD) cystatin C level was 0.99 (0.26 mg/dl) and 1.01 (0.28 mg/dl) in the drug conservation and viral suppression arms, respectively (P = 0.29). In the first month after randomization, 21.8 and 10.6% had at least 0.15 mg/dl increase in cystatin C in the drug conservation and viral suppression arms, respectively (P = 0.0008). The difference in cystatin C between the treatment arms was maintained through 1 year after randomization. After adjustment, participants in the viral suppression arm had significantly reduced odds of at least 0.15 mg/dl increase in cystatin C in the first month (odds ratio 0.42; 95% confidence interval 0.23-0.74, P = 0.0023). CONCLUSION: These results demonstrate that interruption of antiretroviral therapy is associated with an increase in cystatin C, which may reflect worsened renal function.

OBJECTIVE To describe the time from first viral rebound on highly active antiretroviral therapy to first treatment change, identify factors associated with more rapid switching, and investigate whether treatment changes are in line with treatment guidelines. DESIGN AND SETTING A multicentre cohort study. METHODS We described the time to first treatment switch among individuals experiencing confirmed virological rebound after initiating highly active antiretroviral therapy; factors associated with more rapid switching were identified using proportional hazards regression and predictors of a switch in line with guidelines were identified using logistic regression. RESULTS Thirty-four percent of the 694 patients experiencing virological rebound remained on a failing regimen for more than 6 months. Factors associated with more rapid switching were lower CD4 cell count (hazard ratio, 0.84 /100 cells/mul higher, P < 0.001), higher viral load (1.29 /log10 copies/ml higher, P < 0.001), older age (1.06 /5 years older, P = 0.07), and changing/adding drugs to the regimen prior to rebound (1.16, P = 0.16). Two hundred and eighteen of the 394 treatment changes (55%) were in line with guidelines; those receiving nonnucleoside reverse transcriptase inhibitor-containing regimens were more likely to make changes in line with guidelines (adjusted odds ratio, 2.80, P < 0.001), whereas those who had previously added drugs to their regimen were less likely to make changes in line with guidelines (0.15, P = 0.001). CONCLUSION A substantial minority of patients remain on a failing highly active antiretroviral therapy regimen for periods of 6 months or longer without adding new drugs. Changes made are often not in line with treatment guidelines, raising concerns about the development of resistance and long-term clinical outcomes in these individuals.

The 2008 BHIVA Guidelines have been updated to incorporate all the new relevant information (including presentations at the 15th Conference on Retroviruses and Opportunistic Infections 2008) since the last iteration. The guidelines follow the methodology outlined below and all the peer-reviewed publications and important, potentially treatment-changing abstracts from the last 2 years have been reviewed. The translation of data into clinical practice is often difficult even with the best possible evidence (i.e. two randomized controlled trials) because of trial design, inclusion criteria and precise surrogate marker endpoints (see Appendix). The recommendations based upon expert opinion have the least good evidence but perhaps provide an important reason for writing the guidelines to produce a consensual opinion about current practice. It must, however, be appreciated that such opinion is often wrong and should not stifle research to challenge it. Similarly, although the Writing Group seeks to provide guidelines to optimize treatment, such care needs to be individualized and we have not constructed a document that we would wish to see used as a ‘standard’ for litigation.

Objective: We investigated whether previous treatment interruptions are associated with a raised risk of viral rebound in individuals who have attained virological suppression.Methods: All patients achieving an undetectable viral load while on therapy were followed until viral rebound or the time of the last viral load. Poisson regression was used to describe the independent impact of treatment interruptions on rebound rates.Results: A total of 12 977 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) Study achieved a viral load of less than 50 copies/ml. These patients contributed a total of 37 314 person-years of follow-up. The overall rebound rate was 8.07 (7.78, 8.36) per 100 person-years. In adjusted analyses, rates of viral rebound were up to 64% higher (rate ratio 1.64; 1.43, 1.88) in those who had previously interrupted therapy compared with those who had not. Patients who had interrupted at detectable viral loads had upto a 74% (1.74; 1.42, 2.14) higher chance of rebounding compared with those who had not interrupted with a detectable viral load. We found no evidence to suggest interrupting treatment at an undetectable viral load was associated with viral rebound.Conclusion: Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound. (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.

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 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.

A trial to evaluate the risks and benefits of initiation of antiretroviral therapy (ART) in patients with high CD4 count (eg,or =500 cells/mm3), in comparison with deferral (eg, to350 cells/mm3), merits consideration. Two issues for consideration in designing such a trial are the proportion of patients seen in clinics who present with high CD4 count and the time it will take for those randomized to deferring ART to reach a level where ART must be initiated. Among 13,572 patients in the UK CHIC Study presenting since 1996, 3631 (27%) had a countor =500 cells/mm3. Among 4268 ART-naive patients with at least one CD4 count in the 500 to 650 cells/mm3 range, the median time to350 cells/mm3 (or start of ART) was 2.5 years, with a range of 2.1 to 3.1 years depending on the analysis approach. Viral load at baseline was a strong predictor of the time taken for the CD4 count to reach350 cells/mm3, with the median ranging from 0.7 years in those with viral loador =500,000 copies/mL to 4.7 years in those with1000 copies/mL. This provides timely background data on ART-naive patients seen in clinical practice to support design of a trial to compare immediate with deferred ART in people with high CD4 count.

Objectives: To demonstrate that HIV-1 immunocapture with an antibody against CD8 specifically captures virions derived from infected CD8 T cells, and to determine the proportion of HIV-1 derived from CD8 lymphocytes in plasma samples from HIV-infected individuals. Methods: A virus capture method was developed to enable the detection of HIV-1 virions based upon the presence of certain cell-specific host-derived proteins (CD8, CD3, CD36) within the viral envelope. HIV-1 virions were captured using antibodies against these proteins and levels of bound virus were determined by quantitative reverse transcriptase–polymerase chain reaction. Highly pure CD8 and CD3+CD8− T-cell cultures were used as in-vitro models to determine the specificity of the virus capture technique. Results: The in-vitro model demonstrates that incorporation of the CD8 molecule into released virions is specific to infection of CD8 T cells. Levels of HIV-1 immunocaptured from plasma of infected individuals using the anti-CD8 antibody indicate that up to 15% (range 10–33) of the plasma viral load is derived from CD8 lymphocytes. Conclusion: This study demonstrates for the first time that HIV-1-infected CD8 T cells can contribute substantially to levels of circulating virus during the course of infection. Levels of CD8-derived virus did not correlate with the level of infection of circulating CD8 T cells, but do show a significantly good fit to plasma viral loads based on a power model. The extensive infection of CD8 T cells implied by these results may contribute towards immune dysfunction and disease progression to AIDS.

BACKGROUND Atazanavir is a once-daily protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infection that has previously been studied in cohorts of treatment-naive and treatment-experienced patients. Limited data are available on the usefulness of switching from a PI-based regimen to a regimen based on a different PI, such as atazanavir, in HIV-infected patients experiencing virologic suppression but seeking regimen simplification. METHODS The Switch to Another Protease Inhibitor (SWAN) study was a 48-week, open-label trial involving HIV-positive patients with virologic suppression who were receiving stable PI-based regimens (with or without ritonavir). Patients were randomized 2 : 1 to switch to atazanavir (400 mg per day)--or, if they were receiving tenofovir, to atazanavir-ritonavir (300/100 mg per day)--or to continue to receive their existing PI. The proportion of patients who experienced virologic rebound (defined as an HIV RNA load >or=50 copies/mL) was compared through study week 48. RESULTS Patients either received an atazanavir-containing regimen (278 patients) or continued to receive a comparator PI-containing regimen (141 patients). The proportion of patients who experienced virologic rebound was significantly lower among those who switched to an atazanavir-containing regimen (19 [7%] of 278) than it was among those who continued to receive a comparator PI regimen (22 [16%] of 141; P=.004). Patients who switched to atazanavir therapy experienced significantly fewer total cholesterol, fasting triglyceride, and non-high density lipoprotein cholesterol elevations than did patients in the comparator PI group (P

The human immunodeficiency virus (HIV) and the hepatitis B virus share common routes of transmission, and hence, coinfection with these two viruses is common. Chronic hepatitis B does not influence the progression of HIV disease or the response to highly active antiretroviral therapy. It is clear, however, that HIV infection does impact the course of hepatitis B, as higher rates of chronic carriage, lower seroconversion rates, and accelerated progression towards cirrhosis have been observed. Vaccination against hepatitis B is less effective in HIV-infected individuals. Coinfected subjects have a poor response to interferon therapy. Lamivudine is more effective in coinfected subjects but must not be used as monotherapy because of the risk of resistance developing. Combination therapy with lamivudine and tenofovir has shown promise and is currently being investigated in clinical trials, while new drugs and other combinations are in development.

Item does not contain fulltext BACKGROUND: The association between combination antiretroviral therapy (cART) and cancer risk, especially regimens containing protease inhibitors (PIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs), is unclear. METHODS: Participants were followed from the latest of D:A:D study entry or January 1, 2004, until the earliest of a first cancer diagnosis, February 1, 2012, death, or 6 months after the last visit. Multivariable Poisson regression models assessed associations between cumulative (per year) use of either any cART or PI/NNRTI, and the incidence of any cancer, non-AIDS-defining cancers (NADC), AIDS-defining cancers (ADC), and the most frequently occurring ADC (Kaposi sarcoma, non-Hodgkin lymphoma) and NADC (lung, invasive anal, head/neck cancers, and Hodgkin lymphoma). RESULTS: A total of 41,762 persons contributed 241,556 person-years (PY). A total of 1832 cancers were diagnosed [incidence rate: 0.76/100 PY (95% confidence interval: 0.72 to 0.79)], 718 ADC [0.30/100 PY (0.28-0.32)], and 1114 NADC [0.46/100 PY (0.43-0.49)]. Longer exposure to cART was associated with a lower ADC risk [adjusted rate ratio: 0.88/year (0.85-0.92)] but a higher NADC risk [1.02/year (1.00-1.03)]. Both PI and NNRTI use were associated with a lower ADC risk [PI: 0.96/year (0.92-1.00); NNRTI: 0.86/year (0.81-0.91)]. PI use was associated with a higher NADC risk [1.03/year (1.01-1.05)]. Although this was largely driven by an association with anal cancer [1.08/year (1.04-1.13)], the association remained after excluding anal cancers from the end point [1.02/year (1.01-1.04)]. No association was seen between NNRTI use and NADC [1.00/year (0.98-1.02)]. CONCLUSIONS: Cumulative use of PIs may be associated with a higher risk of anal cancer and possibly other NADC. Further investigation of biological mechanisms is warranted.

Current clinical guidelines consider regimens consisting of either ritonavir-boosted atazanavir or ritonavir-boosted lopinavir and a nucleoside reverse transcriptase inhibitor (NRTI) backbone among their recommended and alternative first-line antiretroviral regimens. However, these guidelines are based on limited evidence from randomized clinical trials and clinical experience.We compared these regimens with respect to clinical, immunologic, and virologic outcomes using data from prospective studies of human immunodeficiency virus (HIV)-infected individuals in Europe and the United States in the HIV-CAUSAL Collaboration, 2004-2013. Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started a lopinavir or an atazanavir regimen. We estimated the 'intention-to-treat' effect for atazanavir vs lopinavir regimens on each of the outcomes.A total of 6668 individuals started a lopinavir regimen (213 deaths, 457 AIDS-defining illnesses or deaths), and 4301 individuals started an atazanavir regimen (83 deaths, 157 AIDS-defining illnesses or deaths). The adjusted intention-to-treat hazard ratios for atazanavir vs lopinavir regimens were 0.70 (95% confidence interval [CI], .53-.91) for death, 0.67 (95% CI, .55-.82) for AIDS-defining illness or death, and 0.91 (95% CI, .84-.99) for virologic failure at 12 months. The mean 12-month increase in CD4 count was 8.15 (95% CI, -.13 to 16.43) cells/?L higher in the atazanavir group. Estimates differed by NRTI backbone.Our estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a greater 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for atazanavir compared with lopinavir regimens.? The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Many patients with HIV infection present at a late stage of disease. Late diagnosis is associated with increased morbidity and mortality. One strategy to encourage earlier HIV diagnosis is the promotion of HIV testing outside of a specialist HIV setting. This study aimed to determine whether the diagnosis of HIV could be made sooner by non-HIV specialists consulting HIV-positive patients in the year preceding diagnosis. A case note review of all newly diagnosed HIV-positive patients seen over a 12-month period ending in September 2006, was performed to analyse whether patients had consulted a doctor in the year prior to diagnosis, whether they were offered HIV testing and whether they had symptoms or risk factors suggesting HIV infection. Fifty-one newly diagnosed HIV-positive patients were seen during the study period. Twenty-nine of these patients had consulted a doctor in the year prior to diagnosis. Of these, 10 were offered HIV testing and 19 were not. All patients who were not offered HIV testing had risk factors for-, or symptoms of HIV infection. The majority of newly diagnosed HIV patients had consulted a doctor in the year prior to diagnosis. Most were not offered HIV testing despite having risk factors for HIV infection. HIV diagnosis may have been made earlier by testing for HIV outside of a specialist setting.

Non-alcoholic fatty liver disease (NAFLD) in HIV-positive patients is associated with HIV specific factors, such as lipodystrophy and the use of antiretroviral therapy (ART), as well as traditional risk factors (including obesity, insulin resistance and the metabolic syndrome). 2 The risk of metabolic syndrome is doubled in HIV-positive patients compared to healthy controls, and this increased incidence is observed in both antiretroviralexperienced and antiretroviral-na€ive patients. In addition, HIV infection is associated with a higher risk of insulin resistance. As a consequence, and given the ageing HIV population, NAFLD has been reported in up to 15–60% of HIV-infected individuals. 5, 6 Vodkin et al. report that patients with HIV-associated NAFLD had significantly elevated aminotransferases and serum triglycerides, higher scores for non-invasive markers of fibrosis, increased rates of non-alcoholic steatohepatitis (NASH) and more features of liver injury on biopsy when compared to age–sex-matched controls with similar metabolic characteristics. Longer duration of HIV infection was the only variable significantly associated with the presence of NASH. It would be interesting to see data on the duration of ART, which the authors speculate may explain this observation. The authors did not find an association between antiretroviral regimen and incidence of NASH although numbers in each group were small and few patients were on antiretrovirals classically linked with NAFLD. Despite its limitations, this study provides important information on the severity of HIV-associated NAFLD. Non-invasive assessment of liver steatosis using transient elastography is now available. Diagnosing and assessing severity of NAFLD/NASH should form part of the monitoring of HIV-positive individuals particularly for those with metabolic syndrome, or lipodystrophy and/or abnormal LFTs. Presently, lifestyle modification and dietary advice represent the only interventions for HIV-associated NAFLD outwith the treatment of specific metabolic disorders, and should be implemented aggressively as part of a multi-disciplinary approach to patient care. 10

Background In the general population, raised levels of inflammatory markers are stronger predictors of fatal than nonfatal cardiovascular disease ( CVD ) events. People with HIV have elevated levels of interleukin‐6 ( IL ‐6), high‐sensitivity C‐reactive protein (hs CRP ), and D‐dimer; HIV ‐induced activation of inflammatory and coagulation pathways may be responsible for their greater risk of CVD . Whether the enhanced inflammation and coagulation associated with HIV is associated with more fatal CVD events has not been investigated. Methods and Results Biomarkers were measured at baseline for 9764 patients with HIV and no history of CVD . Of these patients, we focus on the 288 that experienced either a fatal (n=74) or nonfatal (n=214) CVD event over a median of 5 years. Odds ratios ( OR s) (fatal versus nonfatal CVD ) (95% confidence intervals [ CIs ]) associated with a doubling of IL ‐6, D‐dimer, hs CRP , and a 1‐unit increase in an IL ‐6 and D‐dimer score, measured a median of 2.6 years before the event, were 1.39 (1.07 to 1.79), 1.40 (1.10 to 1.78), 1.09 (0.93 to 1.28), and 1.51 (1.15 to 1.97), respectively. Of the 214 patients with nonfatal CVD , 23 died during follow‐up. Hazard ratios (95% CI ) for all‐cause mortality were 1.72 (1.28 to 2.31), 1.73 (1.27 to 2.36), 1.44 (1.15 to 1.80), and 1.88 (1.39 to 2.55), respectively, for IL ‐6, D‐dimer, hs CRP , and the IL ‐6 and D‐dimer score. Conclusions Higher IL ‐6 and D‐dimer levels reflecting enhanced inflammation and coagulation associated with HIV are associated with a greater risk of fatal CVD and a greater risk of death after a nonfatal CVD event. Clinical Trial Registration URL: http://www.clinicaltrial.gov Unique identifier: SMART: NCT00027352, ESPRIT: NCT00004978, SILCAAT: NCT00013611.

Objectives: The aim of the study was to statistically model the relative increased risk of cardiovascular disease (CVD) per year older in Data collection on Adverse events of anti-HIV Drugs (D:A:D) and to compare this with the relative increased risk of CVD per year older in general population risk equations. Methods: We analysed three endpoints: myocardial infarction (MI), coronary heart disease (CHD: MI or invasive coronary procedure) and CVD (CHD or stroke). We fitted a number of parametric age effects, adjusting for known risk factors and antiretroviral therapy (ART) use. The best-fitting age effect was determined using the Akaike information criterion. We compared the ageing effect from D:A:D with that from the general population risk equations: the Framingham Heart Study, CUORE and ASSIGN risk scores. Results: A total of 24323 men were included in analyses. Crude MI, CHD and CVD event rates per 1000 person-years increased from 2.29, 3.11 and 3.65 in those aged 40-45 years to 6.53, 11.91 and 15.89 in those aged 60-65 years, respectively. The best-fitting models included inverse age for MI and age + age(2) for CHD and CVD. In D:A:D there was a slowly accelerating increased risk of CHD and CVD per year older, which appeared to be only modest yet was consistently raised compared with the risk in the general population. The relative risk of MI with age was not different between D:A:D and the general population. Conclusions: We found only limited evidence of accelerating increased risk of CVD with age in D:A:D compared with the general population. The absolute risk of CVD associated with HIV infection remains uncertain.

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

Bacterial meningitis in adults (those aged over 15 years) is an uncommon but serious condition. The principles of prevention and treatment are easy to state but, unlike recommendations in guidelines for other conditions, the evidence base for many of our recommendations is lacking or a subject of controversy. The British Infection Society therefore convened a working party comprising clinicians, microbiologists, epidemiologists, general practitioner (GP) and Public Health representatives to assess current evidence and issue a clinically based consensus paper on the management of adult patients with suspected bacterial meningitis which would be useful for non-specialist physicians. The Working Party was aware that they had to make several recommendations using incomplete evidence. evidence from childhood meningitis, or from animal models. The grading of levels of evidence, adapted from AHCPR 1992 ’ . is given in Table I and the grading for our recommendations in Table II. We have included management of septicaemic presentations of meningococcal infection although such patients may not have meningitis. Adults with a meningitic presentation of meningococcal sepsis may have had a relatively mild bacteraemic phase and have a mortality rate of 5% or less whereas those who present with meningococcal septicaemia or sepsis unaccompanied by meningitis may have a mortality rate of 15-40% We have not included advice on management of meningitis following trauma or neurosurgery (except for recommendations for antibiotic treatment of pneumococcal meningitis).

A novel form of therapy, the intravitreal ganciclovir implant (Vitrasert), was used to treat cytomegalovirus (CMV) retinitis in AIDS, when it was not possible to continue systemic therapy or disease progression was evident despite conventional intravenous treatment. A review of the ophthalmic and general health data, operative records and fundus photographs of 9 individuals who had Vitrasert implantation surgery in Edinburgh. Two patients received bilateral replacement implant procedures. Visual acuity, concomitant anti-CMV therapy, complications of implantation and control of retinitis were documented until final follow-up. Control of CMV retinitis was achieved in all individuals at one month postoperatively and remained controlled for a mean period of 5.8 months. Postoperative complications were mild and transient in all but 2 eyes of 2 patients who developed non-progressive macula oedema. Blinding complications as a result of surgery were not encountered and retinal detachment was not observed in this series. Vitrasert implantation is an acceptable and well tolerated treatment for CMV retinitis when systemic therapy fails to control disease progression.

Summary: A retrospective review of AIDS-related oesophageal candidiasis was undertaken to identify clinical features helpful in predicting response to azole therapy and patient survival. Patients who had received daily azole prophylaxis against candidiasis were significantly less likely to respond to azole therapy than < those who had not ( P 0.001). Patients who had lost the 2 months before oesophageal candidiasis were less likely to respond to azoles < than the others ( P 0.001). Amongst those who had not received daily azoles, < + patients with a CD4 cell count 25/mm were less likely to respond to azole treatment ( P = 0.05). The median survival beyond oesophageal candidiasis was 18 months. Survival from oesophageal candidiasis was significantly poorer for patients who did not respond to azole therapy but AIDS survival did not differ between azole responders and non-responders. Non-responders who had been taking daily azole prophylaxis had the poorest survival (median = 4 months). > 5% of their body weight in 3

Chickenpox is a highly transmissible, unpleasant illness in adults, with occasional mortality. Some 5-10% are susceptible, and the incidence, hospital admission numbers and death rates are all increasing in the U.K. Certain risk factors for severe varicella pneumonitis, such as smoking and pregnancy, occur mainly in adult life. In England and Wales during the last two decades, the incidence of chickenpox in those aged >14 years has more than doubled to 183.7 per 100 000 with parallel increases in hospital admissions and death rates, I-3 This upward shift has also been observed in other industrialized nations2 Currently, an average of nearly 17 deaths a year from chickenpox occur in adults; immunosuppression is a contributory factor in one quarter, s The proportion of susceptible adults in Western nations is approximately 7%, as judged by negative varicellazoster antibodies. 6-9 In tropical countries these figures are significantly higher (18-42%), 1° ~2 and consequently chickenpox is more frequently seen in adults. This is also true for those adults born abroad who adopt residency in the West.13 Susceptible adults are highly likely to develop infection after exposure to a case; over 70% of susceptible adults involved in outbreaks in military barracks have been affected.9, ~4 Adults 'at risk' of complications of chickenpox include pregnant women, heavy smokers and those with severe chronic lung disease. These patients are more likely to develop severe or fatal varicella pnemnonitis. ~ s 2o

Contains fulltext : 135923.pdf (Publisher’s version ) (Open Access) BACKGROUND: The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated. METHODS: Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models. RESULTS: 2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37-2.81, p

Contains fulltext : 137128.pdf (Publisher’s version ) (Closed access) BACKGROUND: With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. METHODS: Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. FINDINGS: 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). INTERPRETATION: Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. FUNDING: Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals.

Objectives: To determine the relationship between measures of renal function [current estimated glomerular filtration rate (eGFR) and proportion of follow-up with a low eGFR (%FU ≤60 ml/min)] and fatal/nonfatal AIDS, non-AIDS events and all-cause mortality. Design: An observational, longitudinal cohort study of 12 155 persons from EuroSIDA. Methods: Persons with at least one eGFR measurement after 1 January 2004, using the CKD-EPI formula, were included. Poisson regression analyses were used to determine whether current eGFR or %FU of 60 ml/min or less were independent prognostic markers for clinical events. Results: During 61 425 person-years of follow-up (PYFU), the crude incidence of deaths was 11.1/1000 PYFU [95% confidence interval (CI) 10.0-12.1] at current eGFR more than 90 ml/min and 199.6 (95% CI 1144.3-254.3/1000 PYFU) when current eGFR was 30 ml/min or less. Corresponding figures for AIDS were 12.2 (11.1-13.3) and 63.9 (36.5-103.7) and for non-AIDS were 16.0 (14.8-17.3) and 203.6 (147.7-259.5). After adjustment, current eGFR of 30 ml/min or less was a strong predictor of death [adjusted incidence rate ratios (aIRR) 4.35; 95% CI 3.20-5.91] and non-AIDS events (3.63; 95% CI 2.57-5.13), although the relationship with AIDS was less strong (1.45; 95% CI 1.01-2.08). After adjustment, %FU of 60 ml/min or less was associated with a 22% increased incidence of death (aIRR 1.22 per 10% longer; 95% CI 1.18-1.27), a 13% increased incidence of non-AIDS events (95% CI 1.08-1.18) and a 15% increased incidence of AIDS events (95% CI 1.06-1.24). Conclusion: Both current eGFR and %FU of 60 ml/min or less were associated with death and non-AIDS events in HIV-positive persons. Our findings highlight the association between underlying renal dysfunction and morbidity and mortality in HIV infection, although reverse causality cannot be excluded. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

We prospectively collected data on deaths in the Edinburgh City Hospital HIV cohort of patients (60-70% acquired via injection drug use) from October 1986 to September 1994. Sixty-four patients (25% of all HIV deaths or 2.5/100 person-years) had died without an AIDS diagnosis, and 42 (66%) of these had autopsy data available. Some pre-AIDS deaths (20% or 0.5/100 person-years) were the expected consequence of underlying medical conditions diagnosed during life: the remainder (80% or 1.98/100 person-years) were sudden or unexpected. Examining the underlying conditions, drug overdoses accounted for 45% or 1.1/100 person-years; bacterial sepsis, 25% or 0.6/100 person-years; liver disease, 26% or 0.6/100 person-years; and an undiagnosed AIDS condition, 9% or 0.2/100 person-years. Drug overdoses were the commonest cause of pre-AIDS death in this cohort of patients predominantly infected via IDU, but many of the sudden deaths had significant underlying pathology, which may have increased their susceptibility to an overdose of drugs. In future, death before an AIDS diagnosis should be classified into Medical or Expected Non-AIDS (MNA or ENA) and Sudden Non-AIDS (SNA).

Central venous catheters (CVCs) for patients with AIDS are at risk of a number of complications including bacterial infections. A 6-year retrospective review was undertaken of the records of the 33 patients (42% infected by injection drug use (IDU)) who received intravenous therapy both in hospital and at home via CVCs. Twenty-eight per cent of 53 insertions suffered a complication, the commonest of which was a pneumothorax (8%). The post insertion complication rate was 0.98/100 catheter days (cd). Thrombotic occlusion (0.15/100 cd) was the commonest non septic event while sepsis was overall the commonest event (0.69/ 100 cd) of which half were considered serious (0.33/100 cd). The most frequently isolated organisms were Staphylococci spp. (71%). The median time to an exit site infection was 59 days and to serious catheter sepsis 86 days. Infection did not differ significantly with age, gender, transmission risk activity or catheter type although Portacaths had the lowest rate of infection (0.33/100 cd). The median survival of the 53 CVCs was 88 days although if the temporary catheters were excluded it was 118 days. Kaplan-Meier estimates of survival analysis revealed 55%, 32% and 19% of all the CVCs surviving 3, 6 and 12 months respectively. Our experience suggests that home intravenous therapy and previous IDU does not preclude the use of CVCs although further research is needed on reducing the infection-related complications of such therapy.

Objective: To assess CD4+ cell count recovery in people severely immunosuppressed at start of antiretroviral therapy (ART) who achieve and maintain viral load suppression. Methods: Eligible participants from the UK Collaborative HIV Cohort Study started ART with at least three drugs after 1 January 2000. Participants were required to have pre-ART CD4+ cell count below 100 cells/μl, at least 2 years of follow-up on ART, have achieved viral load suppression (≤50 copies/ml) by 9 months after starting ART and to have maintained this throughout follow-up. Participants were further required to be regularly engaged with care. We calculated the proportion of people who failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500 cells/μl by the time of the last follow-up, or 5 years from start of ART, whichever occurred first (censoring date). Results: Of the 400 participants [median (interquartile range) pre-ART CD4+ cell count of 38 (14–65) cells/μl], 2 (0.5%), 8 (2%), 28 (7%), 131 (33%) and 259 (65%) failed to achieve a CD4+ cell count of more than 100, 150, 200, 350 and 500 cells/μl, by the censoring date, respectively. Kaplan–Meier estimates of the proportion of people reaching each CD4+ cell count threshold after 1 year on ART were 88, 70, 50, 14 and 3%, respectively, and after 3 years on ART, 98, 95, 90, 59 and 25%, respectively. Median (interquartile range) follow-up on ART was 3.9 (2.7–4.8) years. Conclusion: Given a person with pre-ART CD4+ cell count below 100 cells/μl survives and maintains consistent viral load suppression on ART, there is over a 90% chance of reaching a CD4+ cell count above 200 cells/μl by 3 years.

Objective: In addition to hypersensitivity reactions to abacavir, HLA B∗5701 has been associated with slow or nonprogression of HIV infection. We explored the effect of HLA B∗5701 on CD4+ cell count and viral load in untreated patients and on responses to nonabacavir-containing combination antiretroviral therapy (cART) in a large UK-based cohort. Design: Analysis of a cohort of HIV-infected adults. Methods: In untreated patients, CD4+ cell count and viral load at study entry were compared in HLAB∗5701-positive and HLAB∗5701-negative individuals and linear regression tested for an interaction effect of viral load and HLA B∗5701 on CD4+ cell count. In patients starting a nonabacavir cART regimen, Cox proportional hazards models compared virological responses to cART among HLA B∗5701-negative, HLA B∗5701-positive, and those not tested. Six-month and 12-month changes in CD4+ cell count were used as outcomes in linear regression to compare immunological response to cART in these groups. Results: ART-naive HLA B∗5701-positive individuals had higher CD4+ cell count (P

OBJECTIVES The pharmacokinetic and pharmacodynamic effects of antiretroviral therapy may differ in older compared with younger subjects with HIV infection. We aimed to assess factors associated with plasma antiretroviral drug exposure, including age, within a large HIV-infected cohort undergoing therapeutic drug monitoring (TDM). METHODS Data from the Liverpool TDM Registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. All TDM of protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) was included and in order to account for different antiretroviral drugs the plasma concentrations were standardized by group measurements according to drug, dosing and timing of TDM. Regression modelling was used to evaluate associations of drug exposure with age and clinical parameters, including hepatic transaminase results and time to antiretroviral treatment modification. RESULTS Data from 3589 TDM samples were available from 2447 subjects. The greatest numbers of plasma concentrations were assessed for lopinavir (22.4%), efavirenz (18.5%), atazanavir (17.0%) and saquinavir (11.6%). As age increased, median standardized NNRTI concentrations remained constant, whereas PI concentrations increased (correlation coefficient 0.04, P = 0.033). In a regression analysis stratified by antiretroviral drug class, standardized plasma concentrations were significantly associated with age for PIs (0.05 increase in standard deviation of drug concentration with each 10 year increase in age, P = 0.044), but not for NNRTIs or other clinical parameters, including hepatic transaminase results or time to antiretroviral treatment modification. CONCLUSIONS With increasing age, statistically significant rises in plasma PI exposure, but not NNRTI exposure, were observed. The clinical relevance of this observation merits further investigation.

Previous reports indicate that venous thrombosis is an infrequent problem in patients with HIV infection. Despite this, various HIV-related factors have been proposed as potentially thrombogenic and an HIV-related hypercoagulability has been suggested. At the present time, there exists no consensus of opinion regarding prophylaxis against venous thrombosis for hospitalized patients with HIV. This article aims to provide an overview of venous thrombosis in HIV infection with particular reference to published and personal evidence for possible risk factors and their implications for prophylaxis.

Objective: To consider associations between the latest/nadir CD4 + cell count, and time spent with CD4+ cell count less than 200 cells/ml (duration of immune depression), and myocardial infarction (MI), coronary heart disease (CHD), stroke, or cardiovascular disease (CVD) (CHD or stroke) in 33 301 HIV-positive individuals. Design: Longitudinal cohort study. Methods: Analyses were undertaken using Poisson regression. To investigate whether analyses of stroke were robust to the type of endpoint, we additionally included strokelike events and rejected strokes into the stroke endpoint. Results: Participants experienced 716 MI, 1056 CHD, 303 stroke, and 1284 CVD events. Whereas there was no evidence of a higher MI/CHD risk in those with lower latest/nadir CD4+ cell counts after adjustment [current CD4+

Background: Despite advances in HIV treatment, bacterial pneumonia continues to cause considerable morbidity and mortality in patients with HIV infection. Studies of biomarker associations with bacterial pneumonia risk in treated HIV-infected patients do not currently exist. Methods: We performed a nested, matched, case-control study among participants randomized to continuous combination antiretroviral therapy (cART) in the Strategies for Management of Antiretroviral Therapy trial. Patients who developed bacterial pneumonia (cases) and patients without bacterial pneumonia (controls) were matched 1:1 on clinical center, smoking status, age, and baseline cART use. Baseline levels of Club Cell Secretory Protein 16 (CC16), Surfactant Protein D (SP-D), C-reactive protein (hsCRP), interleukin-6 (IL-6), and d-dimer were compared between cases and controls. Results: Cases (n = 72) and controls (n = 72) were 25.7% female, 51.4% black, 65.3% current smokers, 9.7% diabetic, 36.1% co-infected with Hepatitis B/C, and 75.0% were on cART at baseline. Median (IQR) age was 45 (41, 51) years with CD4+ count of 553 (436, 690) cells/mm3. Baseline CC16 and SP-D were similar between cases and controls, but hsCRP was significantly higher in cases than controls (2.94 µg/mL in cases vs. 1.93 µg/mL in controls; p = 0.02). IL-6 and d-dimer levels were also higher in cases compared to controls, though differences were not statistically significant (p-value 0.06 and 0.10, respectively). Conclusions: In patients with cART-treated HIV infection, higher levels of systemic inflammatory markers were associated with increased bacterial pneumonia risk, while two pulmonary-specific inflammatory biomarkers, CC16 and SP-D, were not associated with bacterial pneumonia risk.

Background: Several studies have reported on an association between hepatitis C virus (HCV) antibody status and the development of chronic kidney disease (CKD), but the role of HCV viremia and genotype are not well defined. Methods: Patients with at least three serum creatinine measurements after 1 January 2004 and known HCV antibody status were included. Baseline was defined as the first eligible estimated glomerular filtration rate (eGFR) (Cockcroft‐Gault equation), and CKD was either a confirmed (>3 months apart) eGFR of 60ml/min per 1.73m 2 or less for patients with a baseline eGFR more than 60ml/min per 1.73m 2 or a confirmed 25% decline in eGFR for patients with a baseline eGFR of 60ml/min per 1.73m 2 or less. Incidence rates of CKD were compared between HCV groups (anti-HCV-negative, antiHCV-positive with or without viremia) using Poisson regression. Results: Of 8235 patients with known anti-HCV status, 2052 (24.9%) were anti-HCVpositive of whom 983 (47.9%) were HCV-RNA-positive, 193 (9.4%) HCV-RNAnegative and 876 (42.7%) had unknown HCV-RNA. At baseline, the median eGFR was 97.6 (interquartile range 83.8‐113.0) ml/min per 1.73m 2 . During 36123 personyears of follow-up (PYFU), 495 patients progressed to CKD (6.0%) with an incidence rate of 14.5 per 1000 PYFU (95% confidence interval 12.5‐14.9). In a multivariate Poisson model, patients who were anti-HCV-positive with HCV viremia had a higher incidence rate of CKD, whereas patients with cleared HCV infection had a similar incidence rate of CKD compared with anti-HCV-negative patients. There was no association between CKD and HCV genotype. Conclusion: Compared with HIV-monoinfected patients, HIV-positive patients with chronic rather than cleared HCV infection were at increased risk of developing CKD, suggesting a contribution from active HCV infection toward the pathogenesis of CKD. 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2012, 26:1917‐1926

The overall purpose of these guidelines is to provide guidance on best clinical practice in the treatment and management of adults with HIV infection with antiretroviral therapy (ART). The scope includes: (i) guidance on the initiation of ART in those previously naïve to therapy; (ii)support of patients on treatment; (iii) management of patients experiencing virological failure; and (iv) recommendations in specific patient populations where other factors need to be taken into consideration. The guidelines are aimed at clinical professionals directly involved with and responsible for the care of adults with HIV infection and at community advocates responsible for promoting the best interests and care of HIV-positive adults. They should be read in conjunction with other published BHIVA guidelines.

Background Dynamic changes in Human Immunodeficiency Virus 1 (HIV-1) sequence diversity and divergence are associated with immune control during primary infection and progression to AIDS. Consensus sequencing or single genome amplification sequencing of the HIV-1 envelope (env) gene, in particular the variable (V) regions, is used as a marker for HIV-1 genome diversity, but population diversity is only minimally, or semi-quantitatively sampled using these methods. Results Here we use second generation deep sequencing to determine inter-and intra-patient sequence heterogeneity and to quantify minor variants in a cohort of individuals either receiving or not receiving antiretroviral treatment following seroconversion; the SPARTAC trial. We show, through a cross-sectional study of sequence diversity of the env V3 in 30 antiretroviral-naive patients during primary infection that considerable population structure diversity exists, with some individuals exhibiting highly constrained plasma virus diversity. Diversity was independent of clinical markers (viral load, time from seroconversion, CD4 cell count) of infection. Serial sampling over 60 weeks of non-treated individuals that define three initially different diversity profiles showed that complex patterns of continuing HIV-1 sequence diversification and divergence could be readily detected. Evidence for minor sequence turnover, emergence of new variants and re-emergence of archived variants could be inferred from this analysis. Analysis of viral divergence over the same time period in patients who received short (12 weeks, ART12) or long course antiretroviral therapy (48 weeks, ART48) and a non-treated control group revealed that ART48 successfully suppressed viral divergence while ART12 did not have a significant effect. Conclusions Deep sequencing is a sensitive and reliable method for investigating the diversity of the env V3 as an important component of HIV-1 genome diversity. Detailed insights into the complex early intra-patient dynamics of env V3 diversity and divergence were explored in antiretroviral-naïve recent seroconverters. Long course antiretroviral therapy, initiated soon after seroconversion and administered for 48 weeks, restricts HIV-1 divergence significantly. The effect of ART12 and ART48 on clinical markers of HIV infection and progression is currently investigated in the SPARTAC trial.